The Role of AMH in The Pathophysiology of

ARTICLE IN PRESS
Reproductive BioMedicine Online (2016) ■■, ■■–■■
w w w. s c i e n c e d i r e c t . c o m
w w w. r b m o n l i n e . c o m
1 bs_bs_query
Q2 REVIEW
2 bs_bs_query
3 bs_bs_query The role of AMH in the pathophysiology of

4
polycystic ovarian syndrome
bs_bs_query
5 bs_bs_query
6 bs_bs_query
7 bs_bs_query
Q1 Deepika Garg a, Reshef Tal b,*
8 bs_bs_query
a
9 bs_bs_query Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, New York; b Division of Reproductive
10 bs_bs_query Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of
11 bs_bs_query Medicine, New Haven, Connecticut
12 bs_bs_query * Corresponding author. E-mail address: reshef.tal@yale.edu (R Tal).
13
14 bs_bs_query
bs_bs_query Reshef Tal is currently completing his Reproductive Endocrinology and Infertility fellowship at the Yale Univer-
15 bs_bs_query sity School of Medicine. He received his medical degree and PhD in Molecular Biology from the Sackler School
16 bs_bs_query of Medicine at Tel-Aviv University (Israel). He completed a post-doctoral research fellowship at the Samuel Lunenfeld
17 bs_bs_query Institute in University of Toronto. He subsequently completed his residency in Obstetrics and Gynecology at
18 bs_bs_query Maimonides Medical Center (NY). His research is focused upon AMH as a predictor of ovarian reserve and as-
19 bs_bs_query sisted reproductive technology outcomes, and understanding the role of angiogenesis and stem cells in repro-
20 bs_bs_query ductive biology and pathology.
21 bs_bs_query
22 bs_bs_query Abstract Polycystic ovarian syndrome (PCOS) affects 5 − 10% of reproductive age women, but its pathogenesis is still poorly under-
23 bs_bs_query stood. The aim of this review is to collate evidence and summarize our current knowledge of the role of anti-Müllerian hormone (AMH)
24 bs_bs_query in PCOS pathogenesis. AMH is increased and correlated with the various reproductive and metabolic/endocrine alterations in PCOS.
25 bs_bs_query AMH plays an inhibitory role in follicular development and recruitment, contributing to follicular arrest. AMH inhibitory action on
26 bs_bs_query FSH-induced aromatase production likely contributes to hyperandrogenism in PCOS, which further enhances insulin resistance in these
27 bs_bs_query women. Elevated serum AMH concentrations are predictive of poor response to various treatments of PCOS including weight loss,
28 bs_bs_query ovulation induction and laparoscopic ovarian drilling, while improvement in various clinical parameters following treatment is as-
29 bs_bs_query sociated with serum AMH decline, further supporting an important role for AMH in the pathophysiology of this syndrome. This review
30 bs_bs_query emphasizes the need for understanding the exact mechanism of action of AMH in the pathophysiology of PCOS. This may lead to the
31 bs_bs_query development of new treatment modalities targeting AMH to treat PCOS, as well as help clinicians in prognostication and better tai-
32 bs_bs_query loring existing treatments for this disease.
33 bs_bs_query © 2016 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
34 bs_bs_query
35 bs_bs_query KEYWORDS: AMH, hyperandrogenism, insulin resistance, ovulatory dysfunction, pathophysiology, PCOS
36 bs_bs_query
37 bs_bs_query http://dx.doi.org/10.1016/j.rbmo.2016.04.007
38 bs_bs_query 1472-6483/© 2016 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
Please cite this article in press as: Deepika Garg, Reshef Tal, The role of AMH in the pathophysiology of polycystic ovarian syndrome, Reproductive BioMedicine Online
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
2 D Garg, R Tal
39 bs_bs_query Introduction AMH and ovarian physiology 99 bs_bs_query
40 bs_bs_query 100 bs_bs_query
41 bs_bs_query Polycystic ovary syndrome (PCOS) is the most common AMH aka Müllerian inhibiting substance (MIS) is a homodimeric 101 bs_bs_query
42 bs_bs_query endocrinopathy in reproductive age affecting 5 − 10% of glycoprotein hormone that belongs to the transforming growth 102 bs_bs_query
43 bs_bs_query women, and is the leading cause of ovulatory dysfunction factor-β superfamily (Cate et al., 1986). It is structurally 103 bs_bs_query
44 bs_bs_query (Diamanti-Kandarakis et al., 1999; Franks, 1995; Knochenhauer related with the 35 other members of this superfamily, which 104 bs_bs_query
45 bs_bs_query et al., 1998). According to the Rotterdam 2003 consensus, two includes growth differentiation factors, inhibins and bone mor- 105 bs_bs_query
46 bs_bs_query out of three criteria are required for the diagnosis of this syn- phogenetic proteins (BMP), some of which are also involved 106 bs_bs_query
47 bs_bs_query drome: oligo- or anovulation, clinical or biochemical in the process of folliculogenesis in the ovaries (Knight and 107 bs_bs_query
48 bs_bs_query hyperandrogenism and/or polycystic ovaries on ultrasound Glister, 2006). While most of these ligands show a broad ex- 108 bs_bs_query
49 bs_bs_query (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop pression pattern and a wide range of functions, the expres- 109 bs_bs_query
50 bs_bs_query Group, 2004). It can also be associated with insulin resis- sion of AMH is restricted to the gonads and AMH is thought 110 bs_bs_query
51 bs_bs_query tance, obesity and altered gonadotrophin release. PCOS was to exert its effects only on reproductive organs (Massague and 111
bs_bs_query
52 bs_bs_query first described by Stein and Leventhal in 1935 in a series of Chen, 2000). 112 bs_bs_query
53 bs_bs_query seven patients with polycystic ovaries, amenorrhoea, infer- The gene which encodes for AMH is localized on the small 113 bs_bs_query
54 bs_bs_query tility and hirsutism (Stein and Leventhal, 1935). It is now well arm of chromosome 19 (Cohen-Haguenauer et al., 1987). AMH 114 bs_bs_query
55 bs_bs_query established that ovarian hyperthecosis and increased andro- is produced as a pro-hormone, which after secretion under- 115 bs_bs_query
56 bs_bs_query gen production are central to the endocrine disturbance in goes cleavage to generate a transforming growth factor-beta- 116 bs_bs_query
57 bs_bs_query PCOS. In addition, numerous genetic and environmental factors like noncovalently-linked biologically active C-terminal 117 bs_bs_query
58 bs_bs_query have been postulated to interact and play a role in the un- fragment (Pepinsky et al., 1988; Wilson et al., 1993). AMH in 118 bs_bs_query
59 bs_bs_query derlying pathophysiology of this syndrome (Vink et al., 2006). the female is produced exclusively by ovarian granulosa cells 119 bs_bs_query
60 bs_bs_query PCOS is clearly familial in a large majority of cases and mo- (Ueno et al., 1989), its concnetration declines with age and 120 bs_bs_query
61 bs_bs_query lecular genetic pathways have been implicated in the meta- become undetectable after menopause (Vigier et al., 1984). 121 bs_bs_query
62 bs_bs_query bolic and biochemical alterations associated with PCOS The concentration of this hormone slightly fluctuates during 122 bs_bs_query
63 bs_bs_query (Escobar-Morreale et al., 2005; Urbanek, 2007). In addition different phases of the menstrual cycle but not significantly 123 bs_bs_query
64 bs_bs_query to genetic predisposition, environmental exposure is thought enough to affect its measurement (Cook et al., 2000; Streuli 124 bs_bs_query
65 bs_bs_query to play a major role in PCOS development. This notion is et al., 2009). 125 bs_bs_query
66 bs_bs_query supported by experiments in rhesus monkeys injected with AMH is also found in Sertoli cells and plays an integral role 126 bs_bs_query
67 bs_bs_query androgens during pregnancy showing that their female in the embryonic development of the reproductive tract and 127 bs_bs_query
68 bs_bs_query offspring had polycystic ovarian morphology and various sex differentiation by inhibiting the development of Müllerian 128 bs_bs_query
69 bs_bs_query PCOS-like manifestations (Abbott et al., 2002). However, ducts (Rajpert-De Meyts et al., 1999; Rey et al., 2003). During 129 bs_bs_query
70 bs_bs_query despite many decades of extensive research, the exact ae- embryogenesis, if AMH production is absent or its receptors 130 bs_bs_query
71 bs_bs_query tiology and pathogenesis of this complex disorder remain are defective, Müllerian ducts persist to form the Fallopian 131 bs_bs_query
72 bs_bs_query largely unknown. tubes, uterus and upper one third of the vagina (Behringer 132 bs_bs_query
73 bs_bs_query Anti-Müllerian hormone (AMH) is an important regulator et al., 1994). 133 bs_bs_query
74 bs_bs_query of folliculogenesis in the ovaries (Visser et al., 2006). It is se- During human folliculogenesis, AMH protein expression 134 bs_bs_query
75 bs_bs_query creted by granulosa cells of the ovarian follicles and its serum begins at the primary follicle stage, highest expression is de- 135 bs_bs_query
76 bs_bs_query levels are elevated 2- to 3- fold in women with PCOS in com- tected in FSH-dependent pre-antral and small antral fol- 136 bs_bs_query
77 bs_bs_query parison with normo-ovulatory women, consistent with the in- licles of ≤4 mm in diameter, and AMH expression gradually 137 bs_bs_query
78 bs_bs_query creased number of small antral follicles in PCOS (Laven et al., declines in subsequent stages and is absent in follicles larger 138 bs_bs_query
79 bs_bs_query 2004; Pigny et al., 2003). However, it is unclear whether AMH than 8 mm (Stubbs et al., 2005; Weenen et al., 2004). Studies 139 bs_bs_query
80 bs_bs_query is simply a marker which is increased in PCOS, or actually an measuring AMH messenger RNA (mRNA) expression in granu- 140 bs_bs_query
81 bs_bs_query important contributing factor to its pathophysiology. This losa cells of isolated human follicles and AMH protein con- 141 bs_bs_query
82 bs_bs_query article will review the role of AMH in ovarian physiology and centration in follicular fluid confirmed this pattern of 142 bs_bs_query
83 bs_bs_query the accumulating evidence implicating AMH in the pathogen- expression (Andersen et al., 2010; Jeppesen et al., 2013; Modi 143 bs_bs_query
84 bs_bs_query esis of PCOS. Improved understanding of the association et al., 2006). Baarends et al. studied in vivo the expression 144 bs_bs_query
85 bs_bs_query between AMH and PCOS may pave the way for development of AMH and anti-Müllerian hormone receptor type II (AMHRII) 145 bs_bs_query
86 bs_bs_query of new therapies for PCOS. mRNA in adult rat ovaries and suggested the role of FSH and 146 bs_bs_query
87 bs_bs_query
oestrogens in down-regulation of expression of AMH and AMHRII 147 bs_bs_query
mRNA during differentiation of small antral follicles into large 148 bs_bs_query
88 bs_bs_query Materials and methods antral follicles (Baarends et al., 1995). Cessation of AMH pro- 149 bs_bs_query
89 bs_bs_query
duction from larger antral follicles ≥10 mm, is thought to be 150 bs_bs_query
90 bs_bs_query The published literature was searched for relevant publica- essential for dominant follicle selection (Pellatt et al., 2007a; Q3 151 bs_bs_query
91 bs_bs_query tions using PubMed, Medline and Google Scholar databases Visser et al., 2006) (Figure 1). 152 bs_bs_query
92 bs_bs_query until November 2015 with combinations of the search terms It is well established that AMH acts as an important in- 153 bs_bs_query
93 bs_bs_query “polycystic ovarian syndrome”, “PCOS”, “antimullerian hibitory factor for follicular growth. AMH-null mice exhibit 154 bs_bs_query
94 bs_bs_query hormone”, “AMH”, “pathogenesis, ‘ovulatory dysfunc- accelerated folliculogenesis with increased numbers of growing 155 bs_bs_query
95 bs_bs_query tion’”, “hyperandrogenism”, “insulin resistance”, “ovula- follicles resulting in early depletion of ovarian follicles 156 bs_bs_query
96 bs_bs_query tion induction”, “IVF”, “metformin”, “laparoscopic ovarian (Durlinger et al., 1999, 2001). In-vitro, AMH treatment of rat 157 bs_bs_query
97 bs_bs_query drilling” and “treatment outcome”. Only original articles in granulosa cells leads to a reduction in FSH and cAMP-stimulated 158 bs_bs_query
98 bs_bs_query English were included. aromatase activity (Diclemente et al., 1994). In the same 159 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
The role of AMH in the pathogenesis of PCOS 3
AMH
-
- FSH
Small Large
Primordial Preantral Small Antral Large Antral Pre ovulatory

Follicle Follicle Follicle Follicle Follicle
LH
+ - FSH -
AMH
AMHR
-
T T Aromatase E2
Theca Cell Granulosa Cell
160 bs_bs_query Figure 1 AMH production and action according to follicular stage. AMH is secreted primarily from pre-antral and small antral fol-
161 bs_bs_query licles. The inhibitory actions of AMH are shown on the FSH-independent initial recruitment of primary follicles from the primordial
162 bs_bs_query follicle pool and on the FSH-dependent follicular maturation and selection of the dominant follicle by decreasing follicular sensitiv-
163 bs_bs_query ity to FSH. The inset shows the interplay between AMH, FSH and LH actions at the molecular level. AMH inhibits FSH-induced aromatase
164 bs_bs_query expression in granulosa cells, reducing the conversion of testosterone to oestradiol, which inhibits AMH in turn. In addition to stimu-
165 bs_bs_query lating theca cell to produce testosterone, LH acts directly on granulosa cells down-regulating the expression of AMHRII. AMHRII =
166 bs_bs_query anti-Müllerian hormone receptor II; E2 = oestradiol; T = testosterone.
167 bs_bs_query
168 bs_bs_query study, AMH was shown to reduce aromatase mRNA expres- become more sensitive to FSH leading to increased oestro- 197 bs_bs_query
169 bs_bs_query sion in cAMP-stimulated cells and LH receptor mRNA expres- gen production, follicular selection and subsequent ovula- 198 bs_bs_query
170 bs_bs_query sion in porcine granulosa cells stimulated with FSH (Diclemente tion in the normal ovary. 199 bs_bs_query
171 bs_bs_query et al., 1994). Similarly, AMH treatment has been demon- 200 bs_bs_query
172 bs_bs_query strated to result in decreased aromatase mRNA expression and

