今日の臨床サポート

続発性無月経

著者: 佐藤幸保 高松赤十字病院 産婦人科

監修: 小西郁生 独立行政法人国立病院機構 京都医療センター

著者校正/監修レビュー済:2021/04/07
参考ガイドライン:
  1. 日本産科婦人科学会:産婦人科診療ガイドライン 婦人科外来編2020
患者向け説明資料

概要・推奨   

  1. 無月経女性では、身長と体重から肥満あるいはやせの重症度を評価する(推奨度1)。
  1. 無月経を改善させるためには、肥満女性では減量、やせ女性では増量により標準体重に近づけることが強く推奨される(推奨度1)
  1. 月経異常を示す肥満女性では、まず食事・運動療法により体重を減少させることが推奨される(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
佐藤幸保 : 特に申告事項無し[2021年]
監修:小西郁生 : 未申告[2021年]

改訂のポイント:
  1. 産婦人科診療ガイドライン 婦人科外来編2020ガイドラインの主要項目を追加した。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 無月経とは周期的な月経が発来すべき年齢層の女性において月経がない状態のことをいい、妊娠・授乳期を除いた生殖年齢女性の3~4%にみられる。
  1. 18歳になっても初経をみない原発性無月経といったん発来した月経が3カ月以上停止する続発性無月経とに分けられる。
  1. 月経停止期間が39日以上3カ月未満のものは希発月経と呼ばれる。
  1. 内因性エストロゲン分泌のある第1度無月経(血中E2≧30 pg/mL)と内因性エストロゲン分泌のない第2度無月経(血中E2<30 pg/mL)に分けられる。
  1. 続発性無月経あるいは不正出血を主訴に来院した女性では必ず妊娠を除外することが重要である。
  1. 続発性無月経は障害部位により視床下部性、下垂体性、卵巣性、子宮性に分けられる。
  1. 視床下部性無月経:体重減少性無月経(食行動異常を伴う重症例は神経性やせ症(神経性無食欲症))、心因性無月経、運動性無月経、機能性あるいは薬剤性高プロラクチン血症、多嚢胞性卵巣症候群
  1. 下垂体性無月経:分娩後汎下垂体機能低下症(Sheehan症候群)、下垂体腫瘍(非機能性腺腫40%、プロラクチン産生性腺腫30%、成長ホルモン産生性腺腫20%、その他10%)、empty sella症候群
  1. 卵巣性無月経:早発卵巣機能不全、アンドロゲンあるいはエストロゲン産生性卵巣腫瘍
  1. 子宮性無月経:外傷性子宮腔癒着症(Asherman症候群)
問診・診察のポイント  
 
  1. 問診で下記事項の有無を確認する。

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文献 

著者: R S Legro, A R Kunselman, W C Dodson, A Dunaif
雑誌名: J Clin Endocrinol Metab. 1999 Jan;84(1):165-9. doi: 10.1210/jcem.84.1.5393.
Abstract/Text Women with polycystic ovary syndrome (PCOS) are insulin resistant, have insulin secretory defects, and are at high risk for glucose intolerance. We performed this study to determine the prevalence of glucose intolerance and parameters associated with risk for this in PCOS women. Two-hundred and fifty-four PCOS women, aged 14-44 yr, were prospectively evaluated at 2 centers, 1 urban and ethnically diverse (n = 110) and 1 rural and ethnically homogeneous (n = 144). The rural PCOS women were compared to 80 control women of similar weight, ethnicity, and age. A 75-g oral glucose challenge was administered after a 3-day 300-g carbohydrate diet and an overnight fast with 0 and 2 h blood samples for glucose levels. Diabetes was categorized according to WHO criteria. The prevalence of glucose intolerance was 31.1% impaired glucose intolerance (IGT) and 7.5% diabetes. In nonobese PCOS women (body mass index, <27 kg/m2), 10.3% IGT and 1.5% diabetes were found. The prevalence of glucose intolerance was significantly higher in PCOS vs. control women (chi2 = 7.0; P = 0.01; odds ratio = 2.76; 95% confidence interval = 1.23-6.57). Variables most associated with postchallenge glucose levels were fasting glucose levels (P < 0.0001), PCOS status (P = 0.002), waist/hip ratio (P = 0.01), and body mass index (P = 0.021). The American Diabetes Association criteria applied to fasting glucose significantly underdiagnosed diabetes compared to the WHO criteria (3.2% vs. 7.5%; chi2 = 4.7; P = 0.046; odds ratio = 2.48; 95% confidence interval = 1.01-6.69). We conclude that 1) PCOS women are at significantly increased risk for IGT and type 2 diabetes mellitus at all weights and at a young age; 2) these prevalence rates are similar in 2 different populations of PCOS women, suggesting that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women; and 3) the American Diabetes Association diabetes diagnostic criteria failed to detect a significant number of PCOS women with diabetes by postchallenge glucose values.

