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This e-newsletter presents reviews of important, recently published scientific articles selected by members of The North American Menopause Society (NAMS), the leading nonprofit scientific organization dedicated to improving women’s health and quality of life through an understanding of menopause. Each has a commentary from a recognized expert that addresses the clinical relevance of the item. Opinions expressed in the commentaries are those of the authors and are not necessarily endorsed by NAMS. Disclosures are available on request. Oversight for this newsletter issue was by Robert A. Wild, MD, PhD, MPH, Chair-Elect, 2006-2007 NAMS Professional Education Committee. Past issues of this e-newsletter may be viewed on the NAMS Web site ( Breast cancer risk elevated after
purchases since 1994. They were followed for 5 years of some types of estrogen-
breast cancer until the end of 2002 or death. A total of 2,171 cancer cases were identified from only therapy
the Finnish Cancer Registry, which receives notification of cancers from physicians, hospitals, Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in and laboratories and for which coverage is almost postmenopausal women using estrogen-only therapy.
Obstet Gynecol 2006;108:1354-1360. Level of evidence:
After 5 years of use, estradiol was associated Use of oral or transdermal estradiol for less than with an increased risk of breast cancer. Oral 5 years does not increase the risk for breast estriol and vaginal estrogen were not associated cancer, but risk does occur after 5 years of use with any increase in risk. The incidence ratio for and increases with longer duration and dosage, breast cancer with systemic estradiol use of less according to this study from Finland of a cohort than 5 years was 0.93 (95% confidence interval representing the nation’s entire postmenopausal [CI], 0.80-1.04), and for 5 years or more, 1.44 population. The study evaluated risk for breast (95% CI, 1.29-1.59) with similar risk for the oral cancer with estrogen-only therapy and whether it and transdermal formulations. The standardized varies by dose, constituent, and route of incidence ratio related to estimated estradiol use administration. of 5 to 10 years was 1.34 (95% CI, 1.16-1.54); for 10 to 20 years, 1.57 (95% CI, 1.31-1.86); and All women over age 50 (N= 283,680) who had for more than 20 years, 1.75 (95% CI, 1.16-2.55). used an estrogen-only regimen (oral or transdermal estradiol [n = 84,729], oral estriol [n Risk was significantly elevated when the mean = 7,941], or vaginal estrogens [n = 18,314]) for 6 dose of oral estradiol was higher than 1.9 mg/day months or more from 1994 to 2001 were and was used for 5 years or more. The trend for identified. Women using conjugated estrogens dose, however, was not statistically significant (P were excluded. All women using a particular for trend = 0.27). For the transdermal route, risk regimen were identified from the Finnish was not associated with dosage. The authors note National Reimbursement Register, which con- that the risk associated with estradiol use of 5 to tains data on postmenopausal hormone therapy 10 years results in two to three additional cases of breast cancer per 1,000 women in 10 years of Lyytinin indicates that long-term estrogen alone may increase the relative risk (RR) of breast cancer (RR, 1.44; 95% CI, 1.29-1.59 for >5 Comment. Several recent publications have years’ use). Notably, increased risk was observed
confirmed previous observational data that up to
with oral, transdermal, and gel preparations. The 5 years of postmenopausal use of estrogen alone NHS, in contrast, reported that this risk began to does not increase, and may even decrease, increase only after more than 15 years of invasive breast cancer risk. The Lyytinen study predominantly oral therapy with the rate of captures observational data from all Finnish ER+/PR+ tumors statistically significantly women older than age 50 who filled a increased after 15 years current use (RR, 1.48; prescription for estradiol (tablets, patches, gels) 95% CI, 1.05-2.07). If confirmed in additional based on a national registry (110,984 women and studies, these data suggest that the mechanisms 648,022 women-years). This population provides of estrogen effect, when used short term particularly important data on use of short-term (antihyperinsulinemic, proapoptotic), may differ versus