173 bs_bs_query activity as well as oestradiol production in human granulosa Role of AMH in PCOS pathogenesis 201 bs_bs_query
174 bs_bs_query cells (Grossman et al., 2008; Pellatt et al., 2007a). Consis- 202 bs_bs_query
175 bs_bs_query tent with this, AMH has been shown to reduce the growth of It is well known that PCOS ovaries comprise a higher number 203 bs_bs_query
176 bs_bs_query early growing follicles by 40 ± 50% following 4 − 5 days in of pre-antral and small antral follicles (Franks et al., 2000, 204 bs_bs_query
177 bs_bs_query culture (Weenen et al., 2004). AMH-induced decrease in granu- 2006; Hughesdon, 1982), indicating arrest of follicular de- 205 bs_bs_query
178 bs_bs_query losa cells sensitivity to FSH was also confirmed in vivo as AMH- velopment at the stage when AMH production is greatest. 206 bs_bs_query
179 bs_bs_query deficient mice were more sensitive to FSH than the wild- Indeed, several studies have demonstrated that serum AMH 207 bs_bs_query
180 bs_bs_query type ones (Durlinger et al., 2001). concentration is elevated in PCOS women compared with 208 bs_bs_query
181 bs_bs_query AMH signals through two types of serine–threonine kinase women with normal ovaries (Fallat et al., 1997; Laven et al., 209 bs_bs_query
182 bs_bs_query transmembrane receptors known as type I receptor (AMHRI) 2004; Mulders et al., 2004; Pellatt et al., 2007a). In addi- 210 bs_bs_query
183 bs_bs_query and type II receptor (AMHRII) which are present on gonads and tion, the concentration of AMH in follicular fluid from women 211 bs_bs_query
184 bs_bs_query Müllerιan ducts (La Marca and Volpe, 2006). Interaction of AMH with anovulatory PCOS was found to be 5-fold greater com- 212 bs_bs_query
185 bs_bs_query with its receptors stimulates a signalling pathway which in- pared with ovulatory women (Das et al., 2008). Moreover, 213 bs_bs_query
186 bs_bs_query volves Smad proteins (Massague and Chen, 2000). Granulosa Pellatt et al. showed that AMH production per granulosa cell 214 bs_bs_query
187 bs_bs_query cells of pre-antral and small antral follicles have a high ex- is increased on average 75-fold in granulosa cells of anovu- 215 bs_bs_query
188 bs_bs_query pression of AMH and AMH receptor mRNA (Hirobe et al., 1992). latory PCOS compared with granulosa cells of normal ovaries 216 bs_bs_query
189 bs_bs_query Interestingly, the presence of AMHRII mRNA has been iden- (Pellatt et al., 2007a). Catteau-Jonard et al. corroborated 217 bs_bs_query
190 bs_bs_query tified in theca cells along with granulosa luteal cells (GLC), these findings showing that granulosa cells of polycystic ovaries 218 bs_bs_query
191 bs_bs_query suggesting the possibility of an AMH-based signalling pathway have increased AMH mRNA expression (Catteau-Jonard et al., 219 bs_bs_query
192 bs_bs_query between these cells during folliculogenesis (Hanna et al., 2008). Taken together, these data suggest that it is not only 220 bs_bs_query
193 bs_bs_query 2006). Collectively, the role of AMH in folliculogenesis appears the increased number of follicles, with resultant increased 221 bs_bs_query
194 bs_bs_query to be the inhibition of premature recruitment and matura- granulosa cell mass, but also greater production by indi- 222 bs_bs_query
195 bs_bs_query tion of follicles. Once the follicles reach the large antral stage, vidual granulosa cells that is underlying AMH overproduc- 223 bs_bs_query
196 bs_bs_query the expression of AMH is downregulated and these follicles tion in PCOS. Several studies have demonstrated that AMH is 224 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
4 D Garg, R Tal
225 bs_bs_query correlated with severity of PCOS manifestations, including warranted to directly assess the effects of inhibiting AMH 286
bs_bs_query
226 bs_bs_query oligo/amenorrhoea, hyperandrogenism and polycystic ovarian action on folliculogenesis and PCOS manifestations using in- 287
bs_bs_query
227 bs_bs_query morphology (Eldar-Geva et al., 2005; Homburg et al., 2013; vitro and experimental animal models. 288
bs_bs_query
228 bs_bs_query Lin et al., 2011; Pigny et al., 2003; Piouka et al., 2009; Tal While it is likely that elevated AMH contributes to the 289
bs_bs_query
229 bs_bs_query et al., 2014) lending support to the notion that AMH is not pathogenesis of anovulation in PCOS, the cause/s of its in- 290
bs_bs_query
230 bs_bs_query only a biomarker of disease but actually contributes to PCOS creased production remain unknown. However, factors which 291
bs_bs_query
231 bs_bs_query pathogenesis. are closely related to PCOS pathophysiology such as in- 292
bs_bs_query
creased LH, androgen levels and insulin resistance may be im- 293
232
bs_bs_query
bs_bs_query
plicated (Figure 2). Several studies have shown that serum 294
bs_bs_query
233 bs_bs_query The role of AMH in ovulatory dysfunctions in PCOS AMH is correlated with LH and androgen levels (Eldar-Geva 295
bs_bs_query
234 bs_bs_query
et al., 2005; Homburg et al., 2013; Lin et al., 2011; Pigny 296
bs_bs_query
235 bs_bs_query Previous studies have directed our attention towards the role et al., 2003; Piouka et al., 2009; Tal et al., 2014). LH in- 297
bs_bs_query
236 bs_bs_query of AMH in inhibiting folliculogenesis by interference with the creases AMH production 4-fold in granulosa cells of PCOS 298
bs_bs_query
237 bs_bs_query concentration and the actions of FSH in the ovaries (Josso ovaries but not of normal ovaries (Pellatt et al., 2007a). In 299
bs_bs_query
238 bs_bs_query et al., 2001; Pellatt et al., 2010; Singer et al., 2009). Inter- addition, LH has been shown to increase AMH expression in 300
bs_bs_query
239 bs_bs_query estingly, several investigators have reported that AMH con- granulosa cells of oligo/anovulatory women but not of ovu- 301
bs_bs_query
240 bs_bs_query centrations are correlated with the degree of ovulatory latory PCOS and control women, and had no effect on AMHRII 302
bs_bs_query
241 bs_bs_query dysfunction. Laven et al. showed that normogonadotrophic expression in granulosa cells of oligo/anovulatory PCOS women 303
bs_bs_query
242 bs_bs_query anovulatory women with or without PCOS have higher AMH while decreasing its expression in granulosa cells of ovula- 304
bs_bs_query
243 bs_bs_query concentrations than their normo-ovulatory counterparts, and tory PCOS and control women (Pierre et al., 2013), suggest- 305
bs_bs_query
244 bs_bs_query that serum AMH is correlated with menstrual cycle duration ing a role for LH in AMH overexpression and AMH-induced 306
bs_bs_query
245 bs_bs_query (Laven et al., 2004). Moreover, Pellatt et al. have sug- follicular arrest. Moreover, androgens play a role in stimu- 307
bs_bs_query
246 bs_bs_query gested that PCOS can be divided into anovulatory and ovu- lating early (FSH independent) stages of follicular growth 308
bs_bs_query
247 bs_bs_query latory based on the serum AMH concentrations as women with (Vendola et al., 1998; Weil et al., 1999) and may thus con- 309
bs_bs_query
248 bs_bs_query anovulatory PCOS were found to have 18 times higher AMH tribute to increased AMH production. However, Carlsen et al. 310
bs_bs_query
249 bs_bs_query concentrations than the women with ovulatory PCOS with no reported that 6-month androgen suppression with dexametha- 311
bs_bs_query
250 bs_bs_query overlapping areas (Pellatt et al., 2010). Pigny et al. investi- sone did not change AMH concentrations, suggesting that other 312
bs_bs_query
251 bs_bs_query gated the correlation of serum AMH concentrations with FSH mechanisms are likely responsible for the induction and main- 313
bs_bs_query
252 bs_bs_query in PCOS and found a positive correlation between AMH con- tenance of AMH production in PCOS women (Carlsen et al., 314
bs_bs_query
253 bs_bs_query centration and small antral follicle number (P < 0.0001) but 2009a, 2009b). Q5 315
bs_bs_query
254 bs_bs_query a negative correlation with serum FSH concentration (P < 0.04), Another candidate which may contribute to elevated AMH 316
bs_bs_query
255 bs_bs_query suggesting the role of increased AMH in the follicular arrest in PCOS is insulin. Compensatory hyperinsulinaemia second- 317
bs_bs_query
256 bs_bs_query in PCOS by inhibiting FSH early in folliculogenesis (Pigny et al., ary to insulin resistance is found in PCOS and Homeostatic 318
bs_bs_query
257 bs_bs_query 2003). They also reported that AMH concentration is tightly Model Assessment (HOMA-IR) has been shown to be corre- 319
bs_bs_query
258 bs_bs_query correlated with the 2 − 5 mm but not the 6 − 9 mm follicular lated with the AMH concentrations in this population (La Marca 320
bs_bs_query
259 bs_bs_query number (Pigny et al., 2003), implying that greater AMH con- et al., 2004a, 2004b). Nardo et al. found a positive correla- Q6 321
bs_bs_query
260 bs_bs_query centrations would reflect a greater number of AMH-producing tion between AMH and fasting insulin levels in women with 322
bs_bs_query
261 bs_bs_query 2 − 5 mm follicles. Interestingly, in a different study by the and without PCOS (Nardo et al., 2009). This could be ex- 323
bs_bs_query
262 bs_bs_query same group, the authors reported a strong negative relation- plained by an abnormal effect of insulin on AMH secretion 324
bs_bs_query
263 bs_bs_query ship between the 2 − 5 mm and the 6 − 9 mm follicular from granulosa cells as suggested by Park et al. in women 325
bs_bs_query
264 bs_bs_query numbers, suggesting the presence of a physiological nega- without PCOS (Park et al., 2010a, 2010b), or may be due 326
bs_bs_query
265 bs_bs_query tive influence from the 2 − 5 mm follicle pool on the termi- to increased androgen production in the presence of 327
bs_bs_query
266 bs_bs_query nal follicle growth at the time of selection (Dewailly et al., hyperinsulinaemia in PCOS (Park et al., 2010a, 2010b). Further 328
bs_bs_query
267 bs_bs_query 2007). Importantly, the authors noted that the 2 − 5 mm fol- research is required in this area to characterize the nature 329
bs_bs_query
268 bs_bs_query licular number was positively correlated with the severity of of the association between insulin and AMH concentrations 330
bs_bs_query
269 bs_bs_query the menstrual disorder in PCOS, being highest in women with and to delineate the mechanism for insulin-dependent el- 331
bs_bs_query
270 bs_bs_query amenorrhoea (Dewailly et al., 2007). Subsequently, Park et evation of AMH in PCOS. 332
bs_bs_query
271 bs_bs_query al. reported that adolescent girls with oligomenorrhoea have It is also possible that genetic factors may underlie AMH 333
bs_bs_query
272 bs_bs_query elevated AMH concentrations compared with normo-ovulatory overexpression in PCOS. Kevenaar et al. investigated the role 334
bs_bs_query
273 bs_bs_query
Q4 controls (Park et al., 2010a, 2010b). Moreover, Tal et al. re- of ALK2, its receptor and their encoding gene ACVR1 gene, 335
bs_bs_query
274 bs_bs_query cently reported that serum AMH concentration had a strong which are involved in AMH/BMP signalling, in the aberrant fol- 336
bs_bs_query
275 bs_bs_query predictive ability for amenorrhoea in their study population licle development in PCOS. They found an association between 337
bs_bs_query
276 bs_bs_query of women with elevated AMH, having 91.7% specificity and a genetic variant of ACVR1 with AMH concentrations and 338
bs_bs_query
277 bs_bs_query 79.4% sensitivity in predicting amenorrhoea when the thresh- folliculogenesis in PCOS suggesting the role of ALK2 signal- 339
bs_bs_query
278 bs_bs_query old AMH concentration was 11.4 ng/ml (Tal et al., 2014). Taken ing in ovulatory disturbances in PCOS (Kevenaar et al., 2009). 340
bs_bs_query
279 bs_bs_query together, these observations suggest that anovulatory PCOS Stubbs et al. investigated the role of AMH in the transition 341
bs_bs_query
280 bs_bs_query women have an increased number of AMH-producing small of primordial follicles to primary follicles in women with 342
bs_bs_query
281 bs_bs_query antral follicles (2 − 5 mm), presumably creating an extreme normal and polycystic ovaries and found AMH immunostaining 343
bs_bs_query
282 bs_bs_query AMH-dominated micro-environment, which impairs the action in fewer primordial follicles in polycystic ovaries of anovu- 344
bs_bs_query
283 bs_bs_query of FSH on the selectable follicles leading to anovulation. latory women in comparison with normo-ovulatory women with 345
bs_bs_query
284 bs_bs_query However, these observations provide only indirect evidence polycystic ovaries (Stubbs et al., 2005). However, the inten- 346
bs_bs_query
285 bs_bs_query for AMH role in PCOS-related anovulation. Further studies are sity of AMH staining in pre-antral and antral follicles was not 347
bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
PCOS
Increased Elevated Elevated AGEs Genetic Factors?

Elevated LH
androgens and decrease
insulin
in sRAGE
?
Elevated
AMH
Decreased aromatase Decreased FSH

expression sensitivity
Anovulation
348 bs_bs_query Figure 2 The various factors leading to elevated anti-Müllerian hormone (AMH) and the downstream effects of AMH overproduc-
349 bs_bs_query tion. Overproduction of AMH in polycystic ovarian syndrome (PCOS) could be due to several factors which are abnormally elevated
350 bs_bs_query (LH, androgens, insulin, advanced-glycation end products [AGE]) or decreased (soluble receptor for AGE [sRAGE]) in PCOS. In addi-
351 bs_bs_query tion, genetic factors such as variants of ACVR1 gene likely contribute to AMH overexpression. The abnormal increase in AMH dimin-
352 bs_bs_query ishes aromatase expression and follicular sensitivity to FSH leading to anovulation and hyperandrogenism. The exact relationship between
353 bs_bs_query AMH and insulin resistance has not been fully elucidated.
354 bs_bs_query
355 bs_bs_query different between these groups. Based on these observa- tivity in GLC. The authors proposed this interaction as a pos- 386 bs_bs_query
356 bs_bs_query tions, it may be postulated that AMH exhibits less inhibition sible explanation for the association of high AMH 387 bs_bs_query
357 bs_bs_query on primordial follicles in anovulatory PCOS women, leading concentrations and low FF oestradiol concentrations in PCOS 388 bs_bs_query
358 bs_bs_query to increased early folliculogenesis and accumulation of (Grossman et al., 2008). Similar decrease in FSH-induced 389 bs_bs_query
359 bs_bs_query pre-antral and small antral follicles, resulting in AMH aromatase mRNA expression and oestrogen production in re- 390 bs_bs_query
360 bs_bs_query overproduction. sponse to AMH has also been recently reported by Chang et al. 391 bs_bs_query
(2013). In addition to direct inhibitory effects of AMH on granu- 392 bs_bs_query
361 bs_bs_query
losa cell aromatase expression/activity leading to increased 393 bs_bs_query
362 bs_bs_query AMH and hyperandrogenism in PCOS androgen levels, it can be conceptualized that AMH may have 394 bs_bs_query
a paracrine effect on theca interna cells given the presence 395

