ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
Age-specific serum antim€ ullerian hormone levels in women with and without polycystic ovary syndrome Yuqian Cui, M.D., Ph.D.,a,b Yuhua Shi, M.D., Ph.D.,a Linlin Cui, M.D., Ph.D.,a Ting Han, M.D.,a Xuan Gao, M.D.,a and Zi-Jiang Chen, M.D., Ph.D.a,b a
Center for Reproductive Medicine, Provincial Hospital Affiliated with Shandong University; National Research Center for Assisted Reproductive Technology and Reproductive Genetics; Key Laboratory for Reproductive Endocrinology of the Ministry of Education; and Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China; and b Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
Objective: To determine the serum antim€ ullerian hormone (AMH) reference values in Chinese women with and without polycystic ovary syndrome (PCOS), and the associations of AMH with clinical or biochemical characteristics. Design: Retrospective study. Setting: Academic institutions. Patient(s): Totals of 1,896 infertile control women and 304 women with PCOS. Intervention(s): None. Main Outcome Measure(s): Serum basal AMH levels and clinical, endocrine, and metabolic parameters. Result(s): In the same age group, serum AMH levels were higher in PCOS women than those without PCOS. AMH levels were not significantly related to indices of insulin resistance or metabolic-related variables in both groups. In the infertile control group, AMH increased with antral follicle count (AFC) and LH and decreased with age, body mass index (BMI), and FSH. In the PCOS group, AMH levels showed positive correlations with LH, AFC, and T and negative correlations with BMI. The median AMH levels were 2.35 ng/mL for ages 20–31 years, 1.58 ng/mL for ages 32–34 years, 1.30 ng/mL for ages 35–37 years, 0.96 ng/mL for ages 38– 40 years, 1.05 ng/mL for ages 41–43 years, and 0.67 ng/mL for ages >43 years in the control group and 4.38 ng/mL for ages 20– 31 years, 3.47 ng/mL for ages 32–34 years, and 3.30 ng/mL for ages 35–37 years in the PCOS group. Conclusion(s): This study determined reference values of serum AMH in Chinese women with and without PCOS. Elevated serum AMH levels do not affect the risk of insulin resistance or Use your smartphone metabolic syndrome. (Fertil SterilÒ 2014;-:-–-. Ó2014 by American Society for Reproducto scan this QR code tive Medicine.) and connect to the Key Words: AMH, ovarian reserve, AFC, PCOS Discuss: You can discuss this article with its authors and other ASRM members at http:// fertstertforum.com/cuiy-age-specific-serum-amh-level-pcos/
O
varian reserve is defined as the number and quality of the follicles left in the ovary at any given time. The true size of the follicle pool is not used as the benchmark for evaluation (1). Along
with FSH and other ovarian reserve tests, antim€ ullerian hormone (AMH) has been evaluated as a potential novel clinical marker of ovarian reserve (2, 3). Almog et al. found an age-related decline of AMH in infertile
Received July 14, 2013; revised March 16, 2014; accepted March 18, 2014. Y.C. has nothing to disclose. Y.S. has nothing to disclose. L.C. has nothing to disclose. T.H. has nothing to disclose. X.G. has nothing to disclose. Z.-J.C. has nothing to disclose. Y.C. and Y.S. should be considered similar in author order. Supported by Science Research Foundation Item of No-Earnings Health Vocation (201002013), National Science and Technology Support Program (2011BAI17B00), National Basic Research Program of China (973 Program; 2011CB944500-G), National Natural Science Foundation of China (81070461, 81300459), and China Postdoctoral Science Foundation (2012M520909). Reprint requests: Zi-Jiang Chen, M.D., Ph.D., 324 Jingwu Road, Jinan 250021, People's Republic of China (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.03.032 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
women without polycystic ovaries (PCO) (4). A study of circadian variation of AMH in regularly menstruating females found that there was a slight decrease in serum AMH during the late night, but it appeared to be not clinically relevant (5). La Marca found that the highest AMH value was at day 12 and the lowest at day 14, but the difference was not significant (6), and serum AMH demonstrated less individual intra- and intercycle variation than antral follicle count (AFC) (7). Furthermore, AMH levels seem to be unmodified under conditions of pregnancy (8), GnRH agonist treatment (9), and short-term oral contraceptive 1
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY administration (10, 11). It seemed that AMH had bright clinical application prospects (12). AMH is a member of the transforming growth factor b family, which exerts its biologic effects through a transmembrane serine/threonine kinase type II receptor (AMHR II) (13). In women, AMH is secreted by granulosa cells of preantral and antral follicles (14) and its serum levels have been shown to correlate with ovarian follicular pool. The main physiologic role of AMH in the ovary seems to be limited to the inhibition of the early stages of follicular development (15) and preventing recruitment of nondominant follicles (16). The absence of AMH has been shown to enhance FSH-induced follicle growth in female mice (17). This hormone appears in the 36th week of gestation and decreases continuously through puberty. It becomes undetectable when menopause occurs (18). In 2003, Fanchin et al. demonstrated that AFC was closely related to serum AMH level on cycle day 3 in infertile women, more strongly than other hormonal markers, such as inhibin B, E2, and FSH (19). Thus, serum AMH levels are considered to reflect the number of small growing follicles and are reduced through reproductive life. Currently, serum AMH level is often measured during an initial work-up for fertility. However, there are little agerelated reference values for AMH levels based on a large Chinese population. The aim of the present study was to establish reference values for AMH and explore the relationship between endocrine/metabolic indicators and AMH in women with and without PCOS.