long-term estradiol without a progestogen. For short-term use (<5 years), the results are reassuring, with a standardized incidence ratio of 0.93 (95% CI, 0.80-1.04) in the subgroup who As with other observational data, this study never took estrogen prior to entry into the study serves to point out potential confounding factors (ie, estrogen-naive). This study is concordant in interpretation, such as the presence or absence with the randomized controlled trial Women’s of ovaries after hysterectomy, the lumping Health Initiative (WHI) estrogen-alone data together of estrogen-naive and preexposed (hazard ratio [HR], 0.77; 95% CI, 0.59-1.01)1 and women, the lack of distinction between lean and the observational Nurses’ Health Study (NHS) obese women, the identification of women with (HR, 0.96; 95% CI, 0.75-1.22)2 for similar the metabolic syndrome/insulin resistance, and estrogen-naive patients. the use of a control group composed of estrogen users and nonusers. Taking these issues into It is interesting to note that Lyytinen, the WHI account, current data suggest no increase and update on breast cancer,3 and the NHS all perhaps a decrease in breast cancer risk with reported trends toward reduced risks of breast estrogen alone for less than 5 years in estrogen- cancer in women receiving estrogen alone for naive women and an increased risk if taken long less than 5 years. The results were statistically term, particularly for more than 5 years in significant in WHI for subgroups with no prior women of normal body mass index—longer in menopausal hormone use (HR, 0.65; 95% CI, 0.46-0.65), localized disease (HR, 0.69; 95% CI, 0.51-0.95), and drug compliance (HR, 0.67;95% CI, 0.47-0.97). This short-term reduction in risk with oral estrogen in particular may reflect an University of Virginia Health Science Center Charlottesville, VA effect of estrogen in reducing hyperinsulinemia, a risk factor for breast cancer, as it has been Prince Henry’s Institute of Medical Research estimated that 50% of the participants in the WHI estrogen-only arm would have the metabolic syndrome.4,5 This paradoxical reduction in risk may also reflect a proapoptotic effect of estrogen Emeritus Director Prince Henry’s Institute of Medical Research on a reservoir of preexisting tumors exposed to low concentrations of estrogen since menopause, particularly given the significant reduction in the number who never used hormones in the WHI 1. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized years after randomization: mean difference, controlled trial. JAMA 2004;291:1701-1712. –0.01; 95% confidence interval [CI], –0.04-0.03). 2. Chen WY, Manson JE, Hankinson SE, et al. Unopposed In addition, there were no differences in the estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006;166:1027-1032. global scores between the vitamin E and placebo 3. Stefanick ML, Anderson GL, Margolis KL, et al. Effects groups at the two follow-up assessments (after of conjugated equine estrogens on breast cancer and 9.6 years of treatment: mean difference, 0.00; mammography screening in postmenopausal women with 95% CI, –0.04-0.04). For the secondary endpoint hysterectomy. JAMA 2006;295:1647-1657. of verbal memory, there were no differences in 4. Kuhl H, Stevenson J. The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits—an scores between groups at any of the assessments attempt to interpret the Women’s Health Initiative results. (at final assessment: mean difference, 0.01; 95% Gynecol Endocrinol 2006;22:303-317. CI, –0.03-0.05). There were no differences in 5. Ford ES, Giles WH, Dietz WH. Prevalence of the mean change in cognitive performance for any of metabolic syndrome among US adults: findings from the the assessments between the treatment groups. third National Health and Nutrition Examination Survey. There was a suggestion of a positive effect in women who previously had low dietary intake of Effects of vitamin E or B on
vitamin E (<6.1 mg/d). For these women, the cognitive function (two studies)
vitamin E recipients had less decline in cognitive function compared with the placebo group. The Kang JH, Cook N, Manson J, Buring JE, Grodstein F. difference in mean change in global score over A randomized trial of vitamin E supplementation and time between the two groups was 0.05 (95% CI, cognitive function in women. Arch Intern Med 0.01-0.09). For women with previously high 2006;166:2462-2468. Level of evidence: I.