363
bs_bs_query
bs_bs_query
of AMHRII in these cells, leading to theca cell dysregulation 396 bs_bs_query
364 Androgens are produced in theca interna cells and con-

in PCOS (Ingraham et al., 2000). It can be speculated that AMH-
bs_bs_query
397 bs_bs_query
365 verted to oestrogens in granulosa cells by the action

dependent inhibition of FSH-induced aromatase activity may
bs_bs_query
398 bs_bs_query
366 of aromatase (Erickson et al., 1979). LH stimulates

also lead to the abnormal follicular development in PCOS
bs_bs_query
399 bs_bs_query
367 steroidonegenesis by producing androgens from theca interna

(Jonard and Dewailly, 2004). Furthermore, a study by Kevenaar
bs_bs_query
400 bs_bs_query
368 cells. Elevated serum AMH concentration in PCOS has been

et al. provides a possible genetic explanation for a mecha-
bs_bs_query
401 bs_bs_query
369 shown to be positively associated with androgen levels such

nistic link between AMH and androgen levels. The investiga-
bs_bs_query
402 bs_bs_query
370 as serum testosterone and androstenedione (Carlsen et al.,

tors found an association between AMH gene Ile (49) Ser
bs_bs_query
403 bs_bs_query
371 2009a, 2009b; Cassar et al., 2014; Pigny et al., 2003; Piltonen
polymorphism and androgen levels in women with PCOS, which
bs_bs_query
404 bs_bs_query
372 et al., 2005), supporting the notion that AMH may contrib-
may be due to AMH influence on FSH-induced aromatase ac-
bs_bs_query
405 bs_bs_query
373 ute to the development of hyperandrogenism in women with

tivity (Kevenaar et al., 2008). Of note, the existing evi-
bs_bs_query
406 bs_bs_query
374 PCOS. While the specific mechanism/s of action of AMH leading

dence highlights the role of AMH in hyperandrogenism
bs_bs_query
407 bs_bs_query
375 to hyperandrogensim in PCOS has not yet been fully eluci-

associated with PCOS, but there are several other factors that
bs_bs_query
408 bs_bs_query
376 dated, such effect may be mediated by the reduction in

also contribute to the metabolic and hormonal dynamics in
bs_bs_query
409 bs_bs_query
377 aromatase activity in granulosa cells of polycystic ovaries

PCOS.
bs_bs_query
410 bs_bs_query
378 bs_bs_query (Laven et al., 2002; Pellatt et al., 2007b). di Clemente et al.
379 bs_bs_query found reduced aromatase activity and mRNA expression in re- 411 bs_bs_query
380 bs_bs_query sponse to AMH in rat fetal ovaries (di Clemente et al., 1992).
381 bs_bs_query Grossman et al. investigated the role of AMH in the expres- AMH and metabolic manifestations 412 bs_bs_query
382 bs_bs_query sion of cytochrome P450 aromatase (CYP19) mRNA and protein 413 bs_bs_query
383 bs_bs_query in human GLC and demonstrated significant reduction in FSH- The rate of metabolic syndrome in PCOS is two to three times 414 bs_bs_query
384 bs_bs_query induced oestradiol production via AMH-induced inhibition of greater than healthy women of the same age group 415 bs_bs_query
385 bs_bs_query CYP19 gene expression and cytochrome P450 aromatase ac- (Apridonidze et al., 2005). The most common metabolic 416 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
6 D Garg, R Tal
417 bs_bs_query abnormalities associated with PCOS are insulin resistance (IR) nized in the ovulatory and metabolic disturbances associ- 479 bs_bs_query
418 bs_bs_query and obesity, affecting anovulatory women more than ovula- ated with PCOS (Diamanti-Kandarakis et al., 2005, 2008), and 480 bs_bs_query
419 bs_bs_query tory women with PCOS, which also play an important role in recently a link to AMH has been suggested. Advanced glycation 481 bs_bs_query
420 bs_bs_query regulation of androgen levels (Conway and Jacobs, 1993). end products are the products of nonenzymatic modifica- 482 bs_bs_query
421 bs_bs_query Although IR is amplified by increasing obesity, women with tion of proteins, lipids and nucleic acids by glucose. Their gen- 483 bs_bs_query
422 bs_bs_query PCOS are more insulin resistant than can be accounted for by eration is accelerated by conditions such as diabetes and IR 484 bs_bs_query
423 bs_bs_query their obesity alone (Dunaif et al., 1989, 1992). It has been (Unoki and Yamagishi, 2008), and AGE have been shown to 485 bs_bs_query
424 bs_bs_query suggested that IR can affect AMH concentrations and also be be elevated in serum as well as ovaries of PCOS women 486 bs_bs_query
425 bs_bs_query associated with hyperandrogensim related with PCOS (Diamanti-Kandarakis et al., 2007, 2008). Furthermore, AGE 487 bs_bs_query
426 bs_bs_query (Baillargeon and Nestler, 2006). However, evidence regard- have been shown to interfere with insulin signalling in granu- 488 bs_bs_query
427 bs_bs_query ing the association between elevated AMH and IR as well as losa cells (Diamanti-Kandarakis et al., 2015). In contrast to 489 bs_bs_query
428 bs_bs_query other metabolic manifestations of PCOS is conflicting. RAGE, the soluble receptor for RAGE (sRAGE) is an extracel- 490 bs_bs_query
429 bs_bs_query Direct correlation between serum AMH and insulin resis- lular form of RAGE which circulates in the blood binding AGE 491 bs_bs_query
430 bs_bs_query tance, as measured by (HOMA-IR), was first reported by La and reducing their free circulating levels, thus preventing the 492 bs_bs_query
431 bs_bs_query Marca et al. (2004a,b) in a study which included 14 women adverse intracellular events of AGE-RAGE interaction (Kalea 493 bs_bs_query
432 bs_bs_query with PCOS. Consistent with this observation, a cross-sectional et al., 2009). Diamanti-Kandarakis et al. demonstrated a posi- 494 bs_bs_query
433 bs_bs_query study by Fonseca et al. showed significantly higher AMH con- tive correlation between elevated AMH concentrations and 495 bs_bs_query
434 bs_bs_query centrations in PCOS patients with IR in comparison to PCOS AGE in women with PCOS. They further showed that eleva- 496 bs_bs_query
435 bs_bs_query patients without IR (Fonseca et al., 2014). Moreover, Nardo tion in both AMH and AGE was more pronounced in women 497 bs_bs_query
436 bs_bs_query et al. assessed the relationships between AMH and IR in a study with anovulatory PCOS, suggesting an interrelated role 498 bs_bs_query
437 bs_bs_query of 49 patients with PCOS and 183 without PCOS undergoing for these molecules in ovulatory dysfunction in PCOS 499 bs_bs_query
438 bs_bs_query IVF treatment and found a positive correlation between AMH (Diamanti-Kandarakis et al., 2009). Moreover, Irani et al. re- 500 bs_bs_query
439 bs_bs_query concentrations and HOMA-IR as well as insulin levels, and a ported that vitamin D supplementation, which is known to 501 bs_bs_query
440 bs_bs_query negative correlation between AMH and HOMA-B in both groups, improve various manifestations of PCOS (Irani et al., 2015), 502 bs_bs_query
441 bs_bs_query suggesting that the relationship between AMH and IR is in- led to a decrease in serum AMH accompanied by an increase 503 bs_bs_query
442 bs_bs_query dependent of PCOS status (Nardo et al., 2009). Skalba et al. in serum concentrations of sRAGE in women with PCOS (Irani 504 bs_bs_query
443 bs_bs_query also reported a positive correlation between AMH and HOMA- et al., 2014b). Recently, Merhi et al. showed that treat- 505 bs_bs_query
444 bs_bs_query IR in a study which included 87 women with PCOS and 50 non- ment of cultured cumulus cells with AGE resulted in in- 506 bs_bs_query
445 bs_bs_query PCOS controls (Skalba et al., 2011). creased mRNA expression of the AMHRII but not AMH, and also 507 bs_bs_query
446 bs_bs_query In contrast, other studies did not find an association between led to increased AMH-induced SMAD 1/5/8 phosphorylation, 508 bs_bs_query
447 bs_bs_query AMH and IR. Eldar-Geva et al. failed to find any association effects that were suppressed by concomitant treatment with 509 bs_bs_query
448 bs_bs_query between AMH and insulin sensitivity in 19 women with PCOS vitamin D (Merhi et al., 2015). Taken together, these data 510 bs_bs_query
449 bs_bs_query and hyperandrogenism (group A), 10 women with PCOS without suggest that AGE potentiate the action of AMH in the ovary 511 bs_bs_query
450 bs_bs_query hyperandrogenism (group B), and 23 normal ovulatory women and that the combined action of AGE and AMH, which are up- 512 bs_bs_query
451 bs_bs_query (group C) as controls who underwent ovarian stimulation with regulated in PCOS, may contribute to ovulatory dysfunction 513 bs_bs_query
452 bs_bs_query long down-regulation protocol (Eldar-Geva et al., 2005). Other as well as various metabolic complications in PCOS such as 514 bs_bs_query
453 bs_bs_query small studies also failed to find an association between AMH insulin resistance. However, it is still unknown whether AMH 515 bs_bs_query
454 bs_bs_query and IR (Caglar et al., 2013; Cassar et al., 2014). While it is may directly affect insulin action locally in the ovary or sys- 516 bs_bs_query
455 bs_bs_query possible that study size may have played a role in these nega- temically, and further studies are warranted to evaluate the 517 bs_bs_query
456 bs_bs_query tive findings, several larger studies reported similar negative possible influence of AMH on the action of AGE in the ovary. 518 bs_bs_query
457 bs_bs_query findings. In a study which included 59 PCOS and 45 non-PCOS 519 bs_bs_query
458 bs_bs_query women, Pigny et al. found no significant correlation between

