Bioidentical Hormones

Iodine-deficiency disorders.

2 billion individuals worldwide have insufficient iodine intake, with those in south Asia and sub-Saharan Africa particularly affected. Iodine deficiency has many adverse effects on growth and development. These effects are due to inadequate production of thyroid hormone and are termed iodine-deficiency disorders. Iodine deficiency is the most common cause of preventable mental impairment worldwide. Assessment methods include urinary iodine concentration, goitre, newborn thyroid-stimulating hormone, and blood thyroglobulin. In nearly all countries, the best strategy to control iodine deficiency is iodisation of salt, which is one of the most cost-effective ways to contribute to economic and social development. When iodisation of salt is not possible, iodine supplements can be given to susceptible groups. Introduction of iodised salt to regions of chronic iodine-deficiency disorders might transiently increase the proportion of thyroid disorders, but overall the small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency. International efforts to control iodine-deficiency disorders are slowing, and reaching the third of the worldwide population that remains deficient poses major challenges.

Lancet. 2008 Oct 4;372(9645):1251-62

Urinary iodine concentration: United States National Health And Nutrition Examination Survey 2001-2002.

Urine iodine has been measured in the US population by the National Health and Nutrition Examination Survey (NHANES) since 1971. A downward trend was noted between NHANES I (320 +/- 6 microg/L in 1971-1974) and NHANES III (145 +/- 3 microg/L in 1988-1994). This report presents data from NHANES 2001-2002 that indicates that the US median urine iodine (UI) level has stabilized since the initial drop between NHANES I and NHANES III. The median UI concentration in the US population in NHANES 2001-2002 was found to be 167.8 microg/L (95% confidence interval [CI] 159.3-177.6). The NHANES 2001-2002 data confirm the current stability of the U.S. iodine intake and continued adequate iodine nutrition for the country.

Thyroid. 2005 Jul;15(7):692-9

Iodine nutrition: iodine content of iodized salt in the United States.

Adequacy of iodine nutrition in the United States has lately been of concern. A major source of dietary iodine for the US population is iodized salt. The US Food and Drug Administration (USFDA) recommends 60-100 mg Kl/kg salt, equivalent to 46-76 mg l/kg salt. All U.S. iodized salt contains 45 mg l/kg according to labels. We collected samples of table salt from freshly opened containers from US volunteers. A sample was sent to us when the can was first purchased. Subsets of volunteers sent further samples when the salt container became half-empty through normal use and a further final sample when the container was nearly finished. We also looked at iodine distribution homogeneity within individual containers, loss of iodine from salt upon exposure to humidity and sunlight, and upon short-term heating (dry and in solution) as may be encountered in cooking. Measurements were made in 0.01% w/v salt solutions by induction coupled plasma-mass spectrometry with 72Ge as an internal standard. The median and mean (+/-sd) I content in freshly opened top-of-the-can salt samples was 44.1 and 47.5 +/- 18.5 mg/kg (n=88, range 12.7-129 mg l/kg) and geometric mean and standard deviation of 44.70 and 1.41. Forty-seven of 88 samples fell below the USFDA recommended I content while 6 exceeded it. The homogeneity in a single can of salt varied greatly: in 5 samples taken from the same container from different depths, the iodine content varied by as little as 1.2x (8.3% coefficient of variance (CV)) to as much as 3.3x (49.3% CV) from one container/brand to another. Iodine is significantly lost upon high humidity storage but light or dry heat has little effect. There is much recent literature on iodine sufficiency and uptake inhibitors; there is also much misinformation and disinformation. We review the relevant literature and discuss our results with reference to the United States.

Environ Sci Technol. 2008 Feb 15;42(4):1315-23

Iodine: deficiency and therapeutic considerations.

Iodine deficiency is generally recognized as the most commonly preventable cause of mental retardation and the most common cause of endocrinopathy (goiter and primary hypothyroidism). Iodine deficiency becomes particularly critical in pregnancy due to the consequences for neurological damage during fetal development as well as during lactation. The safety of therapeutic doses of iodine above the established safe upper limit of 1 mg is evident in the lack of toxicity in the Japanese population that consumes 25 times the median intake of iodine consumption in the United States. Japan’s population suffers no demonstrable increased incidence of autoimmune thyroiditis or hypothyroidism. Studies using 3.0- to 6.0-mg doses to effectively treat fibrocystic breast disease may reveal an important role for iodine in maintaining normal breast tissue architecture and function. Iodine may also have important antioxidant functions in breast tissue and other tissues that concentrate iodine via the sodium iodide symporter.