dietary intake of vitamin E, the groups had similar adverse cognitive change. Among women A substudy of the Women’s Health Study finds who exercised less than once a week, the vitamin there is no improvement or decline in cognitive E group had a more favorable cognitive change function or decline in older women after a mean than the placebo group; the mean change in of 9.6 years of vitamin E supplementation. The global score over time was 0.06 (95% CI, 0.03- double-blind, placebo-controlled trial randomized 0.10). Among women who exercised at least 39,876 healthy US women to receive vitamin E once a week, there was no difference in change in (600 IU of alpha-tocopherol acetate on alternate cognitive function over time between the two days) or placebo between 1992 and 1995. The substudy followed 6,377 of these women (ages 65 or older) for 4 years beginning in 1998, a While the study did not demonstrate overall mean of 5.6 years after randomization, for cognitive benefit or reduced cognitive decline, changes in cognitive function. the authors speculate that initiation of treatment at an earlier age or for longer duration, using General cognition, verbal memory, and category fluency were assessed using five tests conducted tocopherols, could possibly show a positive by telephone interview at the initiation of the study and at 2-year intervals. The tests were adapted from the Mini-Mental State Examination Balk EM, Raman G, Tatsioni A, Chung M, Lau J, and the East Boston Memory Test. The primary Rosenberg IH. Vitamin B6, B12, and folic acid supple-mentation and cognitive function: a systematic review outcome measure was a global composite score of randomized trials. Arch Intern Med 2007;167: on all five tests; a secondary outcome measure 21-30. Level of evidence: III.
Inadequate evidence exists at this time for a At the first assessment, scores on the five tests beneficial effect of supplementation with did not differ for the two treatment groups (5.6 vitamins B6, B12, or folic acid on cognitive function in either normal elderly adults or those observational studies, the referent population is with impaired cognitive function, found this deficient, with exposures measured in decades. In systematic review of studies that examined the the few clinical trials in which the population was effect of these vitamins on cognition. The current deficient, effects on cognitive function were study used a literature search of MEDLINE to observed.1,2 This is due in part to that fact that the identify English language, randomized controlled deficient subjects were experiencing a decline in trials in which specific type of vitamin, dose, and route of administration were reported. All were trials of adult participants with outcomes related What can we conclude from these studies? The to cognitive impairment or function. A total of 14 trials was reviewed. The trials were considered to nondeficient individuals in order to slow be of variable and mostly low quality, with small cognitive decline is uncertain. However, the risks numbers of participants and a large degree of of supplementation are much less so. Several heterogeneity in dose, route of administration, cardiovascular mortality with vitamin E in excess of 400 units per day—no benefit.3 With B Three trials of vitamin B6 and six trials of vitamins designed to lower homocysteine and vitamin B12 found no effect on cognitive cardiovascular endpoints, at least one trial has function. One small study did find an demonstrated a possible increase in cardio-improvement with folate supplementation in vascular events—again no benefit.4 Trials of patients with low baseline folate. Six trials of beta-carotene and vitamin A to reduce cancers supplementation with combinations of the demonstrated increased risk of these cancers and vitamins found no effect on cognitive function. mortality.4 In summary, although there is Given the sparsity of studies that qualified for insufficient evidence that supplementing with inclusion, the low numbers of participants, and heterogeneity of data and outcomes, inadequate requirements in otherwise healthy individuals is evidence currently exists for a beneficial effect of beneficial, there is growing evidence that this B vitamin supplementation on cognitive function, supplementation is harmful. More may not be Comment. Age-associated cognitive decline is
Stanley J. Birge, MD Associate Professor of Medicine characterized by a subtle progressive loss of Division of Geriatrics and Nutritional Sciences cognitive function beginning in the fourth and Washington University School of Medicine fifth decades of life and represents the St. Louis, MO cumulative effects of multiple factors. The challenge of intervention trials in healthy References: 1. Durga J, van Boxtel MP, Schouten EG, et al. Effect of populations is that the outcome is not a defined 3-year folic acid supplementation on cognitive function in event, such as a hip fracture. The outcome is the older adults in the FACIT trial: a randomized, double blind, slowing of the natural trajectory of cognitive controlled trial. Lancet 2007;369:208-216. decline, on the order of 1%-2% per decade. To 2. Nilsson K, Gustafson L, Hultberg B. Improvement of detect a 50% effect, one would have to be able to cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma measure a change of 1% over 10 years. Thus, homocysteine. Int J Geriatr Psychiatry 2001;16:609-614. even the Kang et al study with 6,000 participants 3. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, followed for almost 10 years was underpowered. Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: It is also important to appreciate that these systematic review and meta-analysis. JAMA 2007;297: clinical trials involve populations without 4. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine evidence of a deficiency of the vitamins used in lowering and cardiovascular events after acute myocardial the intervention at superphysiological doses. In infraction. N Engl J Med 2006;354:1578-1588. Gabapentin with an antidepressant
1 week and then discontinued. A total of 91 no more effective in treating hot
flashes than gabapentin alone
Regardless of whether the antidepressant was continued, participants reported an approximately Loprinzi CL, Kugler JW, Barton DL, et al. Phase III trial of gabapentin alone or in conjunction with an antidepressant 50% reduction (P < 0.05) in the frequency of hot in the management of hot flashes in women who have flashes (54%; 95% confidence interval [CI], inadequate control with an antidepressant alone: NCCTG 34%-70% for combined treatment vs 49%; 95% N03C5. J Clin Oncol 2007;25:308-312. Level of
CI, 26%-58% for gabapentin alone), as well as of evidence: I.