PMID 9920077  J Clin Endocrinol Metab. 1999 Jan;84(1):165-9. doi: 10.・・・
著者: Andrew S Rowland, Donna Day Baird, Stuart Long, Ganesa Wegienka, Siobán D Harlow, Michael Alavanja, Dale P Sandler
雑誌名: Epidemiology. 2002 Nov;13(6):668-74. doi: 10.1097/01.EDE.0000024628.42288.8F.
Abstract/Text BACKGROUND: Few studies have described medical and lifestyle factors associated with various menstrual cycle characteristics.
METHODS: We analyzed cross-sectional data collected from 3941 premenopausal women from Iowa or North Carolina participating in the Agricultural Health Study between 1994 and 1996. Eligible women were age 21-40, not taking oral contraceptives, and not currently pregnant or breast feeding. We examined four menstrual cycle patterns: short cycles (24 days or less), long cycles (36 days or more), irregular cycles, and intermenstrual bleeding.
RESULTS: Long and irregular cycles were less common with advancing age and more common with menarche after age 14, with depression, and with increasing body mass index. The adjusted odds of long cycles increased with increasing body mass index, reaching 5.4 (95% confidence interval [CI] = 2.1-13.7) among women with body mass indexes of 35 or higher compared with the reference category (body mass index of 22-23). Smoking was associated with short cycles. Long cycles, irregular cycles, and intermenstrual bleeding were associated with a history of infertility. Having long cycles was associated with a doubling in the adjusted odds of having a fetal loss among women who had been pregnant within the last 5 years (odds ratio = 2.3; 95% CI = 0.9-5.7).
CONCLUSIONS: Menstrual patterns are influenced by a number of host and environmental characteristics. Factors that perturb menstruation may increase a woman's risk of other reproductive disorders.

PMID 12410008  Epidemiology. 2002 Nov;13(6):668-74. doi: 10.1097/01.ED・・・
著者: N H Golden, M S Jacobson, J Schebendach, M V Solanto, S M Hertz, I R Shenker
雑誌名: Arch Pediatr Adolesc Med. 1997 Jan;151(1):16-21.
Abstract/Text OBJECTIVE: To determine factors associated with resumption of menses (ROM) in adolescents with anorexia nervosa.
DESIGN: Cohort study with 2-year follow-up.
SETTING: Tertiary care referral center.
PATIENTS: Consecutive sample of 100 adolescent girls with anorexia nervosa.
INTERVENTIONS: Body weight, percent body fat, and luteinizing hormone, follicle-stimulating hormone, and estradiol levels were measured at baseline and every 3 months until ROM (defined as 2 or more consecutive spontaneous menstrual cycles). Treatment consisted of a combination of medical, nutritional, and psychiatric intervention aimed at weight gain and resolution of psychological conflicts.
MAIN OUTCOME MEASURES: Body weight, body composition, and hormonal status at ROM.
RESULTS: Menses resumed at a mean (+/-SD) of 9.4 +/- 8.2 months after patients were initially seen and required a weight of 2.05 kg more than the weight at which menses were lost. Mean (+/-SD) percent of standard body weight at ROM was 91.6% +/- 9.1%, and 86% of patients resumed menses within 6 months of achieving this weight. At 1-year follow-up, 47 (68%) of 69 patients had resumed menses and 22 (32%) remained amenorrheic. No significant differences were seen in body weight, body mass index, or percent body fat at follow-up in those who resumed menses by 1 year compared with those who had not. Subjects who remained amenorrheic at 1 year had lower levels of luteinizing hormone (P < .001) and follicle-stimulating hormone (P < .05) at baseline and lower levels of luteinizing hormone (P < .01) and estradiol (P < .001) at follow-up. At follow-up, a serum estradiol level of more than 110 pmol/L (30 pg/mL) was associated with ROM (relative risk, 4.6; 95% confidence interval, 1.9-11.2).
CONCLUSIONS: A weight approximately 90% of standard body weight was the average weight at which ROM occurred and is a reasonable treatment goal weight, because 86% of patients who achieved this goal resumed menses within 6 months. Resumption of menses required restoration of hypothalamic-pituitary-ovarian function, which did not depend on the amount of body fat. Serum estradiol levels at follow-up best assess ROM.