Altern Med Rev. 2008 Jun;13(2):116-27

Iodine content of various meals currently consumed by urban Japanese.

Various meals being currently consumed by urban Japanese were determined for iodine. The meal samples were collected in 1982 and 1984. The habitual daily home meals of 4 middle-aged Japanese living in urban areas contained 45-1,921 micrograms (mean; 362, 361, 429, and 1,023 micrograms, respectively) of iodine per day. The regular meals served in two university hospitals contained 95-287 micrograms (mean; 195 micrograms) and 89-4,746 micrograms (mean; 1,290 micrograms) of iodine per day, respectively, and the diets for diabetes mellitus contained 59-144 micrograms (mean; 96 micrograms) of iodine per day. In the daily meals containing iodine exceeding ca. 300 micrograms, some kinds of seaweeds and, in some cases, several foods containing a red food color with low iodine bioavailability, erythrosine, provided a large portion of iodine. The iodine contents of refectory meals in a university were 47-203 micrograms (mean; 113 micrograms) per meal and those of lunches in two elementary schools were 25-31 micrograms (mean; 27 micrograms) and 18-43 micrograms (mean; 36 micrograms) per lunch, respectively. These results suggest that the current daily iodine intake of urban Japanese is not great and that erythrosine elevates the iodine content of meals.

J Nutr Sci Vitaminol (Tokyo). 1986 Oct;32(5):487-95

Iodine replacement in fibrocystic disease of the breast.

OBJECTIVE: To determine the response of patients with fibrocystic breast disease to iodine replacement therapy. DESIGN: Review of three clinical studies beginning in 1975: an uncontrolled study with sodium iodide and protein-bound iodide; a prospective, control, crossover study from iodide to molecular iodine; and a prospective, control, double-blind study with molecular iodine. SETTING: University affiliated breast-treatment clinics. PATIENTS: Study 1: 233 volunteers received sodium iodide for 2 years and 588 received protein-bound iodide for 5 years. Study 2: the treatment of 145 patients from study 1 treated with protein-bound iodide for several months who still had symptoms was switched to molecular iodine 0.08 mg/kg; 108 volunteers were treated initially with molecular iodine. Study 3: 23 patients received molecular iodine, 0.07 to 0.09 mg/kg body weight; 33 received an aqueous mixture of brown vegetable dye and quinine. The numbers in study 2 increased over the review period so that 1,365 volunteers were being treated with molecular iodine by 1989. INTERVENTIONS: All patients in study 3 had pre- and post-treatment mammography and measurement of serum triiodothyronine, thyroxine and thyroid-stimulating hormone levels. MAIN OUTCOME MEASURES: Subjective evaluation—freedom from pain—and objective evaluation—resolution of fibrosis. RESULTS: Study 1: 70% of subjects treated with sodium iodide had clinical improvement in their breast disease, but the rate of side effects was high; 40% of patients treated with protein-bound iodide had clinical improvement. Study 2: 74% of patients in the crossover series had clinical improvement, and objective improvement was noted in 72% of those who received molecular iodine initially. Study 3: in the treatment group 65% had subjective and objective improvement; in the control group there was a subjective placebo effect in 33% and an objective deterioration of 3%. CONCLUSIONS: The fibrocystic breast reacts differently to sodium iodide, protein-bound iodide and molecular iodine. Molecular iodine is nonthyrotropic and was the most beneficial.

Can J Surg. 1993 Oct;36(5):453-60

Effects of kelp supplementation on thyroid function in euthyroid subjects.