MATERIALS AND METHODS We retrospectively evaluated a total of 2,200 patients aged 20–47 years undergoing infertility work-up before their first in vitro fertilization (IVF) treatment. Data were obtained from a database including clinical, hormonal, and ultrasound characteristics from May 2010 to March 2011 in the reproductive medicine center of Shandong Provincial Hospital. Polycystic ovary syndrome (PCOS) was diagnosed according to the criteria from the Rotterdam European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine–Sponsored PCOS Consensus Workshop Group (20). Oligomenorrhea was defined as menstrual interval of 35 days–6 months and amenorrhea was defined as menstrual interval R6 months. Hyperandrogenism was defined as T >60 ng/dL (21), excluding existence of other hyperandrogemism diseases (Supplemental Fig. 1, available online at www.fertstert.org). The subjects with PCOS were divided into four subgroups: PCO/oligomenorrhea (n ¼ 249; 81.91%); PCO/hyperandrogenemia (n ¼ 7; 2.30%); oligomenorrhea/hyperandrogenemia (n ¼ 13; 4.28%); and PCO/oligomenorrhea/hyperandrogenemia (n ¼ 35; 11.51%). The following subjects were excluded from the study and the control populations: 1) women who had been diagnosed with other etiologies that should be excluded; 2) women who received hormones or drugs for major medical diseases; 3) women who presented ovarian cysts or ovarian tumors. Blood samples were drawn for testing of hormone and lipid levels at baseline (on day 2–3 of a spontaneous 2
menstrual cycle or progestin-induced menstrual bleeding with oligomenorrhoea/amenorrhoea). Serum FSH, LH, E2, PRL, total T, TSH, and fasting insulin were measured with the use of chemiluminescence immunization (Beckman Access Health Company). Cholesterol, triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were measured with the use of the precipitation and enzymatic method (FT-7060; Beckman Coulter). The intra- and interassay coefficients of variation were all
Age-specific serum antim€ ullerian hormone levels in women with and without polycystic ovary syndrome Yuqian Cui, M.D., Ph.D.,a,b Yuhua Shi, M.D., Ph.D.,a Linlin Cui, M.D., Ph.D.,a Ting Han, M.D.,a Xuan Gao, M.D.,a and Zi-Jiang Chen, M.D., Ph.D.a,b a
Center for Reproductive Medicine, Provincial Hospital Affiliated with Shandong University; National Research Center for Assisted Reproductive Technology and Reproductive Genetics; Key Laboratory for Reproductive Endocrinology of the Ministry of Education; and Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China; and b Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
Objective: To determine the serum antim€ ullerian hormone (AMH) reference values in Chinese women with and without polycystic ovary syndrome (PCOS), and the associations of AMH with clinical or biochemical characteristics. Design: Retrospective study. Setting: Academic institutions. Patient(s): Totals of 1,896 infertile control women and 304 women with PCOS. Intervention(s): None. Main Outcome Measure(s): Serum basal AMH levels and clinical, endocrine, and metabolic parameters. Result(s): In the same age group, serum AMH levels were higher in PCOS women than those without PCOS. AMH levels were not significantly related to indices of insulin resistance or metabolic-related variables in both groups. In the infertile control group, AMH increased with antral follicle count (AFC) and LH and decreased with age, body mass index (BMI), and FSH. In the PCOS group, AMH levels showed positive correlations with LH, AFC, and T and negative correlations with BMI. The median AMH levels were 2.35 ng/mL for ages 20–31 years, 1.58 ng/mL for ages 32–34 years, 1.30 ng/mL for ages 35–37 years, 0.96 ng/mL for ages 38– 40 years, 1.05 ng/mL for ages 41–43 years, and 0.67 ng/mL for ages >43 years in the control group and 4.38 ng/mL for ages 20– 31 years, 3.47 ng/mL for ages 32–34 years, and 3.30 ng/mL for ages 35–37 years in the PCOS group. Conclusion(s): This study determined reference values of serum AMH in Chinese women with and without PCOS. Elevated serum AMH levels do not affect the risk of insulin resistance or Use your smartphone metabolic syndrome. (Fertil SterilÒ 2014;-:-–-. Ó2014 by American Society for Reproducto scan this QR code tive Medicine.) and connect to the Key Words: AMH, ovarian reserve, AFC, PCOS Discuss: You can discuss this article with its authors and other ASRM members at http:// fertstertforum.com/cuiy-age-specific-serum-amh-level-pcos/
O
varian reserve is defined as the number and quality of the follicles left in the ovary at any given time. The true size of the follicle pool is not used as the benchmark for evaluation (1). Along
with FSH and other ovarian reserve tests, antim€ ullerian hormone (AMH) has been evaluated as a potential novel clinical marker of ovarian reserve (2, 3). Almog et al. found an age-related decline of AMH in infertile
Received July 14, 2013; revised March 16, 2014; accepted March 18, 2014. Y.C. has nothing to disclose. Y.S. has nothing to disclose. L.C. has nothing to disclose. T.H. has nothing to disclose. X.G. has nothing to disclose. Z.-J.C. has nothing to disclose. Y.C. and Y.S. should be considered similar in author order. Supported by Science Research Foundation Item of No-Earnings Health Vocation (201002013), National Science and Technology Support Program (2011BAI17B00), National Basic Research Program of China (973 Program; 2011CB944500-G), National Natural Science Foundation of China (81070461, 81300459), and China Postdoctoral Science Foundation (2012M520909). Reprint requests: Zi-Jiang Chen, M.D., Ph.D., 324 Jingwu Road, Jinan 250021, People's Republic of China (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.03.032 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
women without polycystic ovaries (PCO) (4). A study of circadian variation of AMH in regularly menstruating females found that there was a slight decrease in serum AMH during the late night, but it appeared to be not clinically relevant (5). La Marca found that the highest AMH value was at day 12 and the lowest at day 14, but the difference was not significant (6), and serum AMH demonstrated less individual intra- and intercycle variation than antral follicle count (AFC) (7). Furthermore, AMH levels seem to be unmodified under conditions of pregnancy (8), GnRH agonist treatment (9), and short-term oral contraceptive 1
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY administration (10, 11). It seemed that AMH had bright clinical application prospects (12). AMH is a member of the transforming growth factor b family, which exerts its biologic effects through a transmembrane serine/threonine kinase type II receptor (AMHR II) (13). In women, AMH is secreted by granulosa cells of preantral and antral follicles (14) and its serum levels have been shown to correlate with ovarian follicular pool. The main physiologic role of AMH in the ovary seems to be limited to the inhibition of the early stages of follicular development (15) and preventing recruitment of nondominant follicles (16). The absence of AMH has been shown to enhance FSH-induced follicle growth in female mice (17). This hormone appears in the 36th week of gestation and decreases continuously through puberty. It becomes undetectable when menopause occurs (18). In 2003, Fanchin et al. demonstrated that AFC was closely related to serum AMH level on cycle day 3 in infertile women, more strongly than other hormonal markers, such as inhibin B, E2, and FSH (19). Thus, serum AMH levels are considered to reflect the number of small growing follicles and are reduced through reproductive life. Currently, serum AMH level is often measured during an initial work-up for fertility. However, there are little agerelated reference values for AMH levels based on a large Chinese population. The aim of the present study was to establish reference values for AMH and explore the relationship between endocrine/metabolic indicators and AMH in women with and without PCOS.
MATERIALS AND METHODS We retrospectively evaluated a total of 2,200 patients aged 20–47 years undergoing infertility work-up before their first in vitro fertilization (IVF) treatment. Data were obtained from a database including clinical, hormonal, and ultrasound characteristics from May 2010 to March 2011 in the reproductive medicine center of Shandong Provincial Hospital. Polycystic ovary syndrome (PCOS) was diagnosed according to the criteria from the Rotterdam European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine–Sponsored PCOS Consensus Workshop Group (20). Oligomenorrhea was defined as menstrual interval of 35 days–6 months and amenorrhea was defined as menstrual interval R6 months. Hyperandrogenism was defined as T >60 ng/dL (21), excluding existence of other hyperandrogemism diseases (Supplemental Fig. 1, available online at www.fertstert.org). The subjects with PCOS were divided into four subgroups: PCO/oligomenorrhea (n ¼ 249; 81.91%); PCO/hyperandrogenemia (n ¼ 7; 2.30%); oligomenorrhea/hyperandrogenemia (n ¼ 13; 4.28%); and PCO/oligomenorrhea/hyperandrogenemia (n ¼ 35; 11.51%). The following subjects were excluded from the study and the control populations: 1) women who had been diagnosed with other etiologies that should be excluded; 2) women who received hormones or drugs for major medical diseases; 3) women who presented ovarian cysts or ovarian tumors. Blood samples were drawn for testing of hormone and lipid levels at baseline (on day 2–3 of a spontaneous 2
menstrual cycle or progestin-induced menstrual bleeding with oligomenorrhoea/amenorrhoea). Serum FSH, LH, E2, PRL, total T, TSH, and fasting insulin were measured with the use of chemiluminescence immunization (Beckman Access Health Company). Cholesterol, triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were measured with the use of the precipitation and enzymatic method (FT-7060; Beckman Coulter). The intra- and interassay coefficients of variation were all