459 bs_bs_query AMH concentrations and fasting insulin (Pigny et al., 2003). AMH and infertility 520 bs_bs_query
460 bs_bs_query Moreover, several studies of Asian women with PCOS re- 521 bs_bs_query
461 bs_bs_query ported no significant association between AMH and IR (Chen Does AMH have a role in PCOS-related subfertility? The answer 522 bs_bs_query
462 bs_bs_query et al., 2008; Chun, 2015; Tian et al., 2014). Notably, the PCOS is not straightforward but there are several studies which may 523 bs_bs_query
463 bs_bs_query women in these studies were relatively leaner than in the provide important clues to this question. Studies have shown 524 bs_bs_query
464 bs_bs_query others. Table 1 summarizes the available evidence on the as- that AMH concentrations can be used as a predictor of men- 525 bs_bs_query
465 bs_bs_query sociation between AMH and IR. The conflicting data on the strual response after weight loss in overweight and obese 526 bs_bs_query
466 bs_bs_query association between AMH and IR may be partly explained by women with PCOS. Moran et al. studied the effect of weight 527 bs_bs_query
467 bs_bs_query heterogeneity in study populations. In addition, AMH has been loss treatment on the regulation of menstrual cycles in PCOS 528 bs_bs_query
468 bs_bs_query shown to be negatively correlated with body mass index (BMI) and found lower baseline AMH concentrations in responders 529 bs_bs_query
469 bs_bs_query in some studies but not others (Fleming et al., 2015) and since (P < 0.02) in comparison to non-responders suggesting the use 530 bs_bs_query
470 bs_bs_query insulin resistance is closely associated with obesity, the complex of pretreatment AMH as an important clinical predictor of the 531 bs_bs_query
471 bs_bs_query relationship between AMH and BMI may be an important con- response to weight loss in PCOS (Moran et al., 2007). Thomson 532 bs_bs_query
472 bs_bs_query founder in studies evaluating the association between AMH et al. also reported improvement in menstrual cyclicity and 533 bs_bs_query
473 bs_bs_query and IR. Therefore, larger studies which carefully control for ovulatory function following weight loss in overweight and 534 bs_bs_query
474 bs_bs_query BMI and other confounders are needed to further explore the obese women with PCOS who had lower pretreatment AMH 535 bs_bs_query
475 bs_bs_query nature of the interaction between AMH and IR. concentrations; however, weight loss did not result in a de- 536 bs_bs_query
476 bs_bs_query The role of increased oxidative stress as well as products crease in AMH concentrations (Thomson et al., 2009). Weight 537 bs_bs_query
477 bs_bs_query of oxidation such as advanced glycation end (AGE) products loss improved the menstrual and reproductive functions in 538 bs_bs_query
478 bs_bs_query and their receptors (RAGE) has been increasingly recog- these women with PCOS who already had lower baseline AMH 539 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
The role of AMH in the pathogenesis of PCOS
(2016), doi: 10.1016/j.rbmo.2016.04.007
540 Table 1 Studies evaluating the association between serum AMH and insulin resistance in PCOS women.
541
542 Population characterstics Age (years) BMI (kg/m2) Study size Study design Factors measured Main findings
543 Authors
544 Pigny et al., 2003 Women with and without PCOS (Rotterdam PCOS: mean age 27.4 PCOS: mean BMI 26.7 104 women; 59 symptomatic Cross-sectional Serum AMH concentrations and No significant correlation between AMH
545 criteria) Control: mean age, Control: mean BMI 23.1 PCOS, 45 non-PCOS controls fasting insulin between days 2 concentrations and fasting insulin (r =
546 28.3 and 7 after the last menstrual −0.024, P = NS)
547 period
548 La Marca et al., Women with PCOS (defined by presence of Mean age 23 Mean BMI 24.6 14 women with PCOS and 15 Cross-sectional Serum AMH concentrations and Positive correlation between HOMA score
549 2004a,b oligo/amenorrhoea with hyperandrogenism) non-PCOS women HOMA-IR and serum AMH l concentrations (r = 0.621,
550 and control women P < 0.05)
551 Eldar-Geva et al., Women with PCOS (Rotterdam consensus) 20–39 GroupA: 27.7 ± 6.1 19 women in group A, 10 Prospective Baseline serum AMH and Women with PCO have higher serum AMH
552 2005 and hyperandrogenism (group A), women Group B: 27.2 ± 7.5 women in group B, and 23 fasting insulin levels concentrations during ovarian stimulation
553 with PCOS without hyperandrogenism (group Group C: 25.1 ± 4.5 women in group C than controls; No correlation between AMH
ARTICLE IN PRESS
554 B), normal ovulatory women as controls and fasting insulin levels (r = −0.10, P = NS)
555 (group C) undergoing ovarian stimulation
556 with GnRHa long protocol
557 Chen et al., 2008 Women with PCOS (as per Rotterdam 26 (21–35) 23.05 99 women with PCOS Cross-sectional AMH concentrations and HOMA- Negative association between AMH and
558 criteria) (17.61 − 37.11) IR HOMA-IR (γ = −0.220; P = 0.030)
559 Nardo et al., 2009 PCOS (as per Rotterdam criteria) and non- 22–41 >19 but <30 49 patients with PCOS and 183 Prospective Serum AMH, insulin, HOMA-IR, Positive correlation between AMH
560 PCOS patients undergoing IVF without PCOS HOMA-B concentrations and HOMA-IR (r = 0.40,
561 P = 0.004), negative correlation between
562 AMH and HOMA-B in both groups (r = −0.60,
563 P = 0.046)
564 Skalba et al., Women with and without PCOS (as per 18–35 Normal weight: 18.5 to 87 women with PCOS and 50 Prospective AMH concentration and HOMA- Positive correlation between AMH and
565 2011 Rotterdam criteria) 24.9 Overweight: > 25 women without PCOS as IR HOMA-IR (r = 0.31, P < 0.001)
566 healthy controls
567 Caglar et al., Women with and without PCOS (as per Mean age: 26 Mean BMI: 22 34 women with PCOS and 21 Prospective Serum AMH, HOMA-IR, QUICKI No significant correlation between AMH and
568 2013 Rotterdam Criteria) non-PCOS controls QUICKI or HOMA-IR (r = 0.068, P = NS and
569 r = −0.010, P = NS, respectively)
570 Fonseca et al., Group A: women with PCOS (as per 20 − 44 Mean BMI: Group A: 26 women Cross-sectional Serum AMH, insulin levels, Higher AMH concentrations in PCOS patients
571 2014 Rotterdam criteria) and IR; Group B: women Group A: 28.9 Group B: 30 women HOMA-IR with IR (5.90 ng/ml) in comparison to PCOS
572 with PCOS without IR; Group C: controls Group B: 23.8, Group C: 30 patients without IR (4.45 ng/ml) and
573 without PCOS Group C: 22.6 controls (2.84 ng/m) (P = 0.001)
574 Cassar et al., Lean and overweight women with and Lean control = 27 ± 6, Lean control = 21·9 ± 4·6 22 lean and 21 overweight Cross-sectional Serum AMH and HOMA-IR Increased AMH concentrations in lean and
575 2014 without PCOS (as per Rotterdam criteria) Lean PCOS = 27 ± 4, Lean PCOS = 23·0 ± 4·7 women with PCOS; 19 lean and overweight women with PCOS and positive
576 Overweight control = Overweight control = 16 overweight non-PCOS association with hyperandrogenism but not
577 35 ± 4, Overweight 34·3 ± 5·1 Overweight controls IR (P < 0.001)
578 PCOS = 29 ± 5 PCOS = 34·2 ± 4·6
579 Tian et al., 2014 Women with PCOS (NIH criteria) and control 27.90 ± 4.14 to <25 160 PCOS women and 40 Prospective Serum AMH, HOMA-IR, QUICKI Negative correlation between AMH
580 group 29.62 ± 4.33 women in control group concentrations and HOMA-IR (r = −0.038,
581 P = NS) and a positive correlation with
582 QUICKI (r = 0.063, P = NS)
583 Chun, 2015 Women with PCOS (as per Rotterdam 18 − 33 Group 1: 21.78 ± 4.13, 95 Korean women with PCOS. Retrospective Serum AMH, HOMA-IR, QUICKI No correlation between AMH concentrations
584 criteria) Group 2: 22.62 ± 7.18 Group 1 (AMH <10 n = 53) and HOMA-IR (r = 0.121, P = NS) and QUICKI
585 Group 2 (AMH >10, n = 42) (r = 0.003, P = NS)
586 AMH = anti-Müllerian hormone; BMI = body mass index; COH = controlled ovarian hyperstimulation; HOMA = Homeostatic Model Assessment; HOMA-B = homeostatic model assessment of steady state beta cell function; HOMA-IR = homeostatic model as-
587 sessment of tissue insulin sensitivity; IR = insulin resistance; MIS = Müllerian-inhibiting substance; PCOS = polycystic ovary syndrome; QUICKI index = Quantitative Insulin Sensitivity Check Index.
7
ARTICLE IN PRESS
8 D Garg, R Tal
588
bs_bs_query concentrations and which was not further affected by weight 75th, or >75th AMH percentiles. Among these three groups, 650 bs_bs_query
589
bs_bs_query loss. Moreover, response to ovulation induction also appears they found comparable fertilization rate and quantity of good 651 bs_bs_query
590
bs_bs_query to be related to pre-treatment AMH concentrations. In a study quality embryos, but lower embryo implantation rates were 652 bs_bs_query
591
bs_bs_query which included 68 obese PCOS women, El-Halawaty et al. observed in the high AMH group in comparison to the low and 653 bs_bs_query
592
bs_bs_query (2007) found a significant difference in serum AMH concen- average AMH groups (P < 0.01) (Xi et al., 2012). In addition, 654 bs_bs_query
593
bs_bs_query tration between PCOS women who responded to ovulation in- the authors found a non-significant trend towards lower clini- 655 bs_bs_query
594
bs_bs_query duction with clomiphene citrate versus those who were non- cal pregnancy rates in the high AMH group compared with the 656 bs_bs_query
595
bs_bs_query responders. A threshold value of AMH <1.2 ng/ml was found other two groups (Xi et al., 2012). In a different study, Sahmay 657 bs_bs_query
596
bs_bs_query to predict response to clomiphene citrate in obese women with et al. found no significant correlation between AMH concen- 658 bs_bs_query
597
bs_bs_query PCOS (sensitivity 71%, specificity 65.7%). Similarly, in a study trations and CPR in 150 women with PCOS who underwent IVF 659 bs_bs_query
598
bs_bs_query of 60 anovulatory women with PCOS who underwent ovula- as CPR were 27.8%, 35.0% and 37.8% in <25%, 25%−75% and 660 bs_bs_query
599
bs_bs_query tion induction with clomiphene citrate, serum AMH concen- >75% percentiles of AMH concentrations (Sahmay et al., 2013). 661 bs_bs_query
600
bs_bs_query tration at baseline was found to be predictive of ovulation In a recent meta-analysis, we showed that in spite of some 662 bs_bs_query
601
bs_bs_query and pregnancy. Ovulation and pregnancy rates were signifi- weak association of AMH with implantation and clinical preg- 663 bs_bs_query
602
bs_bs_query
Q7 cantly higher (97%, P < 0.001, and 46%, P = 0.034) in pa- nancy rate outcomes, AMH displayed a trend toward weaker 664 bs_bs_query
603
bs_bs_query tients with low AMH (<3.4 ng/ml) versus women with AMH predictability of clinical pregnancy in women with PCOS 665 bs_bs_query
604
bs_bs_query 3.4 ng/ml or greater (48% and 19%) (Mahran et al., 2013). It (pooled diagnostic OR 1.18, AUC 0.60) compared with women 666 bs_bs_query
605
bs_bs_query may be postulated that in those women with anovulatory PCOS with unspecified or diminished ovarian reserve (pooled diag- 667 bs_bs_query
606
bs_bs_query who have very high granulosa cell production of AMH, as re- nostic OR 2.097, AUC 0.634) (Tal et al., 2015). This particu- 668 bs_bs_query
607
bs_bs_query flected by profoundly elevated serum AMH concentrations, larly weak association of AMH with pregnancy outcome in PCOS 669 bs_bs_query
608
bs_bs_query the inhibitory actions of AMH on folliculogenesis cannot be could be explained by considering the association of AMH with 670 bs_bs_query
609
bs_bs_query overcome by weight loss treatment or gentle ovulation in- the pathogenesis of the syndrome (Lin et al., 2011). AMH is 671 bs_bs_query
610
bs_bs_query duction regimens. correlated with PCOS severity and has a good predictive ac- 672 bs_bs_query
611
bs_bs_query Evidence for the negative role that elevated AMH plays in curacy for PCOS, making it a good candidate for being added 673 bs_bs_query
612
bs_bs_query the fertility of PCOS women also comes from studies on IVF as a criterion for the diagnosis of this syndrome (Iliodromiti 674 bs_bs_query
613
bs_bs_query in this population. While AMH concentrations were higher in et al., 2013). Elevated AMH concentration in PCOS is largely 675 bs_bs_query
614
bs_bs_query the follicular fluid aspirates at the time of oocyte retrieval due to increased AMH production by individual follicles rather 676 bs_bs_query
615
bs_bs_query from the anovulatory women undergoing IVF in comparison than increased follicle number (Pellatt et al., 2007a), which 677 bs_bs_query
616
bs_bs_query to the ovulatory women, these follicular levels were lower may confound its association with ovarian reserve and/or 678 bs_bs_query
617
bs_bs_query in the women who attained pregnancy (Desforges-Bullet et al., quality, thus explaining the poor predictability of AMH for preg- 679 bs_bs_query
618
bs_bs_query 2010). nancy outcome in this population of women. 680 bs_bs_query
619
bs_bs_query The evidence that high AMH concentrations are associ- A better understanding of the interplay between AMH and 681 bs_bs_query
620
bs_bs_query ated with poor assisted reproductive outcome in PCOS women assisted reproduction outcomes in women with PCOS may help 682 bs_bs_query
621
bs_bs_query may appear to contradict existing evidence that high AMH is clinicians find a distinct role for AMH measurement in this 683 bs_bs_query
622
bs_bs_query correlated with good IVF response. However, while it is well population. 684 bs_bs_query
623
bs_bs_query established that AMH is correlated with ovarian response and 685 bs_bs_query
624
bs_bs_query is a good predictor of oocyte yield following assisted repro-
625
bs_bs_query ductive technology, it is still controversial whether it may also AMH in response to treatment in PCOS 686 bs_bs_query
626
bs_bs_query be associated with qualitative outcomes of assisted repro- 687 bs_bs_query
627
bs_bs_query ductive technology (La Marca et al., 2007; Muttukrishna et al., Several lines of evidence demonstrate a close association 688 bs_bs_query
628
bs_bs_query 2005). A recent meta-analysis by Iliodromiti et al. con- between changes in serum AMH concentrations and improve- 689 bs_bs_query
629
bs_bs_query cluded that AMH was a weak predictor of live birth outcome ment in PCOS manifestations in response to treatment, pro- 690 bs_bs_query
630
bs_bs_query in patients following IVF (Iliodromiti et al., 2014). More- viding further support to the notion that AMH is causally 691 bs_bs_query
631