PMID 9006523  Arch Pediatr Adolesc Med. 1997 Jan;151(1):16-21.
著者: Y Nakamura, Y Yoshimura, T Oda, E Katayama, K Kamei, K Tanabe, R Iizuka
雑誌名: Clin Endocrinol (Oxf). 1985 Dec;23(6):643-51.
Abstract/Text Two hundred and forty-three patients with amenorrhoea associated with weight loss were studied. At the onset of amenorrhoea, regardless of percentage weight loss, basal levels of LH were low and LH responses to LHRH were impaired. However, both basal and stimulated levels of FSH were comparable to normal. With resumption of menstruation, the basal and stimulated levels of LH were found to rise to normal, while FSH responses continued to exceed normal. However, 16.6% of 66 unimproved cases had normal responses but remained amenorrhoeic. Furthermore, amenorrhoea persisted in 71% of 31 patients with complete recovery of body weight. No significant correlation was noted between percentage weight loss and responsiveness to LHRH, nor between recovery of body weight and resumption of menstruation. Return to normal weight is desirable for resumption of normal cyclic menstruation and hypothalamic-pituitary function, but is not always effective.

PMID 3938351  Clin Endocrinol (Oxf). 1985 Dec;23(6):643-51.
著者: S Grinspoon, K Miller, C Coyle, J Krempin, C Armstrong, S Pitts, D Herzog, A Klibanski
雑誌名: J Clin Endocrinol Metab. 1999 Jun;84(6):2049-55.
Abstract/Text Reduced bone density is observed in over half of women with anorexia nervosa (AN), in whom the risk of fracture is significantly increased even at a young age. It is unknown to what extent low bone density in AN differs from other conditions of premenopausal osteoporosis and is related to estrogen deficiency and/or other factors, such as nutritional status. We therefore investigated bone loss in nutritionally replete and nutritionally deplete amenorrheic women by comparing patients with AN (n = 30) to age-matched subjects with hypothalamic amenorrhea (HA; n = 19) in whom duration of amenorrhea, prior estrogen use, and age of menarche were comparable. Healthy, age-matched, eumenorrheic women were studied as a control group (NL; n = 30). Weight and nutritionally dependent factors including (body mass index, 20.7 +/- 0.3 vs. 16.7 +/- 0.3 kg/m2; P < 0.0001), insulin-like growth factor I (270 +/- 18 vs. 203 +/- 17 ng/mL; P < 0.01), percent body fat (26% vs. 19%; P < 0.0001), and lean body mass (38.7 +/- 1.1 vs. 34.3 +/- 0.8, P < 0.01) were significantly different between the HA and AN groups, respectively. The bone densities of the anterior-posterior (AP) spine, total hip, and total body measured by dual energy x-ray absortiometry were reduced in both amenorrheic groups compared to those in control subjects, but were significantly lower in women with AN than in those with HA. The t scores for AP spine and hip were -1.80 +/- 0.15 (AN), -0.80 +/- 0.22 (HA), and 0.28 +/- 0.19 SD (NL) for the AP spine and -1.62 +/- 0.17 (AN), -0.51 +/- 0.21 (HA), and 0.25 +/- 0.16 (NL) for the total hip, respectively (P < 0.01 for all comparisons). Among the amenorrheic subjects, duration of amenorrhea, age of menarche, and N-telopeptide were inversely correlated with bone density at all sites, whereas body mass index, insulin-like growth factor I, lean body mass, and fat intake were positively correlated with bone density at all sites measured. In multivariate regression analyses, bone density was most significantly related to lean body mass (P = 0.05 and P = 0.03 for the spine and hip, respectively), but not to the duration of amenorrhea or other indexes of estrogen status among patients with AN. In contrast, bone density of the lumbar spine was significantly related to weight and duration of amenorrhea among patients with HA. These data demonstrate that the severity of osteopenia in AN is greater than that in patients with HA and is critically dependent upon nutritional factors in addition to the degree or duration of estrogen deficiency itself. Lean body mass, independent of the duration or severity of estrogen deficiency, is an important predictor of bone loss among women with AN.

