Journal Club

1. Journal Club Villareal DT, Chode S, Parimi N, Sinacore DR, Hilton T, Armamento-Villareal R, Napoli N, Qualls C, Shah K. Weight loss, exercise, or both and physical function in obese older adults. N Engl J Med. 2011 Mar 31;364(13):1218-29. Ross JL, Quigley CA, Cao D, Feuillan P, Kowal K, Chipman JJ, Cutler GB Jr. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. N Engl J Med. 2011 Mar 31;364(13):1230-42. 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文 Matsuda, Masafumi 2011年4月7日8:30-8:55 ８階　医局

2. Mean Changes in Body Weight and Waist Circumference at Various Time Points Sacks FM, et al.: Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009 Feb 26;360(9):859-73. カロリー低めが有効で、食事の組成(炭水化物、脂質、蛋白比)はあまり問題にはならない。

3. 2010年12月2日　8:30-8:55 「蛋白多め、GIは低め」がよい Larsen TM( Diet, Obesity, and Genes (Diogenes) Project.): Diets with high or low protein content and glycemic index for weight-loss maintenance. N Engl J Med. 2010 Nov 25;363(22):2102-13. N Engl J Med 2010;363:2102-13.

4. the Division of Geriatrics and Nutritional Science (D.T.V., S.C., N.P., D.R.S., K.S.), the Program in Physical Therapy (D.R.S., T.H.), and the Division of Bone and Mineral Diseases (R.A.-V., N.N.), Washington University School of Medicine, St. Louis; and the Sections of Geriatrics (D.T.V.) and Endocrinology (R.A.-V.), New Mexico Veterans Affairs Health Care System; and the Divisions of Geriatrics (D.T.V.) and Endocrinology (R.A.-V.) and the Department of Mathematics and Statistics (C.Q.), University of New Mexico School of Medicine — both in Albuquerque. N Engl J Med 2011;364:1218-29.

5. Background Obesity exacerbates the age-related decline in physical function and causes frailty in older adults; however, the appropriate treatment for obese older adults is controversial.

6. Methods In this 1-year, randomized, controlled trial, we evaluated the independent and combined effects of weight loss and exercise in 107 adults who were 65 years of age or older and obese. Participants were randomly assigned to a control group, a weightmanagement (diet) group, an exercise group, or a weight-management-plus-exercise (diet–exercise) group. The primary outcome was the change in score on the modified Physical Performance Test. Secondary outcomes included other measures of frailty, body composition, bone mineral density, specific physical functions, and quality of life.

7. Physical Function Frailtywas assessed with the use of the modified Physical Performance Test, the measurement of VO2peak, and the Functional Status Questionnaire. The modified Physical Performance Test includes seven standardized tasks (walking 50 ft, putting on and removing a coat, picking up a penny, standing up from a chair, lifting a book, climbing one flight of stairs, and performing a progressive Romberg test) plus two additional tasks (climbing up and down four flights of stairs and performing a 360-degree turn). The score for each task ranges from 0 to 4; a perfect score is 36. A low score on the Physical Performance Test is associated with a high BMI, and the score increases in response to weight-loss therapy. VO2peak was assessed during graded treadmill walking, as described previously. 8 Information regarding the ability to perform activities of daily living was obtained with the use of the Functional Status Questionnaire (on which scores range from 0 to 36, with higher scores indicating better functional status). We also assessed specific physical functions such as strength, balance, and gait and determined one-repetition maximums (the maximal weight a person can lift at one time). We assessed static balance by measuring the time the participant could stand on a single leg and dynamic balance by measuring the time needed to complete an obstacle course. Fast gait speed was determined by a measurement of the time needed to walk 25 ft.