hot flash scores (56%; 95% CI, 26%-71% for combined treatment vs 60%; 95% CI, 33%-73% Gabapentin alleviates hot flashes in women who for gabapentin alone). By week 2, a trend toward have a poor response to treatment of them with more negative mood changes and nervousness antidepressants, and continuing an antidepressant along with gabapentin does not have an additive antidepressants. Overall, self-reported quality of effect. This prospective, randomized trial life parameters were similar throughout the study conducted at the Mayo Clinic and other medical centers (referred from a cancer treatment
randomization office) assessed whether the
combined agents would more effectively Comment: Because vasomotor symptoms are
alleviate hot flashes versus gabapentin alone. In
the 5-week trial, 118 women who were using an postmenopausal women, and many symptomatic antidepressant to treat hot flashes (median age, women are concerned about the risks of hormone 53.5 years) without satisfactory diminishment of symptoms were randomized to receive either nonhormonal treatment of hot flashes. Identifying both the gabapentin and antidepressant or be nonhormonal treatments for menopausal hot weaned from the antidepressant and receive flashes that are more effective than placebo has gabapentin alone. Women kept a diary of proved challenging. Acupuncture, yoga, Chinese frequency and severity of hot flashes and other herbs, dong quai, evening primrose oil, ginseng, symptoms over the course of the 5-week study. kava, red clover extract, black cohosh, and soy/phytoestrogens have not consistently been Approximately three quarters of the participants found more effective than placebo. Likewise, the had a personal history of breast cancer; the antidepressants citalopram and sertraline have remainder were reluctant to use hormone therapy not been found effective, and results for proximately two thirds were using tamoxifen or inconsistent. Although paroxetine has been found an aromatase inhibitor, and most of the women to have a modest benefit in symptomatic breast were using venlafaxine or paroxetine at study cancer survivors, most studies of symptomatic During the first week, the women were observed in order to establish baseline levels of vasomotor The need for three times daily administration is a symptoms. All participants then began disadvantage of treating menopause-related gabapentin, initially 300 mg at bedtime for 3 symptoms with gabapentin. The more frequent days, then twice daily for 3 days, then three times negative mood changes and nervousness in those daily for 22 days. Those randomized to continue randomized to discontinue antidepressants likely antidepressant therapy continued at their current reflect the positive impact that antidepressants dose and schedule; those randomized to were having on those who discontinued these discontinue decreased their dose by half for medications. Overall, these findings indicate that off-label use of gabapentin may be useful in A multivariate-adjusted model was used to study breast cancer survivors taking antiestrogens associations between pancreatic cancer and age at whose vasomotor symptoms do not respond to first birth, number of births, ages at menarche antidepressants. The authors suggest that, in this and menopause, and use of hormone therapy setting, delaying discontinuation of the (HT). Also studied were natural as opposed to antidepressant might be useful so that any medically induced menopause and women with ensuing undesirable mood changes not be intact ovaries compared to others who had inappropriately attributed to gabapentin. oophorectomy. Cases of pancreatic cancer were identified through the Iowa State Health Registry, and only cases of exocrine pancreatic cancer were included. Over the course of 18 years, 228 cases of pancreatic cancers occurred University of Florida Health Science Center Jacksonville, FL No associations were found between pancreatic 1. Grady D. Clinical Practice. Management of menopausal cancer and age at menarche, number of live symptoms. N Engl J Med 2006;355:2338-2347. births, age at first birth, use of HT, or use of oral contraceptives. Incidence of pancreatic cancer Later menopause associated with
reduced risk for pancreatic cancer
menopause at an older age. The hazard ratio Prizment AE, Anderson KE, Hong CP, Folsom AR. experiencing menopause between the ages of 45 Pancreatic cancer incidence in relation to female to 49 was 0.61 (95% confidence interval [CI], reproductive factors: Iowa Women’s Health Study. 0.40-0.94) compared to women who reached JOP 2007;8:16-27. Level of evidence: II-2.