bs_bs_query over, most of these studies have been conducted on women related to PCOS pathophysiology. 692 bs_bs_query
632
bs_bs_query with unspecified ovarian reserve or non-PCOS women. Accu- Significant reduction in AMH concentrations was noted after 693 bs_bs_query
633
bs_bs_query mulating data on the association between AMH and assisted 6-month metformin therapy in PCOS (Piltonen et al., 2005). 694 bs_bs_query
634
bs_bs_query reproductive outcome in PCOS have been very conflicting. In another study, the decrease in AMH concentration was a 695 bs_bs_query
635
bs_bs_query Aleyasin et al. investigated the relationship between AMH delayed response and recognized after eight months of 696 bs_bs_query
636
bs_bs_query concentrations and assisted reproductive technology outcome metformin treatment (but not four months), and was pro- 697 bs_bs_query
637
bs_bs_query in 60 PCOS patients and found a statistically significant posi- posed to be due to increased follicle recruitment in a better 698 bs_bs_query
638
bs_bs_query tive correlation between the AMH concentrations and the endocrine environment of less insulin (Fleming et al., 2005). 699 bs_bs_query
639
bs_bs_query number of oocytes retrieved, presence of mature oocytes and In contrast, a short duration of metformin treatment (one 700 bs_bs_query
640
bs_bs_query embryo transfer. However, in their study AMH was not found week) in patients with PCOS did not affect AMH concentra- 701 bs_bs_query
641
bs_bs_query to be associated with clinical pregnancy outcome (AUC = 0.543, tions despite a significant reduction in the number of antral 702 bs_bs_query
642
bs_bs_query for cut-off of AMH >4.8 ng/ml) (Aleyasin et al., 2011). In con- follicles (Bayrak et al., 2007). The association between serum 703 bs_bs_query
643
bs_bs_query trast, Kaya et al. showed in their study of 60 women with PCOS concentration of AMH and treatment response was also es- 704 bs_bs_query
644
bs_bs_query that day 3 serum AMH concentration ≥3.2 ng/ml was a pre- tablished in the setting of ovulation induction with clomi- 705 bs_bs_query
645
bs_bs_query dictor of IR and clinical pregnancy rate (CPR) with 72.1% and phene citrate in obese PCOS patients. El-Halawaty et al. 706 bs_bs_query
646
bs_bs_query 75.6% sensitivity and 72.7% and 77.3% specificity, respec- evaluated AMH concentration in obese women with PCOS after 707 bs_bs_query
647
bs_bs_query tively (Kaya et al., 2010). Xi et al. also investigated the pre- ovulation induction with clomiphene citrate and found a sig- 708 bs_bs_query
648
bs_bs_query dictive value of AMH on day 3 of IVF cycle in 164 PCOS women nificant decrease in AMH concentrations in responders com- 709 bs_bs_query
649
bs_bs_query and divided the clinical outcomes according to <25th, 25 to pared with non-responders suggesting that AMH plays a role 710 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
The role of AMH in the pathogenesis of PCOS
711 Table 2 Effect of treatment of PCOS on serum AMH concentrations.
(2016), doi: 10.1016/j.rbmo.2016.04.007
712
713 Population characterstics Age (years) BMI (kg/m2) Size Study design Intervention Factors measured Main findings
714 Authors
715 Piltonen et Women with PCOS (Rotterdam 20−41 18–41 26 women with Prospective Metformin 1500 mg daily for Effect of metformin Decrease in AMH concentrations in women with PCOS after
716 al., 2005 criteria) PCOS 6 months (n = 14) vs. on serum AMH metformin treatment with no difference between the two
717 1000 mg daily for 3 months concentrations, dosing protocols (Pre-treatment mean AMH concentration 87.5
718 followed by 2000 mg daily follicle number and vs. 81.4 pmol/l after 6 months of metformin treatment, P <
719 for 3 months (n = 12) ovarian volume 0.01)
720 Fleming et Obese women with PCOS Mean 30.2 Mean 37.1 82 obese women Prospective Metformin treatment for 4 Change in serum AMH Decrease in AMH was noted only after 8 months of metformin
721 al., 2005 (Rotterdam criteria) with PCOS randomized months and 8 months over 4 and 8 months treatment (7.9 vs. 6.1 ng/ml, P = 0.0005) and was similar
722 trial (500 mg three times daily or between the 500 mg and 850 mg dose groups; significant
723 850 mg three times daily) reduction in weight and increase in ovulation rate (P = 0.0001)
724 Bayrak et al., Women with PCOS (diagnosed 23–36 23.4–36 5 women IR + PCOS, Prospective Metformin 850 mg daily for Concentrations of No change in AMH concentrations after one week of metformin
725 2007 by oligoanovulation and 5 women with PCOS 1 week serum AMH and therapy
726 hyperandrogenism) with and without IR, 4 inhibin B, AFC; Serum
727 without IR control women concentrations of T,
728 FSH, and LH, fasting
729 glucose/insulin ratio.
ARTICLE IN PRESS
730 El-Halawaty Obese women with PCOS PCOS: 28.21 ± 4.8 PCOS: 36.7 ± 5.75 68 obese women Prospective Clomiphene citrate (150 mg Serum AMH as a Marked reduction in AMH concentrations in obese women with
731 et al., (Rotterdam criteria) and obese Control: 27.65 ± 5.70 Control: 36.4 ± with PCOS and 17 daily) for 5 days beginning predictor of PCOS who responded to clomiphene citrate treatment (P =
732 2007 normo-ovulatory women as 5.67 normo-ovulatory cycle day 3 clomiphene citrate 0.0081); cut-off value of 1.2 ng/ml predicted response to OI
733 control group (BMI > 30) controls induced OI with 71% sensitivity, and 65.7% specificity)
734 Irani et al., Vitamin D-deficient women PCOS: 27.0 ± 0.9 PCOS: 27 ± 1.3 67 women with (n = Prospective Supplementation of 1,25- Serum levels of sRAGE Vitamin D3 replacement decreases serum AMH concentrations
735 2015 with or without PCOS Control: 28.7 ± 1.3 Control: 28.5 ± 22) or without (n = randomized Dihydroxy- vitamin D3 and AMH were in women with PCOS (P = 0.003), associated with increase in
736 (Rotterdam criteria with serum 1.5 45) PCOS controlled (50,000 IU once weekly for measured at baseline serum sRAGE (P = 0.03); No change in AMH in non-PCOS women
737 AMH > 4 ng/ml replacing trial 8 weeks) and 8 weeks after
738 sonographic criteria) vitamin D
739 supplementation
740 Seyam et al., Group 1- anovulatory women 25–40 20–30 Group-1 (n = 40), Prospective Laparoscopic ovarian drilling Evaluation of serum AMH concentrations decreased in PCOS group following LOD
741 2014 with PCOS (Rotterdam criteria) group-2 (n = 30), controlled (LOD) or incremental doses AMH concentrations from 5.99 ± 2.3 pretreatment to 3.4 ± 1.7, 3.2 ± 1.7 and 3.1 ±
742 undergoing LOD; Group-2 group-3 (n = 20) of CC before and after 1.5 ng/ml in one week, 3- months and 6- months post
743 received incremental doses treatment; AFC and treatment (P = 0.0001). After 6 months of LOD, 75% women
744 (50–150 mg) of CC; Group-3 summed ovarian had regular cycles with ovulation rate of 60% vs. 63.33%
745 healthy women volume (SOV) by TVS regular cycles and 63.33% ovulation rate in CC group
746 Amer et al., Anovulatory women with PCOS LOD: 28.4 (0.9) LOD: 26.9 (0.6) PCOS women Prospective Laparoscopic ovarian drilling Measurement of Significant reduction in AMH concentrations from 6.1 (pre-
747 2009 (Rotterdam criteria) CC: 28.1 (2.0) CC: 24.7 (1.7) undergoing LOD (n (LOD) or CC treatment serum AMH treatment) to 4.6, 4.3 and 4.6 ng/ml after LOD at 1 week, 3
748 = 29) or receiving concentration before months and 6 months, respectively (P = 0.003); AMH
749 CC (n = 18) and one week after concentration was predictive of ovulation after LOD with 78%
750 treatment sensitivity and 76% specificity
751 Weerakiet et PCOS (Rotterdam criteria) LOD group: 33.9 ± LOD group: 24.15 PCOS women who Cross- Laparoscopic ovarian drilling Day-3 serum anti- A non-significant trend towards lower AMH concentrations in
752 al., 2007 women with or without LOD, 4.15, PCOS group: ± 5.28, PCOS had LOD (n = 21); sectional (LOD) Müllerian hormone the LOD (4.60 ± 3.16 ng/ml) vs. the PCOS (5.99 ± 3.36 ng/ml)
753 and healthy controls 32.9 ± 3.91, Control group: 24.86 ± PCOS women (AMH) concentrations group; lower FSH in PCOS group in comparison with LOD and
754 group: 33.8 ± 4.52 6.70, Control without LOD (n = control group (P < 0.01); A non-significant trend towards lower
755 group: 23.58 ± 21); non- PCOS androgens in LOD group (P = NS)
756 4.45 women (n = 21)
757 Elmashad, Anovulatory CC resistant 18–35 26.7 ± 2.4 Anovulatory CC Prospective Laparoscopic ovarian drilling Plasma AMH Significant reduction in plasma levels of AMH and the ovarian
758 2011 women with PCOS (Rotterdam resistent women controlled (LOD) concentration and stromal power Doppler flow indices following LOD, with a
759 criteria) and healthy control with PCOS (n = 23); ovarian stromal 3D positive correlation between the two parameters (r = 0.55, P =
760 group Control group (n = power Doppler blood 0.006; r = 0.60, P = 0.002; and r = 0.016, P = 0.013 for VI, FI,
761 20) flow and VFI, respectively); Ovulation rate 73.9%, spontaneous
762 pregnancy rate 26.1%
763 Hendriks et PCOS women (as per all three 18–45 Laser group: 31.0 Women with PCOS Prospective Laparoscopic ovarian laser Serum AMH and In the first hours after surgery, both groups showed decrease in
764 al., 2014 of the Rotterdam criteria and ± 8.6 DLS group: undergoing laser controlled evaporation or diagnostic endocrine changes AMH. However, testosterone, androstenedione and AMH
765 luteinizing hormone (LH) > 6.5) 26.0 ± 9.4 evaporation (n = laparoscopy before and up to 5 remained at lower than baseline levels only in laser in
766 12) vs. diagnostic days following comparison with DLS group (P < 0.05); In laser group 41.7%
767 laparoscopy (n = 9) laparoscopic laser patients had ovulation within 28 days of the procedure, while
768 evaporation or DLS in DLS group OI was started without wait for spontaneous
769 ovulation
770 AFC = antral follicle count; AMH = anti-Müllerian hormone; BMI = body mass index; CC = clomiphene citrate; DLS = diagnostic laparoscopy; EE = ethinylestradiol; FG = Ferriman-Gallwey score; FI = flow index; FSH = follicle-stimulating hormone; LOD =
771 laparoscopic ovarian drilling; mFG = modified Ferriman-Gallwey score; MIS = Müllerian-inhibiting substance; OC′s = Oral contraceptives; OI = Ovulation induction; PCOS = polycystic ovary syndrome; SOV = summed ovarian volume; T = Testosterone; TVS
772 = transvaginal ultrasound examination; VI = vascularization index; VFI = vascularization flow index.
9
ARTICLE IN PRESS
10 D Garg, R Tal
773 bs_bs_query in responsiveness to clomiphene citrate treatment terventions aimed at inhibiting AMH action such as AMH- 834 bs_bs_query
774 bs_bs_query (El-Halawaty et al., 2007). Alternatively, the decrease in AMH specific antibodies or antagonists may prove to be clinically 835 bs_bs_query
775 bs_bs_query may simply be related to follicular development to a stage useful in improving various aspects of this syndrome. The pos- 836 bs_bs_query
776 bs_bs_query associated with less AMH production, similar to that which sible use of an antibody that blocks AMH or AMHRII action in 837 bs_bs_query
777 bs_bs_query occurs following treatment with gonadotrophins (La Marca the ovary may lead to similar consequences as the knockout 838 bs_bs_query
778 bs_bs_query et al., 2004a, 2004b). of the AMH gene or its receptor in mice (Durlinger et al., 1999, 839 bs_bs_query
779 bs_bs_query Supplementation of 1,25-Dihydroxy-vitamin D3 (vit. D3) in 2001). An increase in the number of primordial follicles re- 840 bs_bs_query
780 bs_bs_query PCOS women who are vit. D3-deficient has been shown to cruited, increased antral follicle sensitivity to FSH and con- 841 bs_bs_query
781 bs_bs_query improve elevated androgen levels, insulin resistance and men- sequently improvement in ovulatory dysfunction should 842 bs_bs_query
782 bs_bs_query strual cyclicity (Pal et al., 2012; Selimoglu et al., 2010). Ab- be expected. Moreover, due to AMH inhibitory action on 843 bs_bs_query
783 bs_bs_query normally elevated AMH concentrations in PCOS women were aromatase expression, AMH inhibition may be expected to 844 bs_bs_query
784 bs_bs_query decreased following vit. D3 administration suggesting that AMH result in greater conversion of androgens to oestrogens and 845 bs_bs_query
785 bs_bs_query may be mechanistically linked to vit D3-induced beneficial improvement in hyperandrogenism. For over three decades, 846 bs_bs_query
786 bs_bs_query effects in PCOS (Irani and Merhi, 2014a; Irani et al., 2014b). different antibodies against bovine or human AMH or AMHRII 847 bs_bs_query
787 bs_bs_query This change in AMH following vit. D3 supplementation may have been developed (Legeai et al., 1986, 1988; Salhi et al., 848 bs_bs_query
788 bs_bs_query be attributed to the presence of a vitamin D response element 2004; Vigier et al., 1982). The monoclonal antibody mAb 12G4, 849 bs_bs_query
789 bs_bs_query on AMH gene promoter which has been shown to be trig- the first mAb to be raised against human AMHRII, has re- 850 bs_bs_query
790 bs_bs_query gered by the active form of vitamin D in prostate cancer cells cently shown promise for ovarian cancer immunotherapy by 851 bs_bs_query
791 bs_bs_query (Krishnan et al., 2007; Malloy et al., 2009). targeting human ovarian cancer cells in vitro and in vivo in 852 bs_bs_query
792 bs_bs_query Accumulating evidence suggests that reduction in AMH con- a nude mouse xenograft model (Kersual et al., 2014). The de- 853 bs_bs_query
793 bs_bs_query centrations is associated with treatment response following velopment of a humanized version of the anti-AMHRII anti- 854 bs_bs_query
794 bs_bs_query laparoscopic ovarian drilling (LOD) in PCOS. Several studies body 12G4, named 3C23K, is ongoing and could prove useful 855 bs_bs_query
795 bs_bs_query on PCOS women reported that serum AMH concentrations were for ovarian and other gynaecologic AMHRII-positive cancers. 856 bs_bs_query
796 bs_bs_query decreased following LOD (Amer et al., 2009; Elmashad, 2011; Experimental studies are warranted to evaluate the poten- 857 bs_bs_query
797 bs_bs_query Seyam et al., 2014; Weerakiet et al., 2007). Hendriks et al. tial of such AMH antibodies or antagonists in the treatment 858 bs_bs_query
798 bs_bs_query reported similar findings following laparoscopic laser evapo- of PCOS. 859 bs_bs_query
799 bs_bs_query ration, noting a sustained decrease in serum AMH only in PCOS 860 bs_bs_query
800 women who underwent ovarian laser evaporation but not