PMID 10372709  J Clin Endocrinol Metab. 1999 Jun;84(6):2049-55.
著者: J D Vescovi, S A Jamal, M J De Souza
雑誌名: Osteoporos Int. 2008 Apr;19(4):465-78. doi: 10.1007/s00198-007-0518-6. Epub 2008 Jan 8.
Abstract/Text UNLABELLED: Functional hypothalamic amenorrhea (FHA) impairs the attainment of peak bone mass and as such can increase the risk of fractures later in life. To document available treatment strategies, we conducted a systematic review of the literature. We report that hormonal therapies have limited effectiveness in increasing bone mass, whereas increased caloric intake resulting in weight gain and/or resumption of menses is an essential strategy for restoring bone mass in women with FHA.
INTRODUCTION: Women with functional hypothalamic amenorrhea (FHA) may not achieve peak bone mass (PBM), which increases the risk of stress fractures, and may increase the risk of osteoporotic fractures in later life.
METHODS: To identify effective treatment strategies for women with FHA, we conducted a systematic review of the literature. We included randomized controlled trials (RCTs), cross-sectional studies, and case studies that reported on the effects of pharmacological and non-pharmacological interventions on bone mineral density (BMD) or bone turnover in women with FHA.
RESULTS: Most published studies (n=26) were designed to treat the hormonal abnormalities observed in women with FHA (such as low estrogen, leptin, insulin-like growth factor-1, and DHEA); however none of these treatments demonstrated consistent improvements in BMD. Therapies containing an estrogen given for 8-24 months resulted in variable improvements (1.0-19.0%) in BMD, but failed to restore bone mass to that of age-matched controls. Three studies reported on the use of bisphosphonates (3-12 months) in anorexic women, which appear to have limited effectiveness to improve BMD compared to nutritional treatments. Another three investigations showed no improvements in BMD after androgen therapy (DHEA and testosterone) in anorexic women. In contrast, reports (n=9) describing an increase in caloric intake that results in weight gain and/or the resumption of menses reported a 1.1-16.9% increase in BMD concomitant with an improvement in bone formation and reduction in bone resorption markers.
CONCLUSIONS: Our literature review indicates that the most successful, and indeed essential strategy for improving BMD in women with FHA is to increase caloric intake such that body mass is increased and there is a resumption of menses. Further long-term studies to determine the persistence of this effect and to determine the effects of this and other strategies on fracture risk are needed.

PMID 18180975  Osteoporos Int. 2008 Apr;19(4):465-78. doi: 10.1007/s00・・・
著者: Catherine M Gordon, Estherann Grace, S Jean Emans, Henry A Feldman, Elizabeth Goodman, Kelly A Becker, Clifford J Rosen, Caren M Gundberg, Meryl S LeBoff
雑誌名: J Clin Endocrinol Metab. 2002 Nov;87(11):4935-41.
Abstract/Text Young women with anorexia nervosa (AN) have subnormal levels of dehydroepiandrosterone (DHEA) and estrogen that may be mechanistically linked to the bone loss seen in this disease. The purpose of this study was to compare the effects of a 1-yr course of oral DHEA treatment vs. conventional hormonal replacement therapy (HRT) in young women with AN. Sixty-one young women were randomly assigned to receive oral DHEA (50 mg/d) or HRT (20 micro g ethinyl estradiol/0.1 mg levonorgestrel). Anthropometric, nutrition, and exercise data were acquired every 3 months, and bone mineral density (BMD) and body composition were measured by dual energy x-ray absorptiometry (DXA) every 6 months over 1 yr. Serum samples were obtained for measurements of hormones, proresorptive cytokines, and bone formation markers, and urine was collected for determinations of bone resorption markers at each visit. In initial analyses, total hip BMD increased significantly and similarly (+1.7%) in both groups. Hip BMD increases were positively correlated with increases in IGF-I (r = 0.44; P = 0.030) and the bone formation marker, bone-specific alkaline phosphatase increased significantly only in the DHEA treatment group (P = 0.003). However, both groups gained significant amounts of weight over the year of therapy, and after controlling for weight gain, no treatment effect was detectable. There was no significant change in lumbar BMD in either group. Both bone formation markers, bone-specific alkaline phosphatase and osteocalcin, increased transiently at 6-9 months in those subjects receiving DHEA compared with the estrogen-treated group (P < 0.05). Both DHEA and HRT significantly reduced levels of the bone resorption markers, urinary N-telopeptides (P < 0.05). There was a positive correlation between changes in IGF-I and changes in weight, body fat determined by DXA, and estradiol for both groups. In addition, patients receiving DHEA exhibited improvement on three validated psychological instruments (Eating Attitudes Test, Anorexia Nervosa Subtest, and Spielberger Anxiety Inventory). Both DHEA and HRT had similar effects on hip and spinal BMD. Over the year of treatment, maintenance of both hip and spinal BMD was seen, but there was no significant increase after accounting for weight gain. Compared with HRT, DHEA appeared to have anabolic effects, evidenced by the positive correlation between increases in hip DXA measurements and IGF-I and significant increases in bone formation markers. Both therapies significantly decreased bone resorption. Replicating results from studies of the elderly, DHEA resulted in improvements in specific psychological parameters in these young women.