experienced menopause between ages 50 to 54, Variables related to an early age at menopause the HR was 0.75 (95% CI, 0.51-1.09); and for influence the risk for pancreatic cancer, and women who experienced menopause after age variables associated with a later age at 55, the HR was 0.35 (95% CI, 0.18-0.68; P for menopause reduce the risk, according to the Iowa Women’s Health Study, a prospective, population-based study designed to examine risk Risk was decreased in women who ovulated for a factors for breast and other cancers. The cohort longer period of their life and who did not have of 37,459 peri- and postmenopausal women total oophorectomy. For women with intact (aged 55-69 at baseline) provided information at ovaries compared to those with oophorectomy, baseline in 1986 and were followed until 2003. the HR was 0.70 (95% CI, 0.50-0.99). Hence, The baseline questionnaire asked about body only reproductive variables related to menopause size, lifestyle and sociodemographic factors, diet, and medical and reproductive history. This oophorectomy, and hysterectomy without total portion of the study evaluated the association oophorectomy) are associated with pancreatic between the incidence of pancreatic cancer and reproductive characteristics. The hypothesis for an association was based upon the facts that Comment. This study draws attention to the fact
pancreatic cancer is more common in men than in that extended endogenous sex steroid exposure in women, steroid hormone receptors occur in the pancreas, and antiestrogenic agents inhibit the effects on disease states outside of those that growth of pancreatic cancer in human models. normally make the news, namely cardiovascular disease, osteoporosis, and breast cancer. From to inhibit the growth of preneoplastic lesions in the clinician’s standpoint, this may further the laboratory setting. reinforce the importance of not arbitrarily removing normal-appearing ovaries at the time of The fact that pancreatic cancer is related to hysterectomy in the pre- or perimenopausal modifiable risk factors such as smoking, diet, and woman if, in fact, a later age of menopause and diabetes further stresses our role as primary care longer periods of ovulation are related to a lower providers in encouraging all of our patients to incidence of pancreatic cancer, which has a poor David A. Hutchins, MD Department of Obstetrics and Gynecology Whether estrogen or other sex steroids have University of Arkansas for Medical Sciences anticarcinogenic effects in humans remains to be determined. However, estrogen has been shown Credentialed NAMS Menopause Practitioner The level of evidence indicated for each study is based on a grading system that evaluates the scientific rigor of the study design, as developed by the U.S. Preventive Services Task Force. A synopsis of the levels is presented below. Well-designed controlled trial but without randomization. Well-designed cohort or case-control analytic study. Multiple time series with or without the intervention (eg, cross-sectional and uncontrolled investigational studies). Meta-analyses; reports from expert committees; descriptive studies and case reports. Submit Your Abstract to NAMS for presentation at the
18th Annual Meeting in Dallas, TX (October 3-6, 2007)
Abstract submission deadline is April 30, 2007. Submit your abstract through the NAMS Web site: Top 20 abstracts will be accepted for oral presentation during the NAMS Annual Meeting; other accepted abstracts will be designated poster presentations. All accepted posters will be eligible to be considered for one first-place poster prize of $1,000 and up to three runner-up prizes of $500. All accepted abstracts will be published in Menopause after the meeting. First to Know® is a registered trademark of The North American Menopause Society Copyright 2007 The North American Menopause Society Tel 440/442-7550 • Fax 440/442-2660 •



Histomorphometric Evaluation of Extraction Sockets and Deficient Alveolar Ridges Treated with Allograft and Barrier Membrane: A Pilot Study Hyman Smukler, BDS, DMD, HDD*/Luca Landi, DDS**/Reza Setayesh, DMD, DMSc*** The aim of the study was to determine the fate of demineralized freeze-dried bone allograft (DFDBA)used in conjunction with a barrier membrane in the management of extraction socket

A first experiment in algorithmic graph theoryA graph is called “properly (2-)colorable” if there is a red/blue coloring of the nodessuch that each of the edges is “mixed” :that is, such that the endnodes of each edgehave different colors. Note that this is an existential graph property; as algorithmic graphtheorists, we are therefore compelled to investigate this property by writing a

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