Conclusions
bs_bs_query
861
801 control PCOS patients who underwent diagnostic laparos-
bs_bs_query
bs_bs_query
802 bs_bs_query copy (Hendriks et al., 2014). In addition, AMH concentra- 862 bs_bs_query
803 bs_bs_query tions were significantly decreased and were correlated with This review summarizes the existing evidence regarding the 863 bs_bs_query
804 bs_bs_query reduced ovarian power Doppler blood flow indices in PCOS contribution of AMH to the pathophysiology of PCOS and its 864 bs_bs_query
805 bs_bs_query women following LOD (Elmashad, 2011). Moreover, in the study various manifestations. In conclusion, AMH plays an inhibi- 865 bs_bs_query
806 bs_bs_query by Amer et al. pre-operative serum AMH concentration was tory role in follicular development and recruitment, contrib- 866 bs_bs_query
807 bs_bs_query shown to be predictive of treatment response to LOD as re- uting to anovulation. It also likely promotes hyperandrogenism 867 bs_bs_query
808 bs_bs_query flected by significantly greater ovulation rate in women with and insulin resistance in PCOS. Elevated serum AMH concen- 868 bs_bs_query
809 bs_bs_query lower pre-treatment AMH concentration. In their study, AMH trations are predictive of poor response to various treat- 869 bs_bs_query
810 bs_bs_query cut-off level of 7.7 ng/ml was predictive of ovulation follow- ments of PCOS including weight loss, ovulation induction and 870 bs_bs_query
811 bs_bs_query ing LOD with 78% sensitivity and 76% specificity (Amer et al., laparoscopic ovarian drilling, while clinical improvement in 871 bs_bs_query
812 bs_bs_query 2009). Although the mechanism of LOD is still unclear, it is various parameters following treatment is associated with 872 bs_bs_query
813 bs_bs_query thought to be mediated by the destruction of ovarian theca serum AMH decline, further supporting an important role for 873 bs_bs_query
814 bs_bs_query cell mass associated with rapid decrease in androgen levels AMH in the pathophysiology of this syndrome. Further basic 874 bs_bs_query
815 bs_bs_query leading to the beneficial clinical effects observed in PCOS and experimental studies will be paramount in improving our 875 bs_bs_query
816 bs_bs_query women following LOD (Flyckt and Goldberg, 2011). However, understanding of AMH related pathophysiology of PCOS, which 876 bs_bs_query
817 bs_bs_query it is unknown whether the decrease seen in AMH following LOD may lead to development of new therapies for this disorder. 877 bs_bs_query
818 bs_bs_query is simply reflective of the destruction of AMH-producing granu- 878 bs_bs_query
819 bs_bs_query losa cells, or is actually mechanistically related to the clini- References 879 bs_bs_query
820 bs_bs_query cal improvement. The predictive ability of pre-operative AMH 880 bs_bs_query
821 bs_bs_query concentration for treatment success would argue for the latter. Abbott, D.H., Dumesic, D.A., Franks, S., 2002. Developmental origin 881 bs_bs_query
822 bs_bs_query It is possible that decreased local ovarian production of AMH of polycystic ovary syndrome–a hypothesis. J. Endocrinol. 174, 882 bs_bs_query
823 bs_bs_query following LOD may lead to increased follicular responsive- 1–5. 883 bs_bs_query
824 bs_bs_query ness to FSH and release from the follicular arrest. Further ex- Aleyasin, A., Aghahoseini, M., Mokhtar, S., Fallahi, P., 2011. Anti- 884 bs_bs_query
825 bs_bs_query perimental studies are needed to investigate this possibility. mullerian hormone as a predictive factor in assisted reproduc- 885 bs_bs_query
826 bs_bs_query Table 2 summarizes the studies reporting serum AMH con- tive technique of polycystic ovary syndrome patients. Acta Med. 886 bs_bs_query
827 bs_bs_query centrations before and after various PCOS treatments. Iran. 49, 715–720. 887 bs_bs_query
Amer, S.A., Li, T.C., Ledger, W.L., 2009. The value of measuring anti- 888 bs_bs_query
828 bs_bs_query
Müllerian hormone in women with anovulatory polycystic ovary 889 bs_bs_query
829 bs_bs_query Future perspectives: AMH inhibition as syndrome undergoing laparoscopic ovarian diathermy. Hum. 890 bs_bs_query
830 bs_bs_query possible treatment for PCOS? Reprod. 24, 2760–2766. 891 bs_bs_query
Andersen, C.Y., Schmidt, K.T., Kristensen, S.G., Rosendahl, M., 892 bs_bs_query
831 bs_bs_query
Byskov, A.G., Ernst, E., 2010. Concentrations of AMH and inhibin-B 893 bs_bs_query
832 bs_bs_query As previously discussed, AMH up-regulation appears to be in relation to follicular diameter in normal human small antral fol- 894 bs_bs_query
833 bs_bs_query central to the pathophysiology of PCOS. Therefore, future in- licles. Hum. Reprod. 25, 1282–1287. 895 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
896
bs_bs_query Apridonidze, T., Essah, P.A., Iuorno, M.J., Nestler, J.E., 2005. Preva- Cook, C.L., Siow, Y., Taylor, S., Fallat, M.E., 2000. Serum mullerian- 964
bs_bs_query
897
bs_bs_query lence and characteristics of the metabolic syndrome in women inhibiting substance levels during normal menstrual cycles. Fertil. 965
bs_bs_query
898
bs_bs_query with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, Steril. 73, 859–861. 966
bs_bs_query
899
bs_bs_query 1929–1935. di Clemente, N., Ghaffari, S., Pepinsky, R.B., Pieau, C., Josso, N., 967
bs_bs_query
900
bs_bs_query Baarends, W.M., Uilenbroek, J.T., Kramer, P., Hoogerbrugge, J.W., Cate, R.L., Vigier, B., 1992. A quantitative and interspecific test 968
bs_bs_query
901
bs_bs_query van Leeuwen, E.C., Themmen, A.P., Grootegoed, J.A., 1995. Anti- for biological activity of anti-mullerian hormone: the fetal ovary 969
bs_bs_query
902
bs_bs_query mullerian hormone and anti-mullerian hormone type II receptor aromatase assay. Development 114, 721–727. 970
bs_bs_query
903
bs_bs_query messenger ribonucleic acid expression in rat ovaries during post- Das, M., Gillott, D.J., Saridogan, E., Djahanbakhch, O., 2008. Anti- 971
bs_bs_query
904
bs_bs_query natal development, the estrous cycle, and gonadotropin-induced Mullerian hormone is increased in follicular fluid from unstimulated 972
bs_bs_query
905
bs_bs_query follicle growth. Endocrinology 136, 4951–4962. ovaries in women with polycystic ovary syndrome. Hum. Reprod. 973
bs_bs_query
906
bs_bs_query Baillargeon, J.P., Nestler, J.E., 2006. Commentary: polycystic ovary 23, 2122–2126. 974
bs_bs_query
907
bs_bs_query syndrome: a syndrome of ovarian hypersensitivity to insulin? Desforges-Bullet, V., Gallo, C., Lefebvre, C., Pigny, P., Dewailly, D., 975
bs_bs_query
908
bs_bs_query J. Clin. Endocrinol. Metab. 91, 22–24. Catteau-Jonard, S., 2010. Increased anti-Mullerian hormone and 976
bs_bs_query
909
bs_bs_query Bayrak, A., Terbell, H., Urwitz-Lane, R., Mor, E., Stanczyk, F.Z., decreased FSH levels in follicular fluid obtained in women with 977
bs_bs_query
910
bs_bs_query Paulson, R.J., 2007. Acute effects of metformin therapy include polycystic ovaries at the time of follicle puncture for in vitro fer- 978
bs_bs_query
911
bs_bs_query improvement of insulin resistance and ovarian morphology. Fertil. tilization. Fertil. Steril. 94, 198–204. 979
bs_bs_query
912
bs_bs_query Steril. 87, 870–875. Dewailly, D., Catteau-Jonard, S., Reyss, A.C., Maunoury-Lefebvre, 980
bs_bs_query
913
bs_bs_query Behringer, R.R., Finegold, M.J., Cate, R.L., 1994. Mullerian-inhibiting C., Poncelet, E., Pigny, P., 2007. The excess in 2–5 mm follicles 981
bs_bs_query
914
bs_bs_query substance function during mammalian sexual development. Cell seen at ovarian ultrasonography is tightly associated to the fol- 982
bs_bs_query
915
bs_bs_query 79, 415–425. licular arrest of the polycystic ovary syndrome. Hum. Reprod. 22, 983
bs_bs_query
916
bs_bs_query Caglar, G.S., Kahyaoglu, I., Pabuccu, R., Demirtas, S., Seker, R., 2013. 1562–1566. 984
bs_bs_query
917
bs_bs_query Anti-Mullerian hormone and insulin resistance in classic pheno- Diamanti-Kandarakis, E., Kouli, C.R., Bergiele, A.T., Filandra, F.A., 985
bs_bs_query
918
bs_bs_query type lean PCOS. Arch. Gynecol. Obstet. 288, 905–910. Tsianateli, T.C., Spina, G.G., Zapanti, E.D., Bartzis, M.I., 1999. 986
bs_bs_query
919
bs_bs_query Carlsen, S.M., Vanky, E., Fleming, R., 2009a. Anti-Mullerian hormone A survey of the polycystic ovary syndrome in the Greek island of 987
bs_bs_query
920
bs_bs_query concentrations in androgen-suppressed women with polycystic Lesbos: hormonal and metabolic profile. J. Clin. Endocrinol. Metab. 988
bs_bs_query
921
bs_bs_query
Q8 ovary syndrome. Hum. Reprod. 24, 1732–1738. 84, 4006–4011. 989
bs_bs_query
922
bs_bs_query Carlsen, S.M., Vanky, E., Fleming, R., 2009b. Anti-Müllerian hormone Diamanti-Kandarakis, E., Piperi, C., Kalofoutis, A., Creatsas, G., 2005. 990
bs_bs_query
923
bs_bs_query concentrations in androgen-suppressed women with polycystic Increased levels of serum advanced glycation end-products in 991
bs_bs_query
924
bs_bs_query ovary syndrome. Hum. Reprod. 24, 1732–1738. women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf) 992
bs_bs_query
925
bs_bs_query Cassar, S., Teede, H.J., Moran, L.J., Joham, A.E., Harrison, C.L., 62, 37–43. 993
bs_bs_query
926
bs_bs_query Strauss, B.J., Stepto, N.K., 2014. Polycystic ovary syndrome and Diamanti-Kandarakis, E., Piperi, C., Patsouris, E., Korkolopoulou, P., 994
bs_bs_query
927
bs_bs_query anti-Mullerian hormone: role of insulin resistance, androgens, Panidis, D., Pawelczyk, L., Papavassiliou, A.G., Duleba, A.J., 2007. 995
bs_bs_query
928
bs_bs_query obesity and gonadotrophins. Clin. Endocrinol. (Oxf) 81, 899– Immunohistochemical localization of advanced glycation end- 996
bs_bs_query
929
bs_bs_query 906. products (AGEs) and their receptor (RAGE) in polycystic and normal 997
bs_bs_query
930
bs_bs_query Cate, R.L., Mattaliano, R.J., Hession, C., Tizard, R., Farber, N.M., ovaries. Histochem. Cell Biol. 127, 581–589. 998
bs_bs_query
931
bs_bs_query Cheung, A., Ninfa, E.G., Frey, A.Z., Gash, D.J., Chow, E.P., Fisher, Diamanti-Kandarakis, E., Katsikis, I., Piperi, C., Kandaraki, E., Piouka, 999
bs_bs_query
932
bs_bs_query R.A., Bertonis, J.M., Torres, G., Wallner, B.P., Ramachandran, A., Papavassiliou, A.G., Panidis, D., 2008. Increased serum ad- 1000
bs_bs_query
933
bs_bs_query K.L., Ragin, R.C., Manganaro, T.F., MacLaughlin, D.T., Donahoe, vanced glycation end-products is a distinct finding in lean women 1001
bs_bs_query
934
bs_bs_query P.K., 1986. Isolation of the bovine and human genes for Mulle- with polycystic ovary syndrome (PCOS). Clin. Endocrinol. (Oxf) 69, 1002
bs_bs_query
935
bs_bs_query rian inhibiting substance and expression of the human gene in 634–641. 1003
bs_bs_query
936
bs_bs_query animal cells. Cell 45, 685–698. Diamanti-Kandarakis, E., Piouka, A., Livadas, S., Piperi, C., Katsikis, 1004
bs_bs_query
937
bs_bs_query Catteau-Jonard, S., Jamin, S.P., Leclerc, A., Gonzales, J., Dewailly, I., Papavassiliou, A.G., Panidis, D., 2009. Anti-mullerian hormone 1005
bs_bs_query
938
bs_bs_query D., di Clemente, N., 2008. Anti-Mullerian hormone, its recep- is associated with advanced glycosylated end products in lean 1006
bs_bs_query
939
bs_bs_query tor, FSH receptor, and androgen receptor genes are overexpressed women with polycystic ovary syndrome. Eur. J. Endocrinol. 160, 1007
bs_bs_query
940
bs_bs_query by granulosa cells from stimulated follicles in women with poly- 847–853. 1008
bs_bs_query
941
bs_bs_query cystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 4456– Diamanti-Kandarakis, E., Chatzigeorgiou, A., Papageorgiou, E., 1009
bs_bs_query
942
bs_bs_query 4461. Koundouras, D., Koutsilieris, M., 2015. Advanced glycation end- 1010
bs_bs_query
943
bs_bs_query Chang, H.M., Klausen, C., Leung, P.C., 2013. Antimullerian products and insulin signaling in granulosa cells. Exp. Biol. Med. 1011
bs_bs_query
944
bs_bs_query hormone inhibits follicle-stimulating hormone-induced adenylyl (Maywood) pii: 1535370215584937. 1012
bs_bs_query
945
bs_bs_query cyclase activation, aromatase expression, and estradiol produc- Diclemente, N., Goxe, B., Remy, J.J., Cate, R., Josso, N., 1013
bs_bs_query
946
bs_bs_query tion in human granulosa-lutein cells. Fertil. Steril. 100, 585– Vigier, B., Salesse, R., 1994. Inhibitory effect of amh upon the 1014
bs_bs_query
947
bs_bs_query 592, e581. expression of aromatase and lh receptors by cultured granulosa- 1015
bs_bs_query
948
bs_bs_query Chen, M.J., Yang, W.S., Chen, C.L., Wu, M.Y., Yang, Y.S., Ho, H.N., cells of rat and porcine immature ovaries. Endocrine 2, 553– 1016
bs_bs_query
949
bs_bs_query 2008. The relationship between anti-Mullerian hormone, andro- 558. 1017
bs_bs_query
950
bs_bs_query gen and insulin resistance on the number of antral follicles in Dunaif, A., Segal, K.R., Futterweit, W., Dobrjansky, A., 1989. Pro- 1018
bs_bs_query
951
bs_bs_query women with polycystic ovary syndrome. Hum. Reprod. 23, 952– found peripheral insulin resistance, independent of obesity, in poly- 1019
bs_bs_query
952
bs_bs_query 957. cystic ovary syndrome. Diabetes 38, 1165–1174. 1020
bs_bs_query
953
bs_bs_query Chun, S., 2015. 1-h Postprandial glucose level is related to the serum Dunaif, A., Segal, K.R., Shelley, D.R., Green, G., Dobrjansky, A., 1021
bs_bs_query
954
bs_bs_query anti-Mullerian hormone level in women with polycystic ovary syn- Licholai, T., 1992. Evidence for distinctive and intrinsic defects 1022
bs_bs_query
955
bs_bs_query drome. Gynecol. Endocrinol. 31, 815–818. in insulin action in polycystic ovary syndrome. Diabetes 41, 1257– 1023
bs_bs_query
956
bs_bs_query Cohen-Haguenauer, O., Picard, J.Y., Mattei, M.G., Serero, S., Nguyen, 1266. 1024
bs_bs_query
957
bs_bs_query V.C., de Tand, M.F., Guerrier, D., Hors-Cayla, M.C., Josso, N., Durlinger, A.L., Kramer, P., Karels, B., de Jong, F.H., Uilenbroek, 1025
bs_bs_query
958
bs_bs_query Frezal, J., 1987. Mapping of the gene for anti-mullerian hormone J.T., Grootegoed, J.A., Themmen, A.P., 1999. Control of primor- 1026
bs_bs_query
959
bs_bs_query to the short arm of human chromosome 19. Cytogenet. Cell Genet. dial follicle recruitment by anti-Mullerian hormone in the mouse 1027
bs_bs_query
960
bs_bs_query 44, 2–6. ovary. Endocrinology 140, 5789–5796. 1028
bs_bs_query
961
bs_bs_query Conway, G.S., Jacobs, H.S., 1993. Clinical implications of Durlinger, A.L., Gruijters, M.J., Kramer, P., Karels, B., Kumar, T.R., 1029
bs_bs_query
962
bs_bs_query hyperinsulinaemia in women. Clin. Endocrinol. (Oxf) 39, 623– Matzuk, M.M., Rose, U.M., de Jong, F.H., Uilenbroek, J.T., 1030
bs_bs_query
963
bs_bs_query 632. Grootegoed, J.A., Themmen, A.P., 2001. Anti-Mullerian hormone 1031
bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
12 D Garg, R Tal
1032 bs_bs_query attenuates the effects of FSH on follicle development in the mouse syndrome: a prospective cohort study. Hum. Reprod. 28, 1077– 1100
bs_bs_query
1033 bs_bs_query ovary. Endocrinology 142, 4891–4899. 1083. 1101