OBJECTIVE: To study the effects of ingestion of two different doses of supplemental kelp on the thyroid function of healthy euthyroid subjects. METHODS: We conducted a double-blind prospective clinical trial involving 36 healthy euthyroid subjects, who were randomly assigned to receive placebo (4 alfalfa capsules per day), low-dose kelp (2 kelp capsules and 2 alfalfa capsules per day), or high-dose kelp (4 kelp capsules per day) for 4 weeks. Thyrotropin (thyroid-stimulating hormone or TSH), free thyroxine, and total triiodothyronine were assessed at weeks 0, 4, and 6. Response to thyrotropin-releasing hormone stimulation, urinary iodine excretion, and basal metabolic rate were determined at weeks 0 and 4. RESULTS: TSH concentrations did not differ significantly between week 0 and week 4 in the placebo group (P = 0.16) but increased significantly in both the low-dose kelp (P = 0.04) and high-dose kelp (P = 0.002) groups. Free thyroxine concentrations decreased slightly but significantly after 4 weeks of placebo but were unchanged in the low-dose and the high-dose kelp groups. In contrast, total triiodothyronine levels did not differ significantly after 4 weeks of placebo or low-dose kelp therapy but were significantly decreased after high-dose kelp therapy (P = 0.04). Similarly, the thyrotropin-releasing hormone stimulation test showed no significant change in poststimulation TSH after 4 weeks in the placebo or low-dose kelp groups but revealed a significantly increased response after high-dose kelp therapy (P = 0.0002). The 24-hour urinary iodine excretion showed dose-dependent increases in the two kelp study groups. Basal metabolic rate did not change significantly in any study group during the 4-week study period. All thyroid laboratory values returned to baseline 2 weeks after cessation of kelp supplementation, except for TSH in the high-dose kelp group, which was significantly decreased. CONCLUSION: Short-term dietary supplementation with kelp significantly increases both basal and poststimulation TSH. These findings corroborate previous studies on the effects of supplemental iodide given to euthyroid subjects for a similar period. Further studies are needed to determine whether long-term kelp supplementation would cause clinically significant thyroid disease.

Endocr Pract. 2003 Sep-Oct;9(5):363-9

Electrolyte loss in sweat and iodine deficiency in a hot environment.

The authors studied electrolyte loss from profuse sweating in soccer-team players and evaluated the relationship between this source of iodine loss and iodine deficiency. Thirteen male soccer-team players and 100 sedentary students from the same high school were evaluated for 8 d, during which the players were training. The authors analyzed 208 sweat samples to determine losses of iodine, sodium, potassium, and calcium in sweat. Excretion of urinary electrolytes by the subjects was also measured. The mean losses of iodine, sodium, potassium, and calcium in sweat following a 1-hr game were 52 microg, 1,896 mg, 248 mg, and 20 mg, respectively; the ratios of sweat loss to urinary daily loss of the four electrolytes were 0.75, 0.2, 1.88, and 0.92, respectively. Urinary iodine was significantly (p < .02) lower than the normal level of 50 microg/gm creatinine in 38.5% of the soccer players, compared with 2% of the sedentary students. Forty-six percent of the players had Grade I goiter, compared with a mere 1% of the sedentary students (p < .01). The results of the study suggest that loss of iodine through profuse sweating may lead to iodine deficiency, and loss of electrolytes through sweating may have a dietary significance for heat-stressed individuals or for individuals who perform heavy workloads.

Arch Environ Health. 2001 May-Jun;56(3):271-7

A review of iodine toxicity reports.

This article summarizes case reports, population studies, and experimental studies from the literature concerning adverse effects of exposure to iodine from the mid-1880s to 1988. Exposure to excessive iodine through foods, dietary supplements, topical medications, and/or iodinated contrast media has resulted in thyroiditis, goiter, hypothyroidism, hyperthyroidism, sensitivity reactions, or acute responses for some individuals. Reports of maternal iodine exposure during pregnancy or lactation affecting newborn or nursing infants are cited. Susceptibility to excess iodine is discussed as well as the relationship between dose and response. It is concluded that some individuals can tolerate very high levels of iodine with no apparent side effects and that iodine intakes less than or equal to 1,000 mg/day are probably safe for the majority of the population, but may cause adverse effects in some individuals. Determination of maximum tolerable levels of iodine intake will require human experimental studies at levels between 0.150 and 1,000 mg/day for normal subjects, subjects with autonomous thyroid tissue, and iodine-sensitive subjects.

J Am Diet Assoc. 1990 Nov;90(11):1571-81

Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study.