PMID 12414853  J Clin Endocrinol Metab. 2002 Nov;87(11):4935-41.
著者: Gary R Strokosch, Andrew J Friedman, Shu-Chen Wu, Marc Kamin
雑誌名: J Adolesc Health. 2006 Dec;39(6):819-27. doi: 10.1016/j.jadohealth.2006.09.010.
Abstract/Text PURPOSE: To evaluate the effect of an oral contraceptive (OC) on bone mineral density (BMD) in adolescent females with anorexia nervosa (AN) or eating disorder not otherwise specified (EDNOS).
METHODS: Females 11-17 years of age with AN or EDNOS entered the study. Subjects were randomized equally to treatment with a triphasic OC containing norgestimate (NGM) 180-250 microg and ethinyl estradiol (EE) 35 microg or placebo for 13 28-day cycles. Dual energy x-ray absorptiometry scans (DXA) of the lumbosacral spine (LS) and hip were obtained at baseline and after 6 and 13 cycles.
RESULTS: Demographic characteristics of the 112 subjects (NGM/EE 53; Placebo 59) who received study drug and had at least one on-treatment DXA were similar between groups for age (mean: 15 years in each group) and body mass index (mean: NGM/EE 17.9 kg/m2; Placebo 17.6 kg/m2). At the end of Cycle 6, there was a significant increase in the mean LS BMD in the NGM/EE group compared with placebo (.020 g/cm2 vs. .008 g/cm2; p = .021); however, at the end of Cycle 13 the mean increase in LS BMD in the NGM/EE group compared with placebo was no longer significant (.026 g/cm2 vs. .019 g/cm2, p = .244). There was no significant difference in change in hip BMD between groups. The incidence of adverse events was similar between groups.
CONCLUSIONS: In a group of adolescent females with AN or EDNOS, treatment with a triphasic OC for 13 cycles did not have a statistically significant effect on LS or hip BMD.

PMID 17116511  J Adolesc Health. 2006 Dec;39(6):819-27. doi: 10.1016/j・・・
著者: Ombretta Viapiana, Davide Gatti, Riccardo Dalle Grave, Tiziana Todesco, Maurizio Rossini, Vania Braga, Luca Idolazzi, Elena Fracassi, Silvano Adami
雑誌名: Bone. 2007 Apr;40(4):1073-7. doi: 10.1016/j.bone.2006.11.015. Epub 2007 Jan 19.
Abstract/Text Anorexia nervosa (AN) is a life-threatening eating disorder characterized by an inability to maintain a normal body weight and amenorrhoea, often associated with osteoporosis and increased risk of fragility fractures. Bone metabolism, including markers of bone turnover (serum total alkaline phosphatase, bone alkaline phosphatase [bone AP], osteocalcin [OC] and type I collagen C-telopeptide breakdown products [sCTX]) and bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) at the spine and at the hip, were evaluated in 55 consecutive women with AN undergoing a 3-month intensive nutritional rehabilitation program. The control group was constituted of 25 healthy young medical students. In AN patients body weight increased during the 3-month nutritional program from 37.8+/-5.1 (mean+/-SD) to 51.5+/-4.5 kg. The corresponding BMI rose to values >17.5 kg/m(2) in all patients. Mean BMD significantly rose by 2.6+/-3.5% and 1.1+/-3.6% at the hip and at the spine, respectively. The markers of bone formation, serum bone AP and osteocalcin, significantly rose by two-folds, while sCTX decreased by 16%. The changes in hip BMD were positively related (p<0.005) to changes in body weight and in bone AP (p<0.02) while the changes in spine BMD were positively related to changes in serum osteocalcin (p<0.05). In the 25 patients who attended the 12-month posttreatment control, mean body weight significantly decreased by 3.6+/-6.0 kg and this was not associated with any significant change in BMD values. In the patients in whom BMI fell again below 17.5 kg/m(2) hip BMD values decreased significantly. On the contrary, in the patients who maintained BMI >17.5 kg/m(2), BMD values continued to rise up to values over the 15-month observation of 4.8+/-6.2 and 7.1+/-12.1 at the spine and hip, respectively. In conclusion, we have demonstrated that substantial gains in weight in women with chronic AN are associated with remarkable increases in BMD at both the hip and the spine. If weight is maintained, the overall improvement approach 1 SD within 1 year. The changes in both weight and BMD are correlated with improvements in bone formation markers and diminutions in a marker of bone resorption.