bs_bs_query
1034 bs_bs_query El-Halawaty, S., Rizk, A., Kamal, M., Aboulhassan, M., Al-Sawah, H., Hughesdon, P.E., 1982. Morphology and morphogenesis of the Stein- 1102
bs_bs_query
1035 bs_bs_query Noah, O., Al-Inany, H., 2007. Clinical significance of serum Leventhal ovary and of so-called “hyperthecosis”. Obstet. Gynecol. 1103
bs_bs_query
1036 bs_bs_query concentration of anti-Mullerian hormone in obese women with Surv. 37, 59–77. 1104
bs_bs_query
1037 bs_bs_query polycystic ovary syndrome. Reprod. Biomed. Online 15, 495– Iliodromiti, S., Kelsey, T.W., Anderson, R.A., Nelson, S.M., 2013. Can 1105
bs_bs_query
1038 bs_bs_query 499. anti-Mullerian hormone predict the diagnosis of polycystic ovary 1106
bs_bs_query
1039 bs_bs_query Eldar-Geva, T., Margalioth, E.J., Gal, M., Ben-Chetrit, A., Algur, N., syndrome? A systematic review and meta-analysis of extracted 1107
bs_bs_query
1040 bs_bs_query Zylber-Haran, E., Brooks, B., Huerta, M., Spitz, I.M., 2005. Serum data. J. Clin. Endocrinol. Metab. 98, 3332–3340. 1108
bs_bs_query
1041 bs_bs_query anti-Mullerian hormone levels during controlled ovarian hyper- Iliodromiti, S., Kelsey, T.W., Wu, O., Anderson, R.A., Nelson, S.M., 1109
bs_bs_query
1042 bs_bs_query stimulation in women with polycystic ovaries with and without 2014. The predictive accuracy of anti-Mullerian hormone 1110
bs_bs_query
1043 bs_bs_query hyperandrogenism. Hum. Reprod. 20, 1814–1819. for live birth after assisted conception: a systematic review and 1111
bs_bs_query
1044 bs_bs_query Elmashad, A.I., 2011. Impact of laparoscopic ovarian drilling on anti- meta-analysis of the literature. Hum. Reprod. Update 20, 560– 1112
bs_bs_query
1045 bs_bs_query Mullerian hormone levels and ovarian stromal blood flow using 570. 1113
bs_bs_query
1046 bs_bs_query three-dimensional power Doppler in women with anovulatory poly- Ingraham, H.A., Hirokawa, Y., Roberts, L.M., Mellon, S.H., McGee, 1114
bs_bs_query
1047 bs_bs_query cystic ovary syndrome. Fertil. Steril. 95, 2342–2346, 2346.e2341. E., Nachtigal, M.W., Visser, J.A., 2000. Autocrine and paracrine 1115
bs_bs_query
1048 bs_bs_query Erickson, G.F., Hsueh, A.J., Quigley, M.E., Rebar, R.W., Yen, S.S., Mullerian inhibiting substance hormone signaling in reproduc- 1116
bs_bs_query
1049 bs_bs_query 1979. Functional studies of aromatase activity in human granu- tion. Recent Prog. Horm. Res. 55, 53–67, discussion 67-58. 1117
bs_bs_query
1050 bs_bs_query losa cells from normal and polycystic ovaries. J. Clin. Endocrinol. Irani, M., Merhi, Z., 2014a. Role of vitamin D in ovarian physiology 1118
bs_bs_query
1051 bs_bs_query Metab. 49, 514–519. and its implication in reproduction: a systematic review. Fertil. 1119
bs_bs_query
1052 bs_bs_query Escobar-Morreale, H.F., Luque-Ramirez, M., San Millan, J.L., 2005. Steril. 102, 460–468, e463. 1120
bs_bs_query
1053 bs_bs_query The molecular-genetic basis of functional hyperandrogenism and Irani, M., Minkoff, H., Seifer, D.B., Merhi, Z., 2014b. Vitamin D in- 1121
bs_bs_query
1054 bs_bs_query the polycystic ovary syndrome. Endocr. Rev. 26, 251–282. creases serum levels of the soluble receptor for advanced glycation 1122
bs_bs_query
1055 bs_bs_query Fallat, M.E., Siow, Y., Marra, M., Cook, C., Carrillo, A., 1997. end products in women with PCOS. J. Clin. Endocrinol. Metab. 99, 1123
bs_bs_query
1056 bs_bs_query Mullerian-inhibiting substance in follicular fluid and serum: a com- E886–E890. 1124
bs_bs_query
1057 bs_bs_query parison of patients with tubal factor infertility, polycystic ovary Irani, M., Seifer, D.B., Grazi, R.V., Julka, N., Bhatt, D., Kalgi, B., Irani, 1125
bs_bs_query
1058 bs_bs_query syndrome, and endometriosis. Fertil. Steril. 67, 962–965. S., Tal, O., Lambert-Messerlian, G., Tal, R., 2015. Vitamin D 1126
bs_bs_query
1059 bs_bs_query Fleming, R., Harborne, L., MacLaughlin, D.T., Ling, D., Norman, J., supplementation decreases TGF-beta1 bioavailability in PCOS: a 1127
bs_bs_query
1060 bs_bs_query Sattar, N., Seifer, D.B., 2005. Metformin reduces serum mullerian- randomized placebo-controlled trial. J. Clin. Endocrinol. Metab. 1128
bs_bs_query
1061 bs_bs_query inhibiting substance levels in women with polycystic ovary syn- 100, 4307–4314. 1129
bs_bs_query
1062 bs_bs_query drome after protracted treatment. Fertil. Steril. 83, 130–136. Jeppesen, J.V., Anderson, R.A., Kelsey, T.W., Christiansen, S.L., 1130
bs_bs_query
1063 bs_bs_query Fleming, R., Seifer, D.B., Frattarelli, J.L., Ruman, J., 2015. Assess- Kristensen, S.G., Jayaprakasan, K., Raine-Fenning, N., Camp- 1131
bs_bs_query
1064 bs_bs_query ing ovarian response: antral follicle count versus anti-Mullerian bell, B.K., Yding Andersen, C., 2013. Which follicles make the most 1132
bs_bs_query
1065 bs_bs_query hormone. Reprod. Biomed. Online 31, 486–496. anti-Mullerian hormone in humans? Evidence for an abrupt decline 1133
bs_bs_query
1066 bs_bs_query Flyckt, R.L., Goldberg, J.M., 2011. Laparoscopic ovarian drilling for in AMH production at the time of follicle selection. Mol. Hum. 1134
bs_bs_query
1067 bs_bs_query clomiphene-resistant polycystic ovary syndrome. Semin. Reprod. Reprod. 19, 519–527. 1135
bs_bs_query
1068 bs_bs_query Med. 29, 138–146. Jonard, S., Dewailly, D., 2004. The follicular excess in polycystic 1136
bs_bs_query
1069 bs_bs_query Fonseca, H.P., Brondi, R.S., Piovesan, F.X., Miklos, T.G., Aldrighi, ovaries, due to intra-ovarian hyperandrogenism, may be the main 1137
bs_bs_query
1070 bs_bs_query J.M., 2014. Anti-Mullerian hormone and insulin resistance in poly- culprit for the follicular arrest. Hum. Reprod. Update 10, 107– 1138
bs_bs_query
1071 bs_bs_query cystic ovary syndrome. Gynecol. Endocrinol. 30, 667–670. 117. 1139
bs_bs_query
1072 bs_bs_query Franks, S., 1995. Polycystic ovary syndrome. N. Engl. J. Med. 333, Josso, N., di Clemente, N., Gouedard, L., 2001. Anti-Mullerian 1140
bs_bs_query
1073 bs_bs_query 853–861. hormone and its receptors. Mol. Cell. Endocrinol. 179, 25–32. 1141
bs_bs_query
1074 bs_bs_query Franks, S., Mason, H., Willis, D., 2000. Follicular dynamics in the poly- Kalea, A.Z., Schmidt, A.M., Hudson, B.I., 2009. RAGE: a novel bio- 1142
bs_bs_query
1075 bs_bs_query cystic ovary syndrome. Mol. Cell. Endocrinol. 163, 49–52. logical and genetic marker for vascular disease. Clin. Sci. (Lond.) 1143
bs_bs_query
1076 bs_bs_query Franks, S., McCarthy, M.I., Hardy, K., 2006. Development of poly- 116, 621–637. 1144
bs_bs_query
1077 bs_bs_query cystic ovary syndrome: involvement of genetic and environmen- Kaya, C., Pabuccu, R., Satiroglu, H., 2010. Serum antimullerian 1145
bs_bs_query
1078 bs_bs_query tal factors. Int. J. Androl. 29, 278–285, discussion 286-290. hormone concentrations on day 3 of the in vitro fertilization stimu- 1146
bs_bs_query
1079 bs_bs_query Grossman, M.P., Nakajima, S.T., Fallat, M.E., Siow, Y., 2008. lation cycle are predictive of the fertilization, implantation, and 1147
bs_bs_query
1080 bs_bs_query Mullerian-inhibiting substance inhibits cytochrome P450 aromatase pregnancy in polycystic ovary syndrome patients undergoing as- 1148
bs_bs_query
1081 bs_bs_query activity in human granulosa lutein cell culture. Fertil. Steril. 89, sisted reproduction. Fertil. Steril. 94, 2202–2207. 1149
bs_bs_query
1082 bs_bs_query 1364–1370. Kersual, N., Garambois, V., Chardes, T., Pouget, J.P., Salhi, I., 1150
bs_bs_query
1083 bs_bs_query Hanna, L.P.L., Rice, S., Whitehead, S., Mason, H.D. Anti-Müllerian Bascoul-Mollevi, C., Bibeau, F., Busson, M., Vie, H., Clemenceau, 1151
bs_bs_query
1084 bs_bs_query hormone (AMH) production by and AMH type II receptor (AMHRII) B., Behrens, C.K., Estupina, P., Pèlegrin, A., Navarro-Teulon, I., 1152
bs_bs_query
1085 bs_bs_query in normal human ovaries. Presented at the 8th European Con- 2014. The human Mullerian inhibiting substance type II receptor 1153
bs_bs_query
1086 bs_bs_query gress of Endocrinology, Glasgow, UK. 2006: Endocrine Abstracts as immunotherapy target for ovarian cancer. Validation using the 1154
bs_bs_query
1087 bs_bs_query 11 P687. mAb 12G4. MAbs 6, 1314–1326. 1155