8. Body Composition and Bone Mineral Density Fat mass, lean body mass, and bone mineral density of the whole body and at the lumbar spine and total hip were measured with the use of dual-energy x-ray absorptiometry (Delphi 4500/w, Hologic), as described previously. Thigh muscle and fat volumes were measured with the use of magnetic resonance imaging (MRI) (Siemens), as described previously. Health-Related Quality of Life The Medical Outcomes 36-Item Short-Form Health Survey (SF-36) was used to evaluate quality of life. The subscales we used were those for the physical component summary and the mental component summary. Scores on these two subscales range from 0 to 100, with higher scores indicating better health status. http://www.i-hope.jp/ http://www.sf-36.org/

9. Functional Status Questionnaire Overview: The Functional Status Questionnaire can be used as a self-administered functional assessment for a patient seen in primary care. It provides information on the patient's physical, psychological, social and role functions. It can be used both to screen initially for problems and to monitor the patient over time. Sections (1) physical function in the activities of daily living (2) psychological function (3) role function (4) social function (5) variety of performance measures Physical Function (Activities of Daily Living, or ADL) Basic ADL: During the past month have you had difficulty with (1) Taking care of yourself, that is, eating, dressing or bathing? (2) Moving in or out of a bed or chair? (3) Walking indoors, such as around your home? Response Points usually did with no difficulty 4 some difficulty 3 much difficulty 2 usually did not do because of healty 1 usually did not do for other reason 0 where: • I will assume that "usually did not do for other reasons" is not a "valid" response, so that the ((maximum response score) - (minimum response score)) =3; see scoring example on page 145 Intermediate ADL: During the past month have you had difficulty with (1) Walking several blocks? (2) Walking one block or climbing one flight of stairs? (3) Doing work around the house, such as cleaning, light yard work or home maintenance? (4) Doing errands such as grocery shopping? (5) Driving a car or using public transportation? Functional Status Questionnaire file:///C|/algoritmo/Functional Status Questionnaire.htm (1 di 7) [30/04/2001 12.50.22] (6) Doing vigourous activities such as running, lifting heavy objects or participating in strenuous sports? Response Points usually did with no difficulty 4 some difficulty 3 much difficulty 2 usually did not do because of healty 1 usually did not do for other reason 0 where: • I will assume that "usually did not do for other reasons" is not a "valid" response, so that the ((maximum response score) - (minimum response score)) =3; see scoring example on page 145 Psychological Function (Mental Health) During the past month, (1) Have you been a very nervous person? (2) Have you felt calm and peaceful? (3) Have you felt downhearted and blue? (4) Were you a happy person? (5) Do you feel so down in the dumps that nothing could cheer you up? Response to 1, 3 and 5 Points all of the time 1 most of the time 2 a good bit of the time 3 some of the time 4 a little of the time 5 none of the time 6 Response to 2 and 4 Points all of the time 6 most of the time 5 a good bit of the time 4 Functional Status Questionnaire file:///C|/algoritmo/Functional Status Questionnaire.htm (2 di 7) [30/04/2001 12.50.22] some of the time 3 a little of the time 2 none of the time 1 where: • ((maximum response score) - (minimum response score)) = 5 • The subgroups of questions are scored in reverse. Since Table2 indicates that 0% is poor and 100% is good, I have scored as in the ables above. Social/Role Function If you were employed during the past month, how was your work performance? (1) Done as much work as others in similar jobs? (2) Worked for short periods of time or taken frequent rests because of your health? (3) Worked your regular number of hours? (4) Done your job as carefully and accurately as others with similar jobs? (5) Worked at your usual job, but with some changes because of your health? (6) Feared losing your job because of your health? Response to 2, 5 and 6 Points all of the time 1 most of the time 2 some of the time 3 none of the time 4 Response to 1, 3 and 4 Points all of the time 4 most of the time 3 some of the time 2 none of the time 1 where: • ((maximum response score) - (minimum response score)) = 3 • The subgroups of questions are scored in reverse. Since Table2 indicates that 0% is poor and 100% is good, I Functional Status Questionnaire file:///C|/algoritmo/Functional Status Questionnaire.htm (3 di 7) [30/04/2001 12.50.22] have scored as in the ables above. Social Activity: During the past month have you : (1) Had difficulty visiting with relatives or friends? (2) Had difficulty participating in community activities, such as religious services, social