BACKGROUND: Recent studies suggest that relatively low thyroid function within the clinical reference range is positively associated with risk factors for coronary heart disease (CHD), but the association with CHD mortality is not resolved. METHODS: In a Norwegian population-based cohort study, we prospectively studied the association between thyrotropin levels and fatal CHD in 17,311 women and 8,002 men without known thyroid or cardiovascular disease or diabetes mellitus at baseline. RESULTS: During median follow-up of 8.3 years, 228 women and 182 men died of CHD. Of these, 192 women and 164 men had thyrotropin levels within the clinical reference range of 0.50 to 3.5 mIU/L. Overall, thyrotropin levels within the reference range were positively associated with CHD mortality (P for trend = .01); the trend was statistically significant in women (P for trend = .005) but not in men. Compared with women in the lower part of the reference range (thyrotropin level, 0.50-1.4 mIU/L), the hazard ratios for coronary death were 1.41 (95% confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories, respectively. CONCLUSIONS: Thyrotropin levels within the reference range were positively and linearly associated with CHD mortality in women. The results indicate that relatively low but clinically normal thyroid function may increase the risk of fatal CHD.

Arch Intern Med. 2008 Apr 28;168(8):855-60

Cognitive improvement in mild to moderate Alzheimer’s dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Parallel with the development of hypotheses regarding cholinergic involvement in geriatric memory dysfunction, the first attempts to treat patients with Alzheimer’s disease (AD) involved the cholinergic-precursor loading approach. Despite encouraging early results, well-controlled clinical trials did not confirm a clinical utility of cholinergic precursors such as choline and lecithin (phosphatidylcholine) in AD. OBJECTIVE: This study assessed the efficacy and tolerability of the cholinergic precursor choline alfoscerate (CA) in the treatment of cognitive impairment due to mild to moderate AD. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, patients affected by mild to moderate dementia of the Alzheimer type were treated with CA (400-mg capsules) or placebo capsules, 3 times daily, for 180 days. Efficacy outcome measures that were assessed at the beginning of the investigation and after 90 and 180 days of treatment included scores of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Mini-Mental State Examination (MMSE), the Global Deterioration Scale (GDS), the Alzheimer’s Disease Assessment Scale-Behavioral Subscale (ADAS-Behav), all items of the Alzheimer’s Disease Assessment Scale (ADAS-Total), and the Clinical Global Impression (CGI) scale. The Global Improvement Scale (GIS) score was assessed after 90 and 180 days of treatment. RESULTS: A total of 261 patients (132 in the CA group, 129 in the placebo group) were enrolled in the study. The mean (SD) age in the CA group was 72.2(7.5) years (range, 60-80 years), and in the placebo group it was 71.7 (7.4) years(range, 60-80 years). The CA group comprised 105 women and 27 men; the placebo group, 94 women and 35 men. The mean decrease in ADAS-Cog score in patients treated with CA was 2.42 points after 90 days of treatment and 3.20 points at the end of the study (day 180) (P < 0.001 vs baseline for both), whereas in patients receiving placebo the mean increase in ADAS-Cog score was 0.36 point <1 after 90 days of treatment and 2.90 points after 180 days of treatment(P < 0.001 vs baseline). In the CA group, all other assessed parameters (MMSE,GDS, ADAS-Behav, ADAS-Total, and CGI) consistently improved after 90 and 180 days versus baseline, whereas in the placebo group they remained unchanged or worsened. Statistically significant differences were observed between treatments after 90 and 180 days in ADAS-Cog, MMSE, GDS, ADAS-Total, and CGI scores and after 180 days of treatment in ADAS-Behav and GIS scores. CONCLUSION: The results of this study suggest the clinical usefulness and tolerability of CA in the treatment of the cognitive symptoms of dementia disorders of the Alzheimer type.

Clin Ther. 2003 Jan;25(1):178-93

The influence of soy-derived phosphatidylserine on cognition in age-associated memory impairment.

Phosphatidylserine (PS) is a phospholipid widely sold as a nutritional supplement. PS has been claimed to enhance neuronal membrane function and hence cognitive function, especially in the elderly. We report the results of a clinical trial of soybean-derived PS (S-PS) in aging subjects with memory complaints. Subjects were 120 elderly (> 57 years) of both sexes who fulfilled the more stringent criteria for age-associated memory impairment (AAMI); some also fulfilled the criteria for age-associated cognitive decline. Subjects were allocated at random to one of the three treatment groups: placebo, 300 mg S-PS daily, or 600 mg S-PS daily. Assessments were carried out at baseline, after 6 and 12 weeks of treatment, and after a wash-out period of 3 weeks. Tests of learning and memory, choice reaction time, planning and attentional functions were administered at each assessment. Delayed recall and recognition of a previously learned word list comprised the primary outcome measures. No significant differences were found in any of the outcome variables between the treatment groups. There were also no significant interactions between treatment and ‘severity of memory complaints’. In conclusion, a daily supplement of S-PS does not affect memory or other cognitive functions in older individuals with memory complaints.