PMID 17240212  Bone. 2007 Apr;40(4):1073-7. doi: 10.1016/j.bone.2006.1・・・
著者: Jennifer Dominguez, Linnea Goodman, Surupa Sen Gupta, Laurel Mayer, Sarah Fischer Etu, B Timothy Walsh, Jack Wang, Richard Pierson, Michelle P Warren
雑誌名: Am J Clin Nutr. 2007 Jul;86(1):92-9.
Abstract/Text BACKGROUND: Recovery from osteoporosis in anorexia nervosa (AN) is uncertain.
OBJECTIVE: The purpose of this study was to understand the changes in bone mineral density (BMD) in women with AN and the mechanisms of recovery from osteopenia.
DESIGN: We studied BMD and markers of bone formation and resorption, osteocalcin and N-telopeptide (NTX), in patients with AN (n=28) who were following a behavioral weight-gain protocol.
RESULTS: Anorexic patients experienced significant percentage increases in BMD (4.38 +/- 7.48% for spine; 3.77 +/- 8.8% for hip; P<0.05 for both) from admission until recovery of 90% ideal body weight, achieved over 2.2 mo. NTX concentrations were higher in patients with AN at admission than in healthy control subjects (n=11; 69.0 +/- 31.09 and 48.3 +/- 14.38 nmol/mmol creatinine, respectively; P<0.05) and in reference control subjects (n=30; 69.0 +/- 31.09 and 37.0+/-6.00 nmol/mmol creatinine, respectively; P<0.001). In weight-recovered subjects with AN, osteocalcin increased (from 8.0 +/- 3.05 to 11.2 +/- 6.54 ng/mL; P<0.05), whereas NTX remained elevated (from 69.0 +/- 31.09 to 66.7 +/- 45.5 nmol/mmol creatinine; NS). A decrease in NTX (from 70.7 +/- 40.84 to 45.9 +/- 22.72 nmol/mmol creatinine; NS) occurred only in the subgroup of subjects who regained menses with weight recovery.
CONCLUSIONS: Nutritional rehabilitation induces a powerful anabolic effect on bone. However, a fall of NTX and a shift from the dominant resorptive state, which we postulate involves full recovery, may involve a hormonal mechanism and require a return of menses. Nutritional rehabilitation appears to be critical to bone recovery and may explain the ineffectiveness of estrogen treatment alone on BMD in the cachectic state.

PMID 17616767  Am J Clin Nutr. 2007 Jul;86(1):92-9.
著者: A M Clark, B Thornley, L Tomlinson, C Galletley, R J Norman
雑誌名: Hum Reprod. 1998 Jun;13(6):1502-5.
Abstract/Text Obesity affects ovulation, response to fertility treatment, pregnancy rates and outcome. In this prospective study, a weight loss programme was assessed to determine whether it could help obese infertile women, irrespective of their infertility diagnosis, to achieve a viable pregnancy, ideally without further medical intervention. The subjects underwent a weekly programme aimed at lifestyle changes in relation to exercise and diet for 6 months; those that did not complete the 6 months were treated as a comparison group. Women in the study lost an average of 10.2 kg/m2, with 60 of the 67 anovulatory subjects resuming spontaneous ovulation, 52 achieving a pregnancy (18 spontaneously) and 45 a live birth. The miscarriage rate was 18%, compared to 75% for the same women prior to the programme. Psychometric measurements also improved. None of these changes occurred in the comparison group. The cost savings of the programme were considerable. Prior to the programme, the 67 women had had treatment costing a total of A$550,000 for two live births, a cost of A$275,000 per baby. After the programme, the same women had treatment costing a total of A$210,000 for 45 babies, a cost of A$4600 per baby. Thus weight loss should be considered as a first option for women who are infertile and overweight.

PMID 9688382  Hum Reprod. 1998 Jun;13(6):1502-5.
著者: B Modan, E Ron, L Lerner-Geva, T Blumstein, J Menczer, J Rabinovici, G Oelsner, L Freedman, S Mashiach, B Lunenfeld
雑誌名: Am J Epidemiol. 1998 Jun 1;147(11):1038-42.
Abstract/Text Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval (CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded.