activities, or volunteer work? (3) Had difficulty taking care of other people such as family members? Response Points usually did with no difficulty 4 some difficulty 3 much difficulty 2 usually didnot do because of health 1 usually did not do for other reasons 0 where: • I will assume that "usually did not do for other reasons" is not a "valid" response, so that the ((maximum response score) - (minimum response score)) =3; see scoring example on page 145 Quality of social interaction: During the past month, have you: (1) Isolated yourself from people around you? (2) Acted affectionate toward others? (3) Acted irritable toward those around you? (4) Made unreasonable demands on your family and friends? (5) Gotten along well with other people? Response to 1, 3 and 4 Points all of the time 1 most of the time 2 a good bit of the time 3 some of the time 4 a little of the time 5 none of the time 6 Response to 2 and 5 Points all of the time 6 Functional Status Questionnaire file:///C|/algoritmo/Functional Status Questionnaire.htm (4 di 7) [30/04/2001 12.50.22] most of the time 5 a good bit of the time 4 some of the time 3 a little of the time 2 none of the time 1 where: • ((maximum response score) - (minimum response score)) = 5 • The subgroups of questions are scored in reverse. Since Table2 indicates that 0% is poor and 100% is good, I have scored as in the ables above. Single Item Questions (1) Which of the following statements describes your work situation during the past month? • working full-time • working part-time • unemployed looking for work • unemployed because of my health • retired because of my health • retired for some other reason (2) During the past month, how many days did illness or injury keep you in bed all or most of the time: • Responses: from 0 to 31 days (3) During the past month, how many days did you cut down on the things you usually do for one-half day or more because of your illness or injury?: • Responses: from 0 to 31 days (4) During the past month, how satisfied were you with your sexual relationships? • very satisfied • satisfied • not sure • dissatisfied • very dissatisfied • did not have any sexual relationships (5) How do you feel about your health? Functional Status Questionnaire file:///C|/algoritmo/Functional Status Questionnaire.htm (5 di 7) [30/04/2001 12.50.22] • very satisfied • satisfied • not sure • dissatisfied • very dissatisfied (6) During the past month, about how often did you get together with friends or relatives, such as going out together, visiting in each other's home, or talking on the telephone? • every day • several times a week • about once a week • 2 or 3 times a month • about once a month • not at all Scoring transformed scale score = = (((SUM of response scores for each grouping) / (number of questions with valid information)) - 1) * (100 / ((maximum valid response score) - (minimum valid response score))) where: • The equation used for the transformed scale score in the original article was corrected in an erratum. • In the implementation I have made it so that there are no unanswered questions, while the original article allows for unanswered questions. Interpretation Based on the diagram in Table 2 (page 145), the following are approximations were made from the length of the lines for the indicated warning zones. Parameter Warning Zone Good basic activities of daily living 0 - 87 88 - 100 intermediate activities of daily living 0 - 77 78 - 100 mental health 0 - 70 71 - 100 work performance (see note) 0 - 78 79 - 100 social activities 0 - 78 79 - 100 quality of interactions 0 - 69 70 - 100 Functional Status Questionnaire file:///C|/algoritmo/Functional Status Questionnaire.htm (6 di 7) [30/04/2001 12.50.22] Note: Work performance not shown in table, so made same was social activities. If the person scores within the warning zone, then the patient has a problem that needs to be investigated more. References: Erratum. J Gen Intern Med. 1986; 1: 427. Jette AM, Davies AR, et al. The Functional Status Questionnaire: Reliability and validity when used in primary care. J Gen Intern Med. 1986; 1: 143-149. Functional Status Questionnaire file:///C|/algoritmo/Functional Status Questionnaire.htm (7 di 7) [30/04/2001 12.50.22] http://rangevoting.org/fun_status_question.pdf

16. † P values between groups after 1 year reflects the equality of changes from baseline to 1 year by mixed-model repeated-measures ANOVA contrasts (using baseline values and gender as covariates). The following contrast statements in the mixed-model repeated-measures ANOVA tested the hypotheses that (1) changes in the DIET group were different than in the CONTROL group, (2) changes in the EXER group were different than in the CONTROL group, and (3) changes in the DIET+EXER group were significantly different than in the DIET and/or EXER groups. The P values for the contrasts are not reported when the overall P values were not significant for the Group x Time interactions.