Nutr Neurosci. 2001;4(2):121-34

Treatment of cognitive dysfunction associated with Alzheimer’s disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?

The observations of the loss of cholinergic function in neocortex and hippocampus in Alzheimer’s disease (AD) developed the hypothesis that replacement of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numerous compounds in development for the treatment of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant benefit of these drugs on all symptom domains of AD. The first attempts in the treatment of AD with cholinergic precursors did not confirm a clinical utility of this class of compounds in well controlled clinical trials. However, cholinergic precursors most largely used such as choline and phosphatidylcholine (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways such as CDP-choline, choline alphoscerate and phosphatidylserine clearly enhanced ACh availability or release and provided a modest improvement of cognitive dysfunction in AD, these effects being more pronounced with choline alphoscerate. Although some positive results cannot be generalized due to the small numbers of patients studied, they probably would justify reconsideration of the most promising molecules in larger carefully controlled trials.

Mech Ageing Dev. 2001 Nov;122(16):2025-40

An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline.

We assessed whether the efficacy of plant-source derived phosphatydilserine (one of the phospholipids which play an important functional role in membrane-related processes in the brain) for treatment of age related cognitive decline is consistent with previous (placebo controlled) positive findings with bovine derivative of PS (BC-PS). Eighteen healthy elderly volunteers meeting Age Associated Memory Impairment inclusion and exclusion criteria were treated for 12 weeks with plant-source derived phosphatydilserine (PS) (100 mg x 3/day p.o.) and evaluated at base line, after 6 weeks of treatment and at the end of the trial. Fifteen concluded the study. All but two outcome measures elicited a significant drug over time effect. Post-hoc paired t-tests showed that the significant effect was attributable to an improvement from base line to week 6 and that effect was maintained at week 12. These results are encouraging. However, they await double-blind controlled verification in a large sample before suggesting that this may be a viable approach to the treatment of age-related cognitive decline, without exposing the patients to possible hazards involved in the treatment with bovine derivative of PS (BC-PS).

Isr J Psychiatry Relat Sci. 2000;37(4):302-7

Cognitive effects of a Ginkgo biloba/vinpocetine compound in normal adults: systematic assessment of perception, attention and memory.

A computerized test battery was used in a double-blind design to assess the cognitive effects of a nutrient compound containing Ginkgo biloba in 24 normal adults. Ten tasks (perceptual, attention and short-term memory) were presented in a standardized manner designed to maximize performance, with substantial pre-test practice employed to minimize response variability. Subjects were given either placebo or Ginkgo biloba extract capsules to consume for 14 days, after which they performed all tasks twice. They then received the other condition, and after 14 days completed the final test session. Response time and error rate stabilized after pre-test practice. A ‘working memory capacity’ paradigm demonstrated a reliable 50 ms response time decrease between the placebo and Ginkgo biloba testing, suggesting that Ginkgo biloba speeds short-term working memory processing in normal adults.

Hum Psychopharmacol. 2001 Jul;16(5):409-416

Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats.

During aging, reductions in hippocampal neurogenesis are associated with memory decline indicating a causal relationship. Indeed, insulin-like growth factor-1 (IGF-1), a major activator of the extracellular receptor kinase pathway that is central in learning and memory processes, is also a key modulator of hippocampal neurogenesis. Previously, we showed that age-related declines in spatial memory tasks can be improved by antioxidant-rich diets containing blueberries. In this study, to begin to understand the mechanisms responsible for the beneficial effects of blueberries, we assessed changes in hippocampal plasticity parameters such as hippocampal neurogenesis, extracellular receptor kinase activation, and IGF-1 and IGF-1R levels in blueberry-supplemented aged animals. Our results show that all these parameters of hippocampal neuronal plasticity are increased in supplemented animals and aspects such as proliferation, extracellular receptor kinase activation and IGF-1 and IGF-1R levels correlate with improvements in spatial memory. Therefore, cognitive improvements afforded by polyphenolic-rich fruits such as blueberries appear, in part, to be mediated by their effects on hippocampal plasticity.

Nutr Neurosci. 2004 Oct-Dec;7(5-6):309-16

Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation.

Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress that may be ameliorated by antioxidants. Our previous study had shown that rats given dietary supplements of fruit and vegetable extracts with high antioxidant activity for 8 months beginning at 6 months of age retarded age-related declines in neuronal and cognitive function. The present study showed that such supplements (strawberry, spinach, or blueberry at 14.8, 9.1, or 18.6 gm of dried aqueous extract per kilogram of diet, respectively) fed for 8 weeks to 19-month-old Fischer 344 rats were also effective in reversing age-related deficits in several neuronal and behavioral parameters including: oxotremorine enhancement of K(+)-evoked release of dopamine from striatal slices, carbachol-stimulated GTPase activity, striatal Ca(45) buffering in striatal synaptosomes, motor behavioral performance on the rod walking and accelerod tasks, and Morris water maze performance. These findings suggest that, in addition to their known beneficial effects on cancer and heart disease, phytochemicals present in antioxidant-rich foods may be beneficial in reversing the course of neuronal and behavioral aging.

J Neurosci. 1999 Sep 15;19(18):8114-21

Effect of a polyphenol-rich wild blueberry extract on cognitive performance of mice, brain antioxidant markers and acetylcholinesterase activity.

The aim of this study was to examine the effect of a polyphenol-rich extract (PrB) of Vaccinium angustifolium (wild blueberries) introduced intraperitoneally (i.p.) at 30 (PrB30) and 60 (PrB60) mg/kg body weight for 7 days, on cognitive performance, brain oxidative status and acetylcholinesterase activity in adult, male, 3-4-month-old Balb-c mice. Evaluation of rodent learning and memory was assessed by a step-through test on day 6 after a double training and an initial acquisition trial on day 5. Antioxidant status was determined by ferric reducing antioxidant power (FRAP), ascorbic acid concentration (FRASC), malondialdehyde and reduced glutathione levels in whole brain homogenates. Acetylcholinesterase (AChE) activity was determined by Ellman’s colorimetric method. Results showed that the PrB60-treated mice exhibited a significant improvement in learning and memory (step-through latency time of 228+/-38 s compared to 101+/-32 s of the control group). PrB extract administration also resulted in reduced lipid peroxidation products (38 and 79%) and higher brain ascorbic acid levels (21 and 64%) in both PrB30 and PrB60-treated groups, respectively, and higher glutathione levels (28%) in the PrB60-treated group. Furthermore, salt- and detergent soluble AChE activity significantly decreased in both PrB-treated groups. Thus, the significant cognitive enhancement observed in adult mice after short-term i.p. supplementation with the blueberry extract concentrated in polyphenols, is closely related to higher brain antioxidant properties and inhibition of AChE activity. These findings stress the critical impact of wild blueberry bioactive components on brain function.

Behav Brain Res. 2009 Mar 17;198(2):352-8.

Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats.

It has been reported that an antioxidant-rich, blueberry-supplemented rat diet may retard brain aging in the rat. The present study determined whether such supplementation could prevent impaired object recognition memory and elevated levels of the oxidative stress-responsive protein, nuclear factor-kappa B (NF-kappaB) in aged Fischer-344 rats. Twelve aged rats had been fed a 2% blueberry supplemented diet for 4 months prior to testing. Eleven aged rats and twelve young rats had been fed a control diet. The rats were tested for object recognition memory on the visual paired comparison task. With a 1-h delay between training and testing, aged control diet rats performed no better than chance. Young rats and aged blueberry diet rats performed similarly and significantly better than the aged control diet group. Levels of NF-kappaB in five brain regions of the above subjects were determined by western blotting assays. In four regions, aged control diet rats had significantly higher average NF-kappaB levels than young animals on the control diet. In four regions, aged blueberry diet rats had significantly lower levels of NF-kappaB than aged control diet rats. Normalized NF-kappaB levels (averaged across regions and in several individual regions) correlated negatively and significantly with the object memory scores.

Nutr Neurosci. 2004 Apr;7(2):75-83

An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk.