bs_bs_query
1088 bs_bs_query Hendriks, M.L., Konig, T., Korsen, T., Melgers, I., Dekker, J., Mijatovic, Kevenaar, M.E., Laven, J.S., Fong, S.L., Uitterlinden, A.G., de Jong, 1156
bs_bs_query
1089 bs_bs_query V., Schats, R., Hompes, P.G., Homburg, R., Kaaijk, E.M., Twisk, F.H., Themmen, A.P., Visser, J.A., 2008. A functional anti- 1157
bs_bs_query
1090 bs_bs_query J.W., Lambalk, C.B., 2014. Short-term changes in hormonal pro- mullerian hormone gene polymorphism is associated with fol- 1158
bs_bs_query
1091 bs_bs_query files after laparoscopic ovarian laser evaporation compared with licle number and androgen levels in polycystic ovary syndrome 1159
bs_bs_query
1092 bs_bs_query diagnostic laparoscopy for PCOS. Hum. Reprod. 29, 2544–2552. patients. J. Clin. Endocrinol. Metab. 93, 1310–1316. 1160
bs_bs_query
1093 bs_bs_query Hirobe, S., He, W.W., Lee, M.M., Donahoe, P.K., 1992. Mullerian in- Kevenaar, M.E., Themmen, A.P., van Kerkwijk, A.J., Valkenburg, O., 1161
bs_bs_query
1094 bs_bs_query hibiting substance messenger ribonucleic acid expression in granu- Uitterlinden, A.G., de Jong, F.H., Laven, J.S., Visser, J.A., 2009. 1162
bs_bs_query
1095 bs_bs_query losa and Sertoli cells coincides with their mitotic activity. Variants in the ACVR1 gene are associated with AMH levels in 1163
bs_bs_query
1096 bs_bs_query Endocrinology 131, 854–862. women with polycystic ovary syndrome. Hum. Reprod. 24, 241– 1164
bs_bs_query
1097 bs_bs_query Homburg, R., Ray, A., Bhide, P., Gudi, A., Shah, A., Timms, P., 249. 1165
bs_bs_query
1098 bs_bs_query Grayson, K., 2013. The relationship of serum anti-Mullerian Knight, P.G., Glister, C., 2006. TGF-beta superfamily members and 1166
bs_bs_query
1099 bs_bs_query hormone with polycystic ovarian morphology and polycystic ovary ovarian follicle development. Reproduction 132, 191–206. 1167
bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
1168
bs_bs_query Knochenhauer, E.S., Key, T.J., Kahsar-Miller, M., Waggoner, W., Boots, normogonadotrophic anovulatory infertility. Hum. Reprod. 19, 1236 bs_bs_query
1169
bs_bs_query L.R., Azziz, R., 1998. Prevalence of the polycystic ovary syn- 2036–2042. 1237 bs_bs_query
1170
bs_bs_query drome in unselected black and white women of the southeast- Muttukrishna, S., McGarrigle, H., Wakim, R., Khadum, I., Ranieri, D.M., 1238 bs_bs_query
1171
bs_bs_query ern United States: a prospective study. J. Clin. Endocrinol. Metab. Serhal, P., 2005. Antral follicle count, anti-mullerian hormone and 1239 bs_bs_query
1172
bs_bs_query 83, 3078–3082. inhibin B: predictors of ovarian response in assisted reproduc- 1240 bs_bs_query
1173
bs_bs_query Krishnan, A.V., Moreno, J., Nonn, L., Malloy, P., Swami, S., Peng, tive technology? BJOG 112, 1384–1390. 1241 bs_bs_query
1174
bs_bs_query L., Peehl, D.M., Feldman, D., 2007. Novel pathways that con- Nardo, L.G., Yates, A.P., Roberts, S.A., Pemberton, P., Laing, I., 2009. 1242 bs_bs_query
1175
bs_bs_query tribute to the anti-proliferative and chemopreventive activities The relationships between AMH, androgens, insulin resistance and 1243 bs_bs_query
1176
bs_bs_query of calcitriol in prostate cancer. J. Steroid Biochem. Mol. Biol. 103, basal ovarian follicular status in non-obese subfertile women with 1244 bs_bs_query
1177
bs_bs_query 694–702. and without polycystic ovary syndrome. Hum. Reprod. 24, 2917– 1245 bs_bs_query
1178
bs_bs_query La Marca, A., Volpe, A., 2006. Anti-Mullerian hormone (AMH) in female 2923. 1246 bs_bs_query
1179
bs_bs_query reproduction: is measurement of circulating AMH a useful tool? Pal, L., Berry, A., Coraluzzi, L., Kustan, E., Danton, C., Shaw, J., 1247 bs_bs_query
1180
bs_bs_query Clin. Endocrinol. (Oxf) 64, 603–610. Taylor, H., 2012. Therapeutic implications of vitamin D and calcium 1248 bs_bs_query
1181
bs_bs_query La Marca, A., Malmusi, S., Giulini, S., Tamaro, L.F., Orvieto, R., in overweight women with polycystic ovary syndrome. Gynecol. 1249 bs_bs_query
1182
bs_bs_query Levratti, P., Volpe, A., 2004a. Anti-Mullerian hormone plasma Endocrinol. 28, 965–968. 1250 bs_bs_query
1183
bs_bs_query levels in spontaneous menstrual cycle and during treatment with Park, A.S., Lawson, M.A., Chuan, S.S., Oberfield, S.E., Hoeger, K.M., 1251 bs_bs_query
1184
bs_bs_query
Q9 FSH to induce ovulation. Hum. Reprod. 19, 2738–2741. Witchel, S.F., Chang, R.J., 2010a. Serum anti-mullerian hormone 1252 bs_bs_query
1185
bs_bs_query La Marca, A., Orvieto, R., Giulini, S., Jasonni, V.M., Volpe, A., De concentrations are elevated in oligomenorrheic girls without evi- 1253 bs_bs_query
1186
bs_bs_query Leo, V., 2004b. Mullerian-inhibiting substance in women with poly- dence of hyperandrogenism. J. Clin. Endocrinol. Metab. 95, 1786– 1254 bs_bs_query
1187
bs_bs_query cystic ovary syndrome: relationship with hormonal and meta- 1792. Q10 1255 bs_bs_query
1188
bs_bs_query bolic characteristics. Fertil. Steril. 82, 970–972. Park, H.T., Cho, G.J., Ahn, K.H., Shin, J.H., Kim, Y.T., Hur, J.Y., 1256 bs_bs_query
1189
bs_bs_query La Marca, A., Giulini, S., Tirelli, A., Bertucci, E., Marsella, T., Xella, Kim, S.H., Lee, K.W., Kim, T., 2010b. Association of insulin 1257 bs_bs_query
1190
bs_bs_query S., Volpe, A., 2007. Anti-Mullerian hormone measurement on any resistance with anti-Mullerian hormone levels in women without 1258 bs_bs_query
1191
bs_bs_query day of the menstrual cycle strongly predicts ovarian response in polycystic ovary syndrome (PCOS). Clin. Endocrinol. (Oxf) 72, 26– 1259 bs_bs_query
1192
bs_bs_query assisted reproductive technology. Hum. Reprod. 22, 766–771. 31. 1260 bs_bs_query
1193
bs_bs_query Laven, J.S., Imani, B., Eijkemans, M.J., Fauser, B.C., 2002. New ap- Pellatt, L., Hanna, L., Brincat, M., Galea, R., Brain, H., Whitehead, 1261 bs_bs_query
1194
bs_bs_query proach to polycystic ovary syndrome and other forms of anovu- S., Mason, H., 2007a. Granulosa cell production of anti-Mullerian 1262 bs_bs_query
1195
bs_bs_query latory infertility. Obstet. Gynecol. Surv. 57, 755–767. hormone is increased in polycystic ovaries. J. Clin. Endocrinol. 1263 bs_bs_query
1196
bs_bs_query Laven, J.S., Mulders, A.G., Visser, J.A., Themmen, A.P., De Jong, Metab. 92, 240–245. Q11 1264 bs_bs_query
1197
bs_bs_query F.H., Fauser, B.C., 2004. Anti-Mullerian hormone serum concen- Pellatt, L., Rice, S., Mason, H.D., 2010. Anti-Mullerian hormone and 1265 bs_bs_query
1198
bs_bs_query trations in normoovulatory and anovulatory women of reproduc- polycystic ovary syndrome: a mountain too high? Reproduction 139, 1266 bs_bs_query
1199
bs_bs_query tive age. J. Clin. Endocrinol. Metab. 89, 318–323. 825–833. 1267 bs_bs_query
1200
bs_bs_query Legeai, L., Vigier, B., Tran, D., Picard, J.Y., Josso, N., 1986. Mono- Pellatt, L.R.S., Brincat, M., Galea, R., Mason, H. Anti-Müllerian 1268 bs_bs_query
1201
bs_bs_query clonal antibodies raised against bovine anti-mullerian hormone: hormone (AMH) inhibits aromatase expression in granulosa cells 1269 bs_bs_query
1202
bs_bs_query bovine, ovine, and caprine hormones share a set of identical from human ovaries. Proceedings of the Endocrine Society USA, 1270 bs_bs_query
1203
bs_bs_query epitopes. Biol. Reprod. 35, 1217–1225. 89th Annual Meeting, Toronto, Canada. 2007b: Oral Presenta- 1271 bs_bs_query
1204
bs_bs_query Legeai, L., Lefevre, G., Vigier, B., Picard, J.Y., Josso, N., 1988. A tion: 48–4. 1272 bs_bs_query
1205
bs_bs_query monoclonal antibody against human testicular anti-mullerian Pepinsky, R.B., Sinclair, L.K., Chow, E.P., Mattaliano, R.J., Manganaro, 1273 bs_bs_query
1206
bs_bs_query hormone. Am. J. Reprod. Immunol. Microbiol. 18, 39–43. T.F., Donahoe, P.K., Cate, R.L., 1988. Proteolytic processing 1274 bs_bs_query
1207
bs_bs_query Lin, Y.H., Chiu, W.C., Wu, C.H., Tzeng, C.R., Hsu, C.S., Hsu, M.I., of mullerian inhibiting substance produces a transforming 1275 bs_bs_query
1208
bs_bs_query 2011. Antimullerian hormone and polycystic ovary syndrome. Fertil. growth factor-beta-like fragment. J. Biol. Chem. 263, 18961– 1276 bs_bs_query
1209
bs_bs_query Steril. 96, 230–235. 18964. 1277 bs_bs_query
1210
bs_bs_query Mahran, A., Abdelmeged, A., El-Adawy, A.R., Eissa, M.K., Shaw, R.W., Pierre, A., Peigne, M., Grynberg, M., Arouche, N., Taieb, J., Hesters, 1278 bs_bs_query
1211
bs_bs_query Amer, S.A., 2013. The predictive value of circulating anti- L., Gonzales, J., Picard, J.Y., Dewailly, D., Fanchin, R., Catteau- 1279 bs_bs_query
1212
bs_bs_query Mullerian hormone in women with polycystic ovarian syndrome Jonard, S., di Clemente, N., 2013. Loss of LH-induced down- 1280 bs_bs_query
1213
bs_bs_query receiving clomiphene citrate: a prospective observational study. regulation of anti-Mullerian hormone receptor expression may 1281 bs_bs_query
1214
bs_bs_query J. Clin. Endocrinol. Metab. 98, 4170–4175. contribute to anovulation in women with polycystic ovary syn- 1282 bs_bs_query
1215
bs_bs_query Malloy, P.J., Peng, L., Wang, J., Feldman, D., 2009. Interaction of drome. Hum. Reprod. 28, 762–769. 1283 bs_bs_query
1216
bs_bs_query the vitamin D receptor with a vitamin D response element in the Pigny, P., Merlen, E., Robert, Y., Cortet-Rudelli, C., Decanter, C., 1284 bs_bs_query
1217
bs_bs_query Mullerian-inhibiting substance (MIS) promoter: regulation of MIS Jonard, S., Dewailly, D., 2003. Elevated serum level of anti- 1285 bs_bs_query
1218
bs_bs_query expression by calcitriol in prostate cancer cells. Endocrinology 150, mullerian hormone in patients with polycystic ovary syndrome: 1286 bs_bs_query
1219
bs_bs_query 1580–1587. relationship to the ovarian follicle excess and to the follicular 1287 bs_bs_query
1220
bs_bs_query Massague, J., Chen, Y.G., 2000. Controlling TGF-beta signaling. Genes arrest. J. Clin. Endocrinol. Metab. 88, 5957–5962. 1288 bs_bs_query
1221
bs_bs_query Dev. 14, 627–644. Piltonen, T., Morin-Papunen, L., Koivunen, R., Perheentupa, A., 1289 bs_bs_query
1222
bs_bs_query Merhi, Z., Fadiel, A., Buyuk, E., Naftolin, F., Cipolla, M., 2015. Vitamin Ruokonen, A., Tapanainen, J.S., 2005. Serum anti-Mullerian 1290 bs_bs_query
1223
bs_bs_query D attenuates the adverse effect of advanced glycation end prod- hormone levels remain high until late reproductive age and de- 1291 bs_bs_query
1224
bs_bs_query ucts on human granulosa cells: implications for women with PCOS. crease during metformin therapy in women with polycystic ovary 1292 bs_bs_query
1225
bs_bs_query Fertil. Steril. 104, e106. syndrome. Hum. Reprod. 20, 1820–1826. 1293 bs_bs_query
1226
bs_bs_query Modi, D., Bhartiya, D., Puri, C., 2006. Developmental expression and Piouka, A., Farmakiotis, D., Katsikis, I., Macut, D., Gerou, S., Panidis, 1294 bs_bs_query
1227
bs_bs_query cellular distribution of Mullerian inhibiting substance in the primate D., 2009. Anti-Mullerian hormone levels reflect severity of PCOS 1295 bs_bs_query
1228
bs_bs_query ovary. Reproduction 132, 443–453. but are negatively influenced by obesity: relationship with in- 1296 bs_bs_query
1229
bs_bs_query Moran, L.J., Noakes, M., Clifton, P.M., Norman, R.J., 2007. The use creased luteinizing hormone levels. Am. J. Physiol. Endocrinol. 1297 bs_bs_query
1230
bs_bs_query of anti-mullerian hormone in predicting menstrual response after Metab. 296, E238–E243. 1298 bs_bs_query
1231
bs_bs_query weight loss in overweight women with polycystic ovary syn- Rajpert-De Meyts, E., Jorgensen, N., Graem, N., Muller, J., Cate, R.L., 1299 bs_bs_query
1232
bs_bs_query drome. J. Clin. Endocrinol. Metab. 92, 3796–3802. Skakkebaek, N.E., 1999. Expression of anti-Mullerian hormone 1300 bs_bs_query
1233
bs_bs_query Mulders, A.G., Laven, J.S., Eijkemans, M.J., de Jong, F.H., Themmen, during normal and pathological gonadal development: associa- 1301 bs_bs_query
1234
bs_bs_query A.P., Fauser, B.C., 2004. Changes in anti-Mullerian hormone serum tion with differentiation of Sertoli and granulosa cells. J. Clin. 1302 bs_bs_query
1235
bs_bs_query concentrations over time suggest delayed ovarian ageing in Endocrinol. Metab. 84, 3836–3844. 1303 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007
ARTICLE IN PRESS
14 D Garg, R Tal
1304
bs_bs_query Rey, R., Lukas-Croisier, C., Lasala, C., Bedecarras, P., 2003. AMH/ with polycystic ovary syndrome and reproductive impairment. 1363 bs_bs_query
1305
bs_bs_query MIS: what we know already about the gene, the protein and its Hum. Reprod. 24, 1976–1981. 1364 bs_bs_query
1306
bs_bs_query regulation. Mol. Cell. Endocrinol. 211, 21–31. Tian, X., Ruan, X., Mueck, A.O., Wallwiener, D., Wang, J., Liu, S., 1365 bs_bs_query
1307
bs_bs_query Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, Yin, D., Lu, Y., Zhang, Y., Wu, H., 2014. Serum anti-Mullerian 1366 bs_bs_query
1308
bs_bs_query 2004. Revised 2003 consensus on diagnostic criteria and long- hormone and insulin resistance in the main phenotypes of non- 1367 bs_bs_query
1309
bs_bs_query term health risks related to polycystic ovary syndrome. Fertil. obese polycystic ovarian syndrome women in China. Gynecol. 1368 bs_bs_query
1310
bs_bs_query Steril. 81, 19–25. Endocrinol. 30, 836–839. 1369 bs_bs_query
1311
bs_bs_query Sahmay, S., Guralp, O., Aydogan, B., Cepni, I., Oral, E., Irez, T., 2013. Ueno, S., Kuroda, T., Maclaughlin, D.T., Ragin, R.C., Manganaro, T.F., 1370 bs_bs_query
1312
bs_bs_query Anti-Mullerian hormone and polycystic ovary syndrome: assess- Donahoe, P.K., 1989. Mullerian inhibiting substance in the adult 1371 bs_bs_query
1313
bs_bs_query ment of the clinical pregnancy rates in in vitro fertilization pa- rat ovary during various stages of the estrous cycle. Endocrinol- 1372 bs_bs_query
1314
bs_bs_query tients. Gynecol. Endocrinol. 29, 440–443. ogy 125, 1060–1066. 1373 bs_bs_query
1315
bs_bs_query Salhi, I., Cambon-Roques, S., Lamarre, I., Laune, D., Molina, F., Unoki, H., Yamagishi, S., 2008. Advanced glycation end products and 1374 bs_bs_query
1316
bs_bs_query Pugniere, M., Pourquier, D., Gutowski, M., Picard, J.Y., Xavier, insulin resistance. Curr. Pharm. Des. 14, 987–989. 1375 bs_bs_query
1317
bs_bs_query F., Pèlegrin, A., Navarro-Teulon, I., 2004. The anti-Mullerian Urbanek, M., 2007. The genetics of the polycystic ovary syndrome. 1376 bs_bs_query
1318
bs_bs_query hormone type II receptor: insights into the binding domains rec- Nat. Clin. Pract. Endocrinol. Metab. 3, 103–111. 1377 bs_bs_query
1319
bs_bs_query ognized by a monoclonal antibody and the natural ligand. Biochem. Vendola, K.A., Zhou, J., Adesanya, O.O., Weil, S.J., Bondy, C.A., 1998. 1378 bs_bs_query
1320
bs_bs_query J. 379, 785–793. Androgens stimulate early stages of follicular growth in the primate 1379 bs_bs_query
1321
bs_bs_query Selimoglu, H., Duran, C., Kiyici, S., Ersoy, C., Guclu, M., Ozkaya, G., ovary. J. Clin. Invest. 101, 2622–2629. 1380 bs_bs_query
1322
bs_bs_query Tuncel, E., Erturk, E., Imamoglu, S., 2010. The effect of vitamin Vigier, B., Legeai, L., Picard, J.Y., Josso, N., 1982. A sensitive ra- 1381 bs_bs_query
1323
bs_bs_query D replacement therapy on insulin resistance and androgen levels dioimmunoassay for bovine anti-Mullerian hormone, allowing its 1382 bs_bs_query
1324
bs_bs_query in women with polycystic ovary syndrome. J. Endocrinol. Invest. detection in male and freemartin fetal serum. Endocrinology 111, 1383 bs_bs_query
1325
bs_bs_query 33, 234–238. 1409–1411. 1384 bs_bs_query
1326
bs_bs_query Seyam, E.M., Mohamed, T.G., Hasan, M.M., Abd Al Mawgood, M.H., Vigier, B., Picard, J.Y., Tran, D., Legeai, L., Josso, N., 1984. Pro- 1385 bs_bs_query
1327
bs_bs_query 2014. Evaluation of ultrasonographic and Anti-Müllerian Hormone duction of anti-Mullerian hormone: another homology between 1386 bs_bs_query
1328
bs_bs_query (AMH) changes as predictors for ovarian reserve after laparo- Sertoli and granulosa cells. Endocrinology 114, 1315–1320. 1387 bs_bs_query
1329
bs_bs_query scopic ovarian drilling for women with polycystic ovarian syn- Vink, J.M., Sadrzadeh, S., Lambalk, C.B., Boomsma, D.I., 2006. Heri- 1388 bs_bs_query
1330
bs_bs_query drome. Middle East Fertil. Soc. J. 19, 314–323. tability of polycystic ovary syndrome in a Dutch twin-family study. 1389 bs_bs_query
1331
bs_bs_query Singer, T., Barad, D.H., Weghofer, A., Gleicher, N., 2009. Correla- J. Clin. Endocrinol. Metab. 91, 2100–2104. 1390 bs_bs_query
1332
bs_bs_query tion of antimullerian hormone and baseline follicle-stimulating Visser, J.A., de Jong, F.H., Laven, J.S., Themmen, A.P., 2006. 1391 bs_bs_query
1333
bs_bs_query hormone levels. Fertil. Steril. 91, 2616–2619. Anti-Mullerian hormone: a new marker for ovarian function. 1392 bs_bs_query
1334
bs_bs_query Skalba, P., Cygal, A., Madej, P., Dabkowska-Huc, A., Sikora, J., Reproduction 131, 1–9. 1393 bs_bs_query
1335
bs_bs_query Martirosian, G., Romanik, M., Olszanecka-Glinianowicz, M., 2011. Weenen, C., Laven, J.S., Von Bergh, A.R., Cranfield, M., Groome, 1394 bs_bs_query
1336
bs_bs_query Is the plasma anti-Mullerian hormone (AMH) level associated with N.P., Visser, J.A., Kramer, P., Fauser, B.C., Themmen, A.P., 2004. 1395 bs_bs_query
1337
bs_bs_query body weight and metabolic, and hormonal disturbances in women Anti-Mullerian hormone expression pattern in the human ovary: 1396 bs_bs_query
1338
bs_bs_query with and without polycystic ovary syndrome? Eur. J. Obstet. potential implications for initial and cyclic follicle recruitment. 1397 bs_bs_query
1339
bs_bs_query Gynecol. Reprod. Biol. 158, 254–259. Mol. Hum. Reprod. 10, 77–83. 1398 bs_bs_query
1340
bs_bs_query Stein, I.F., Leventhal, M.L., 1935. Amenorrhea associated with Weerakiet, S., Lertvikool, S., