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 浅見 奈々子 Asami ID: 301922
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Slide1
Journal Club
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浅見 奈々子Asami, Nanako
2013年6月27日 8:30-8:55８階 医局
Romualdi D, De Cicco S, Gagliano D, Busacca M, Campagna G, Lanzone A, Guido M.How Metformin Acts in PCOS Pregnant Women: Insights into insulin secretion and peripheral action at each trimester of gestation.Diabetes Care. 2013 Jun;36(6):1477-82. doi: 10.2337/dc12-2071. Epub 2013 Jan 11.Slide2
TABLE 1.
Diagnostic criteria for the diagnosis of PCOS
NICHD criteria (9 )
Ultrasonographic criteria (10 )Rotterdam criteria (11 12 )
1) Oligoovulation1) Ultrasonographic polycystic ovaries
1) Oligo- and/or anovulation2) Clinical and/or biochemical hyperandrogenism2) Clinical and/or biochemical hyperandrogenism2) Clinical and/or biochemical hyperandrogenism
3) Polycystic ovaries
Exclusion of secondary etiologies such as congenital adrenal hyperplasia, androgen-secreting tumors, and hyperprolactinemia.
Criteria 1 and 2 must be present for the diagnosis of PCOS according to NICHD and ultrasonographic criteria. The Rotterdam criteria require the presence of two of the three individual criteria. All definitions require exclusion of secondary etiologies.
Endocrine Review 2005: 26(2);
251-282Slide3
TABLE 2.
Studies of familial
aggregation
in functional hyperandrogenism and PCOS Authors1Phenotype in first-degree relatives
Suggested inheritanceCooper et al. (25 )
Women: oligomenorrhea and PCOAutosomal dominant with variable penetranceMen: increased hairinessWilroy
et al
. (26 ), Givens (27 28 )
Women: hyperandrogenism and metabolic disorders
X-linked
Men: oligospermia and LH hypersecretion
Ferriman and Purdie (29 )
Women: infertility, oligomenorrhea, hirsutism
Not determined
Hague
et al
. (30 )
Women: PCO
Not determined
Lunde
et al
. (31 )
Women: hyperandrogenic symptoms
Autosomal dominant
Men: premature baldness and increased hairiness
Carey
et al
. (20 )
Women: PCO
Monogenic
Men: premature baldness
Jahanfar
et al
. (40 41 )
Twin studies: fasting insulin,
androstanediol
glucuronide
, lipid profile
Polygenic
Norman
et al
. (36 )
Men: premature baldness, hypertriglyceridemia, and hyperinsulinemia
Not determined
Legro
et al
. (33 34 39 )
Women: PCOS (NICHD), hyperandrogenemia, insulin resistance
Monogenic
Men: increased DHEA-S
Azziz
et al
. (14 ), Kahsar-Miller
et al
. (32 )
Women: PCOS (NICHD)
Not determined
Mao
et al
. (37 )
Men: premature baldness
Not determined
Yildiz
et al
. (35 )
Women: PCOS (NICHD) and insulin resistance
Not determined
Men: insulin resistance
Endocrine Review 2005: 26(2);
251-282Slide4
Endocrine Review 2005: 26(2);
251-282Slide5
Endocrine Review 2005: 26(2);
251-282Slide6
Figure 1. Pathophysiological Characteristics of the Polycystic Ovary Syndrome (PCOS
).
Insulin resistance results in a compensatory hyperinsulinemia, which stimulates ovarian androgen production in an ovary genetically predisposed to PCOS. Arrest of follicular development (red “X”) and anovulation could be caused by the abnormal secretion of gonadotropins such as follicle-stimulating hormone (FSH) or luteinizing hormone (LH) (perhaps induced by
hyperinsulinemia), intraovarian androgen excess, direct effects of insulin, or a combination of these factors. Insulin resistance, in concert with genetic factors, may also lead to hyperglycemia and an adverse profile of cardiovascular risk factors. PAI-1 denotes plasminogen-activator inhibitor type 1. N Engl J Med 2008;358:47-54.Slide7
Recommendations The obesity, family history of diabetes, and polycystic ovary syndrome of the patient in the vignette put her at high risk for type 2 diabetes. In addition to obesity, she has several signs of insulin resistance, including a low serum high-density lipoprotein cholesterol level and a high triglyceride level, and her data fulfill the Adult Treatment Panel III criteria of the National Cholesterol Education Program for the metabolic
syndrome. Although her glucose tolerance is currently normal, treatment with metformin is reasonable
, and a weight-loss diet and exercise are also encouraged. Although fertility is not an immediate concern, it is likely that metformin will increase the frequency of ovulation
, thereby improving menstrual cyclicity. Once menstrual cyclicity has improved, I would determine whether ovulation is occurring by measuring the serum progesterone level during the presumed luteal phase. Since the patient does not tolerate oral contraceptives, a barrier method of contraception could be recommended. When and if the patient desires pregnancy, fertility may be improved if the frequency of ovulation increases during metformin therapy. If not, the patient should be evaluated for causes of infertility unrelated to anovulation, and the addition of clomiphene to her regimen should be discussed. I would see the patient every 3 months during the first year, not only to monitor the efficacy of metformin but also to reinforce lifestyle changes to reduce weight and increase physical activity. Thereafter, she could be seen every 6 to 12 months, depending on the response to treatment. Given that she is at high risk for diabetes, I would repeat the oral glucose-tolerance test every 2 to 3 years, even if metformin therapy is used. N Engl J Med 2008;358:47-54.Slide8
Diabetes Care 36:1477–1482, 2013
the
1
Department of Obstetrics and Gynaecology, Università Cattolica del Sacro Cuore, Rome, Italy; and the 2OASI Institute for Research, Troina, Italy. Slide9
OBJECTIVEMetformin
has been reported to reduce the risk of gestational diabetes (GD) in women with polycystic ovarian syndrome (PCOS). However, little is known about the mechanisms of action of this drug during pregnancy. In the attempt to fill this gap, we performed a prospective longitudinal study providing a detailed examination of glucose and insulin metabolism in pregnant women with PCOS undergoing metformin therapy. Slide10
RESEARCH DESIGN ANDMETHODS
We enrolled 60 women with PCOS who conceived while undergoing metformin treatment. An oral glucose tolerance test and a euglycemichyperinsulinemic clamp were performed at each trimester of gestation in 47 ongoing pregnancies. Slide11
膵臓
Hyperglycemic clamp
膵臓
の
インスリン分泌
を評価する。
Euglycemic
hyperinsulinemic
clamp
末梢組織（主に筋肉）
の
インスリン感受性
を評価する。
(
インスリンクランプ
)
●
Pancreatic clamp
肝臓
の
インスリン感受性
/
抵抗性
を評価する
筋肉
グルコースクランプ
Steady state
(Direct)
肝臓Slide12
筋肉
0
0
50
50
100
100
150
150
200
200
250
250
10.0
10.0
7.5
7.5
5.0
5.0
2.5
2.5
0
0
糖注入量
糖注入量
(mg/kg per min)
(mg/kg per min)
凸
凸
0
0
20
20
40
40
60
60
80
80
100
100
0
0
40
40
80
80
120
120
(
m
U/ml)
(
m
U/ml)
インスリン
(
動脈側）
（一定にするように注入
)
インスリンクランプ法
0
0
40
40
80
80
120
120
血糖
(
動脈側
)
(mg/dl)
分
分
グルコースクランプ法の一つ
インスリン注入
アルゴリズム
内因性インスリン分泌は無視できるレベルとなるSlide13Slide14Slide15Slide16
RESULTSTwenty-two
of the study subjects had development of GD despite the treatment. At baseline, insulin sensitivity was comparable between women who
had development of GD and women who did not. A progressive decline in this parameter occurred in all subjects, independently of the trimester of GD diagnosis. Insulin secretion was significantly higher during the first trimester in patients with an early failure of metformin treatment. Women with third trimester GD and women with no GD exhibited a significant increase in insulin output as gestation proceeded. All newborns were healthy and only one case of macrosomia was observed. Slide17
CONCLUSIONSWomen
with PCOS who enter pregnancy in a condition of severe hyperinsulinemia have development of GD earlier, independently of metformin treatment. The physiologic deterioration of insulin sensitivity is not affected by the drug and does not predict the timing and severity of the glycemic imbalance. Despite the high incidence of GD observed, the drug itself or the intensive monitoring probably accounted for the good neonatal outcome. Slide18
Message
妊娠中に
m
etforminを使うことは海外ではよくあるようである。妊婦さんにインスリンクランプ法を行った論文！結果はよいようである。Slide19