Results from the Women’s Health Initiative (WHI) trial support findings from observational studies that oestrogen-progestin therapy (EPT) use is associated with an increase in breast cancer risk. We conducted a meta-analysis using EPT-specific results from the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) pooled analysis and studies published since that report to obtain an overview of EPT use and breast cancer risk. We also assessed risk by histologic subtype of breast cancer, by schedule of the progestin component of EPT, and by recency of use. We estimate that overall, EPT results in a 7.6% increase in breast cancer risk per year of use. The risk was statistically significantly lower in US studies than in European studies - 5.2 vs 7.9%. There was a significantly higher risk for continuous-combined than for sequential EPT use in Scandinavian studies where much higher total doses of progestin were used in continuous-combined than in sequential EPT. We observed no overall difference in risk for lobular vs ductal carcinoma but did observe a slightly higher risk for current vs past EPT use.

Br J Cancer. 2005 Jun 6;92(11):2049-58

Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study.

Numerous studies and meta-analyses have shown that hormone replacement therapy (HRT) for menopausal symptoms increases the risk of developing breast cancer, estimated to be 2.3% for each year of use. The influence of different oestrogen-progestin regimens has still not been fully evaluated. Using longitudinal data from the population-based prescription database of the county of North Jutland, Denmark, and the Danish Cancer Registry, we examined the risk of developing breast cancer in relation to HRT in a cohort of 78,380 women aged 40-67 years from 1989 to 2002. A total of 1462 cases of breast cancer were identified during a mean follow-up of 10 years. Use of HRT did not increase the risk of breast cancer in women aged 40-49 years. Restricting the cohort to 48,812 women aged 50 years or more at entry, of whom 15 631 were HRT users, we found an increased risk associated with current use of HRT (relative risk 1.61, 95% confidence interval 1.38-1.88). The risk increased with increasing duration of use and decreased with time since last HRT prescription, reaching unity after 5 years. No material risk difference was observed among the various HRT-regimens. This population-based cohort study provides further confirmation that HRT increases the risk of developing breast cancer in women aged 50 years or more.

Br J Cancer. 2005 Apr 11;92(7):1293-7

Hormone replacement therapy and risk of breast cancer: the role of progestins.

Epidemiological studies have shown an increased risk of breast cancer associated with the use of hormone replacement therapy (HRT). This notion is mostly based on studies from the USA. During the last decades unopposed estrogen treatment has been used to a lesser extent, whereas the combined estrogen-progestin treatment regime is now prescribed worldwide. In the USA the predominant compounds are conjugated estrogens and medroxyprogesterone-acetate, whereas oestradiol combined with testosterone-like progestins is commonly used in Europe. These differences are largely the result of traditions. Recent studies originating from both the USA and Europe suggest that the combined treatment regimens with estrogen and progestin increase the risk of breast cancer beyond the risk following the use of unopposed estrogen. At present it is not known if progestins with different androgenicity influence the risk of breast cancer to a varying degree. This review focuses on studies published after the latest meta-analysis in 1997, with special attention given to the type of progestin used and the treatment mode, i.e., cyclical or continuous regimen.

Acta Obstet Gynecol Scand. 2003 Jul;82(7):335-44

Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.

Large numbers of hormone replacement therapies (HRTs) are available for the treatment of menopausal symptoms. It is still unclear whether some are more deleterious than others regarding breast cancer risk. The goal of this study was to assess and compare the association between different HRTs and breast cancer risk, using data from the French E3N cohort study. Invasive breast cancer cases were identified through biennial self-administered questionnaires completed from 1990 to 2002. During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women. Compared with HRT never-use, use of estrogen alone was associated with a significant 1.29-fold increased risk (95% confidence interval 1.02-1.65). The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83-1.22) for estrogen-progesterone, 1.16 (0.94-1.43) for estrogen-dydrogesterone, and 1.69 (1.50-1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.

Breast Cancer Res Treat. 2008 Jan;107(1):103-11

Intravaginal oestrogen and progestin administration: advantages and disadvantages.

The vagina provides a local and a systemic route for delivering hormones for systemic effects and uterine targeting. Due to the ‘uterine first-pass effect’, hormones concentrate in the uterus and nearby tissues with low systemic exposure. Vaginal oestrogens, progesterone/progestins and danazol are currently used to obtain local (vagina and urethra), regional (uterus, pelvic structures) and systemic effects or contraception. Very low dosages of transvaginal oestrogens in the forms of creams, tablets and rings are effective for vaginal atrophy and urinary incontinence. To avoid endometrial stimulation, no deep vaginal application of low dosages for less than 6 months is recommended. For postmenopausal hormonal therapy by the vaginal route, progesterone is delivered directly to the uterus; the target organ for which it is designed. Worldwide, vaginal progesterone is employed for luteal phase support. Contraceptive vaginal rings offer the advantages of non-oral administration and sustained release. Vaginal administration of steroids is a promising option for the treatment of endometriosis.