18. Results A total of 93 participants (87%) completed the study. In the intention-to-treat analysis, the score on the Physical Performance Test, in which higher scores indicate better physical status, increased more in the diet–exercise group than in the diet group or the exercise group (increases from baseline of 21% vs. 12% and 15%, respectively); the scores in all three of those groups increased more than the scores in the control group (in which the score increased by 1%) (P<0.001 for the between group differences). Moreover, the peak oxygen consumption improved more in the diet–exercise group than in the diet group or the exercise group (increases of 17% vs. 10% and 8%, respectively; P<0.001); the score on the Functional Status Questionnaire, in which higher scores indicate better physical function, increased more in the diet–exercise group than in the diet group (increase of 10% vs. 4%, P<0.001). Body weight decreased by 10% in the diet group and by 9% in the diet–exercise group, but did not decrease in the exercise group or the control group (P<0.001). Lean body mass and bone mineral density at the hip decreased less in the diet–exercise group than in the diet group (reductions of 3% and 1%, respectively, in the diet– exercise group vs. reductions of 5% and 3%, respectively, in the diet group; P<0.05 for both comparisons). Strength, balance, and gait improved consistently in the diet– exercise group (P<0.05 for all comparisons). Adverse events included a small number of exercise-associated musculoskeletal injuries.

19. Conclusions These findings suggest that a combination of weight loss and exercise provides greater improvement in physical function than either intervention alone. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00146107.)

20. Message/Comments 65歳以上の肥満対象者（平均BMIが37kg/m2くらい）には食事療法と運動療法を両方やるのがよい！ 体重の変化だけでは食事療法だろうが、機能的な面からは運動療法の併用がよさそう。

22. 成長ホルモン補充治療で エストロゲンを用いますか？

23. Thomas Jefferson University, Philadelphia ( J.L.R., K.K.); A.I. DuPont Hospital for Children, Wilmington, DE ( J.L.R., K.K.); Lilly Research Laboratories, Indianapolis (C.A.Q., D.C., J.J.C., G.B.C.); and the National Institute of Child Health and Human Development, Bethesda, MD (P.F., G.B.C.). N Engl J Med 2011;364:1230-42.

24. Background Short stature and ovarian failure are characteristic features of Turner’s syndrome. Although recombinant human growth hormone is commonly used to treat the short stature associated with this syndrome, a randomized, placebo-controlled trial is needed to document whether such treatment increases adult height. Furthermore, it is not known whether childhood estrogen replacement combined with growth hormone therapy provides additional benefit. We examined the independent and combined effects of growth hormone and early, ultra-low-dose estrogen on adult height in girls with Turner’s syndrome.

25. Methods In this double-blind, placebo-controlled trial, we randomly assigned 149 girls, 5.0 to 12.5 years of age, to four groups: double placebo (placebo injection plus childhood oral placebo, 39 patients), estrogen alone (placebo injection plus childhood oral lowdose estrogen, 40), growth hormone alone (growth hormone injection plus childhood oral placebo, 35), and growth hormone–estrogen (growth hormone injection plus childhood oral low-dose estrogen, 35). The dose of growth hormone was 0.1 mg per kilogram of body weight three times per week. The doses of ethinyl estradiol (or placebo) were adjusted for chronologic age and pubertal status. At the first visit after the age of 12.0 years, patients in all treatment groups received escalating doses of ethinyl estradiol. Growth hormone injections were terminated when adult height was reached.

26. Figure 1 (facing page). Study Design, Randomization, and Analysis Populations. The factorial study design is shown in Panel A. As shown in Panel B, a total of 149 patients were randomly assigned to four treatment groups: placebo injection plus oral placebo, placebo injection plus childhood oral low-dose estrogen, growth hormone injection plus childhood oral placebo, and growth hormone injection plus childhood oral low-dose estrogen. Patients were stratified according to their baseline height into upper, middle, and lower thirds of the Turner’s syndrome height standards for age3 and were randomly assigned to treatment in a 1:1:1:1 ratio with the use of a computer- generated randomization table. The intention-totreat population consisted of 137 girls whose height measurement was available 120 days or more after randomization; the adult-height population consisted of 91 girls whose height measurement was available after their height velocity was less than 1.5 cm per year.

28. Figure 2. Oral Doses of Ethinyl Estradiol (or Oral Placebo Equivalent) during the Childhood Phase, as Compared with Protocol-Specified Doses, and Average Daily Doses in the Intention-to-Treat Population, According to Age Group. Panel A shows the mean (±SD) dose of estrogen or placebo for each age group, as compared with the protocol-specified dose. During the childhood phase of the study (until the age of 12.0 years), patients were randomly assigned to receive either oral low-dose ethinyl estradiol or oral placebo. Starting at the first visit after 12.0 years of age, all the study groups received pubertal estrogen-replacement therapy in escalating doses. The protocol-specified doses of estradiol (or placebo during the childhood phase of the study) were 25 ng per kilogram of body weight per day from study entry until the age of 8.0 years and 50 ng per kilogram per day after the age of 8.0 years until 12.0 years of age. Pubertalphase doses were 100 ng per kilogram per day after the age of 12.0 to 14.0 years of age, 200 ng per kilogram per day after the age of 14.0 to 15.0 years of age, 400 ng per kilogram per day after the age of 15.0 to 16.0 years of age, and 800 ng per kilogram per day after the age of 16.0 years. To individualize the oral dosage regimen, a protocol-specified dose-reduction schedule was used, whereby the dose could be reduced by 50% at the discretion of the investigator for any of the following reasons: breast development reached Tanner stage 2 or higher before the age of 12.0 years (premature breast development), vaginal bleeding occurred before the age of 14.0 years (premature vaginal bleeding), bone age advanced by 2 years within 1 year, or bone age exceeded chronologic age up to the age of 14.0 years. If the dose was reduced, it was doubled at the next protocol- specified dose increase, but thereafter, the dose remained below the protocol-specified dose according to age. Panel B shows the mean ±SD total daily dose in micrograms according to age group.

31. Figure 3 (facing page). Effects of Treatment on Adult Height. In Panel A, the graph on the left shows the growth hormone treatment effect on adult height. The observed treatment effect (least-squares mean [±SE] difference in the change in standard-deviation score [SDS] from baseline to adult height, 0.78±0.13 [equivalent to 5.0 cm], on the basis of analysis of covariance [ANCOVA]) results from the combined effects of the gain in the height SDS observed in the groups treated with growth hormone and prevention of the height SDS loss observed in the placebo injection groups. The graph on the right shows the effects of the interaction of growth hormone and childhood estrogen therapy. The mean between-group difference (growth hormone plus estrogen vs. growth hormone plus placebo) of 0.32±0.17 in the SDS change (equivalent to 2.1 cm) represents the incremental effect of childhood low-dose estrogen in combination with growth hormone. The graph in Panel B shows the change in the height SDS from baseline for the adult-height population according to number of years in the study. Annual data points represent the ANCOVA least-squares mean (±SE) values, with baseline age and baseline height SDS as covariates. Changes above the horizontal line represent gains in the SDS for height; changes below the horizontal line represent decreases in the SDS for height. In the adult-height population, the groups treated with growth hormone had consistent increases in height for the first 5 years of the study, whereas the groups that received placebo injections had progressive declines in height SDS. Panel C shows the changes in the SDS for height from baseline to the last available height measurement for individual patients in the intention-to-treat population. Solid lines represent patients with adult-height measurements, and dashed lines patients without adult-height measurements. One patient in the estrogen-alone group who received surreptitious growth hormone during the study is not included. Large symbols represent the group means (±SD) at baseline and at the time of the last height measurement. Mean baseline SDS and end-point SDS in the four groups were as follows: double-placebo group, −2.59±0.96 and −3.08±0.95; estrogen-alone group, −3.01±0.74 and −3.40±0.74; growth hormone–alone group, −2.65±0.91 and −2.45±1.13; and growth hormone–estrogen group, −2.71±0.81 and −2.18±1.00 (P<0.001 for the comparison among the four groups). Individual gains in the height SDS for patients with adult-height measurements (i.e., change in height SDS from baseline to adult height >0) were observed for 15% of patients in the double-placebo group, 32% in the estrogen-alone group, 65% in the growth hormone–alone group, and 79% in the growth hormone– estrogen group (P<0.001 for the comparison among the four groups).