PMID 9620047  Am J Epidemiol. 1998 Jun 1;147(11):1038-42.
著者: Julie Brown, Cindy Farquhar, James Beck, Clare Boothroyd, Edward Hughes
雑誌名: Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. doi: 10.1002/14651858.CD002249.pub4. Epub 2009 Oct 7.
Abstract/Text BACKGROUND: Subfertility due to anovulation is a common problem in women. First-line oral treatment is with anti-oestrogens, for example clomiphene citrate, but resistance (failure to ovulate) may be apparent with clomiphene. Alternative and adjunctive treatments have been developed such as tamoxifen, dexamethasone, and bromocriptine.
OBJECTIVES: To determine the relative effectiveness of anti-oestrogen agents alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome (PCOS).
SEARCH STRATEGY: A search was conducted using the Cochrane Menstrual Disorders and Subfertility Group Trials Register (May 2009), CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to May 2009), and EMBASE (1980 to May 2009) for identification of relevant randomised controlled trials (RCTs). The United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs were searched.
SELECTION CRITERIA: RCTs comparing oral anti-oestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility were considered. Insulin sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility were excluded.
DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were done independently by two review authors. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, overstimulation, ovarian hyperstimulation syndrome, and women reported adverse effects.
MAIN RESULTS: This is a substantive update of a previous review. Fifteen RCTs were included. One trial reported live birth. Miscarriage, multiple pregnancy rates and adverse events were poorly reported.Clomiphene was effective in increasing pregnancy rate compared to placebo (OR 5.8, 95% CI 1.6 to 21.5) as was clomiphene plus dexamethasone treatment (OR 9.46, 95% CI 5.1 to 17.7) compared to clomiphene alone. No evidence of a difference in effect was found between clomiphene versus tamoxifen or clomiphene in conjunction with human chorionic gonadotrophin (hCG) versus clomiphene alone.The remaining results had only one study in each comparison. A significant improvement in the pregnancy rate was reported for clomiphene plus combined oral contraceptives versus clomiphene alone. No evidence of a difference in effect on pregnancy rate was found with any of the other comparisons.
AUTHORS' CONCLUSIONS: This review shows evidence supporting the effectiveness of clomiphene citrate and clomiphene in combination with dexamethasone for pregnancy rate only. There is limited evidence on the effects of these drugs on outcomes such as miscarriage. Evidence in favour of these interventions is flawed due to the lack of evidence on live births.

PMID 19821295  Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. do・・・
著者: Thomas I Siebert, Thinus F Kruger, Daniel W Steyn, Saleema Nosarka
雑誌名: Fertil Steril. 2006 Nov;86(5):1432-7. doi: 10.1016/j.fertnstert.2006.06.014. Epub 2006 Sep 27.
Abstract/Text OBJECTIVE: The aim of this literature search is to establish if metformin is efficacious when given to clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) patients.
DESIGN: Medline database was searched from 1 January 1980 to 1 January 2005. Inclusion criteria were prospective randomized control trials where metformin was randomized either with placebo or CC to induce ovulation in the CC-resistant patient.
RESULT(S): Group 1: Four trials were prospective double-blind placebo controlled. When the data of the four trials were pooled, the overall effect of the addition of metformin in the CC patient was P=.0006 with a 95% confidence interval (CI) of odds ratio (OR) 1.81-8.84. Group 2: In two trials the randomization was only prospective. When the data of these two trials were pooled, the overall effect of the addition of metformin in the CC-resistant patient was P<.0001 with a 95% CI of OR 6.24-70.27. Groups 1 and 2: The combined data show an overall effect of P<.0001 with a 95% CI of OR 3.59-12.96.
CONCLUSION(S): The addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction.

PMID 17007847  Fertil Steril. 2006 Nov;86(5):1432-7. doi: 10.1016/j.fe・・・
著者: D C Daly, C A Walters, C E Soto-Albors, N Tohan, D H Riddick
雑誌名: Fertil Steril. 1984 Jun;41(6):844-8.
Abstract/Text Improved understanding of follicular dynamics has led to a reevaluation of suppression of adrenal androgens in ovulation induction. To test whether adrenal suppression during clomiphene citrate (CC) therapy would improve ovulation/pregnancy rates, 64 anovulatory patients who had not previously received CC were randomly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone (CC + DEX). Patients were then screened for dehydroepiandrosterone sulfate (DHEA-S) (normal range, 80 to 320 micrograms/dl), prolactin, testosterone, and semen analysis of the partner. Nine patients discontinued participation prior to completing the first treatment cycle, and ten patients were found to have either elevated prolactin (4), severe male factors (3), or tubal disease (3) and were discontinued. CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred. Once the patient was ovulatory on therapy, a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed. If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC, patients were crossed to the other arm of the treatment protocol. The results revealed a significantly higher rate of ovulation (P less than 0.01) and conception (P less than 0.05) in the CC + DEX-treated group. When correlated with DHEA-S levels, this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl (P less than 0.05).

PMID 6233176  Fertil Steril. 1984 Jun;41(6):844-8.
著者: Mohammad Ebrahim Parsanezhad, Saaid Alborzi, Shahdokht Motazedian, Gholamhossein Omrani
雑誌名: Fertil Steril. 2002 Nov;78(5):1001-4.
Abstract/Text OBJECTIVE: To evaluate the effects of short-course administration of dexamethasone (DEX) combined with clomiphene citrate (CC) in CC-resistant patients with polycystic ovary syndrome (PCOS) and normal DHEAS levels.
DESIGN: Prospective, double-blind, placebo-controlled, randomized study.
SETTING: Referral university hospitals.
PATIENT(S): Two hundred thirty women with PCOS and normal DHEAS who failed to ovulate after a routine protocol of CC.
INTERVENTION(S): The treatment group received 200 mg of CC from day 5 to day 9 and 2 mg of DEX from day 5 to day 14 of the menstrual cycle. The control group received the same protocol of CC combined with placebo.
MAIN OUTCOME MEASURE(S): Follicular development, hormonal status, ovulation rate, pregnancy rate.
RESULT(S): Mean follicular diameters were 18.4124 +/- 2.4314 mm and 13.8585 +/- 2.0722 mm for the treatment and control groups, respectively. Eighty-eight percent of the treatment group and 20% of the control group had evidence of ovulation. The difference in the cumulative pregnancy rate in the treatment and control groups was statistically significant.
CONCLUSION(S): Hormonal levels, follicular development, and cumulative pregnancy rates improved with the addition of DEX to CC in CC-resistant patients with PCOS and normal DHEAS. This regimen is recommended before any gonadotropin therapy or surgical intervention.

PMID 12413984  Fertil Steril. 2002 Nov;78(5):1001-4.
著者: Aboubakr Elnashar, Emad Abdelmageed, Mahmod Fayed, Magdy Sharaf
雑誌名: Hum Reprod. 2006 Jul;21(7):1805-8. doi: 10.1093/humrep/del053. Epub 2006 Mar 16.
Abstract/Text BACKGROUND: The aim of this work was to evaluate the efficacy of adding dexamethazone (DEX) (high dose, short course) to clomiphene citrate (CC) in CC-resistant polycystic ovary syndrome (PCOS) with normal dehydroepiandrosterone sulphate (DHEAS) in induction of ovulation.
METHODS: Eighty infertile women with CC-resistant PCOS were randomly assigned into two groups. Group I: Clomiphene citrate 100 mg/day was given from day 3 to day 7 of the cycle and DEX 2 mg/day from day 3 to day 12 of the cycle. Group II: Same protocol of CC combined with placebo (folic acid tablets) was given from day 3 to day 12 of the cycle. The main outcome was ovulation. Secondary measures included number of follicles >18 mm endometrial thickness and pregnancy rate. Ovarian follicular response was monitored by transvaginal ultrasound. HCG 10,000 U was given when at least one follicle measured 18 mm, and timed intercourse was advised.
RESULTS: There were no statistically significant differences between groups as regards age, duration of infertility, BMI, waist-hip ratio (WHR), menstrual pattern, hirsutism, serum DHEAS or day of HCG administration. The mean number of follicles>18 mm at the time of HCG administration and the mean endometrial thickness were significantly higher in the DEX group than in the placebo group (P<0.05). Similarly, there were significantly higher rates of ovulation (75 versus 15%) (P<0.001) and pregnancy (40 versus 5%) (P<0.05) in the DEX group. Dexamethazone was very well tolerated as no patients complained of any side effect. There was a significant difference between the responders and non-responders in the presence of oligomenorrhea, amenorrhea or hirsutism.
CONCLUSION: Induction of ovulation by adding DEX (high dose, short course) to CC in CC-resistant PCOS with normal DHEAS is associated with no adverse anti-estrogenic effect on the endometrium and higher ovulation and pregnancy rates in a significant number of patients. Induction with DEX appears to be independent on age, period of infertility, BMI or WHR.

PMID 16543255  Hum Reprod. 2006 Jul;21(7):1805-8. doi: 10.1093/humrep/・・・

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