Best Pract Res Clin Obstet Gynaecol. 2008 Apr;22(2):391-405

Estrogen receptors alfa (ERalpha) and beta (ERbeta) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11.

The mitogenic effect of 17beta-estradiol (E2) on the breast is mediated by estrogen receptor alfa (ERalpha), hence ERalpha antagonists are effective in the treatment of breast cancer. The possible use of estrogen receptor beta (ERbeta) as a target in treatment of breast cancer is under investigation. The mouse mammary cell line HC11 expresses both ERs and was used to study the role of the two receptors in proliferation. E2 had no effect on proliferation. The ERalpha-selective agonist 4,4’,4’’-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) stimulated proliferation. The ERbeta-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) inhibited cell growth and induced apoptosis. PPT upregulated while DPN downregulated cyclin D1 and proliferating cell nuclear antigen (PCNA). Upon inhibition of ERalpha expression with RNA interference, E2 caused a decrease in cyclin D1 and PCNA, and increased apoptosis. When ERbeta expression was blocked, E2 induced proliferation and cells gained the capacity to grow in soft agar. In summary, in HC11 mammary epithelial cells, ERalpha drives proliferation in response to E2 while ERbeta is growth inhibitory. The lack of effect of E2 on HC11 cell growth is the result of the combined actions of ERalpha (proliferation) and ERbeta (apoptosis). We suggest that use of ERbeta agonists will be a useful addition in treatment of breast cancer, which, at present, is only aimed at inhibition of ERalpha.

Oncogene. 2005 Oct 6;24(44):6605-16

Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding.

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) alpha or beta subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17beta (E2) and estrone (E1) for human ER alpha and ER beta. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ER alpha and ER beta, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16 alpha-hydroxyestradiol (estriol), 16 beta-hydroxyestradiol-17 alpha, and 16-ketoestrone, had distinct preferential binding affinity for human ER beta over ER alpha (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ER alpha and ER beta, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ER alpha over ER beta, whereas 16 alpha-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ER beta over ER alpha. Hence, facile metabolic conversion of parent hormone E2 to various metabolites under different physiological conditions may serve unique functions by providing differential activation of the ER alpha or ER beta signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ER alpha and ER beta yielded useful information on the structural features that determine the preferential activation of the ER alpha and ER beta subtypes, which may aid in the rational design of selective ligands for each human ER subtype.

Endocrinology. 2006 Sep;147(9):4132-50

The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?

BACKGROUND: The use of bioidentical hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their relative safety compared with traditional synthetic and animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic progestins. Proponents for bioidentical hormones claim that they are safer than comparable synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration and The Endocrine Society, there is little or no evidence to support claims that bioidentical hormones are safer or more effective. OBJECTIVE: This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease. METHODS: Published papers were identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in vitro results, were selected. RESULTS: Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone. CONCLUSION: Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.

Postgrad Med. 2009 Jan;121(1):73-85

Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause.

The authors further analyzed results from the Women’s Health Initiative randomized trials (1993-2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women’s Health Initiative observational study (1993-2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.

Am J Epidemiol. 2009 Jul 1;170(1):12-23

Meat consumption and risk of breast cancer in the UK Women’s Cohort Study.

We performed a survival analysis to assess the effect of meat consumption and meat type on the risk of breast cancer in the UK Women’s Cohort Study. Between 1995 and 1998 a cohort of 35,372 women was recruited, aged between 35 and 69 years with a wide range of dietary intakes, assessed by a 217-item food frequency questionnaire. Hazard ratios (HRs) were estimated using Cox regression adjusted for known confounders. High consumption of total meat compared with none was associated with premenopausal breast cancer, HR=1.20 (95% CI: 0.86-1.68), and high non-processed meat intake compared with none, HR=1.20 (95% CI: 0.86-1.68). Larger effect sizes were found in postmenopausal women for all meat types, with significant associations with total, processed and red meat consumption. Processed meat showed the strongest HR=1.64 (95% CI: 1.14-2.37) for high consumption compared with none. Women, both pre- and postmenopausal, who consumed the most meat had the highest risk of breast cancer.

Br J Cancer. 2007 Apr 10;96(7):1139-46