32. *Events are listed in descending order of frequency for the total patient group. Serious adverse events were defined according to regulatory criteria as any event that resulted in death, was life-threatening, required hospitalization or prolonged the hospital stay, resulted in permanent disability, resulted in a congenital anomaly in an offspring of a study patient, or was otherwise serious in the judgment of the investigator. Serious adverse events were reported for nine patients in the double-placebo group, seven patients in the estrogen-alone group, four patients in the growth hormone (GH)–alone group, and seven patients in the GH–estrogen group (for details, see Table 3 in the Supplementary Appendix). The majority of these events were hospitalizations for procedures or illnesses that are common in patients with Turner’s syndrome. Only one serious adverse event, dysfunctional uterine bleeding, was considered likely to have been related to exposure to the study drug, and it occurred in a patient in the estrogen-alone group. † Significance testing was performed with the use of Fisher’s exact test for the two GH groups combined as compared with the two placebo-injection groups combined and the two estrogen groups combined as compared with the two oral-placebo groups combined. All P values were nonsignificant when adjusted for false discovery rate (multiple-hypothesis testing). ‡ This category includes menstrual problems (e.g., irregular, intermittent, or heavy bleeding); vaginal discharge; and itching, discomfort, or redness in the genital area. § This category includes lipoma, mucocele, pilonidal swelling, “skin benign neoplasm,” “tumor recurrence” (for details, see the Supplementary Appendix), and unspecified growths, lumps, or nodules.

33. Results The mean standard-deviation scores for adult height, attained at an average age of 17.0±1.0 years, after an average study period of 7.2±2.5 years were −2.81±0.85, −3.39±0.74, −2.29±1.10, and −2.10±1.02 for the double-placebo, estrogen-alone, growth hormone–alone, and growth hormone–estrogen groups, respectively (P<0.001). The overall effect of growth hormone treatment (vs. placebo) on adult height was a 0.78±0.13 increase in the height standard-deviation score (5.0 cm) (P<0.001); adult height was greater in the growth hormone–estrogen group than in the growth hormone– alone group, by 0.32±0.17 standard-deviation score (2.1 cm) (P = 0.059), suggesting a modest synergy between childhood low-dose ethinyl estradiol and growth hormone.

34. Conclusions Our study shows that growth hormone treatment increases adult height in patients with Turner’s syndrome. In addition, the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement. (Funded by the National Institute of Child Health and Human Development and Eli Lilly; ClinicalTrials.gov number, NCT00001221.)

35. Message/Comments ターナー症候群の女児149人を対象に、成長ホルモンか低用量エストロゲン単独、または両剤併用の成人身長に対する有効性を無作為化二重盲検プラセボ対照試験で比較。プラセボ群に比べ、成長ホルモン単独群では成人身長のSDスコアが0.78±0.13高く、また成長ホルモン単独群に比べ併用群でSDスコアが0.32±0.17高かった。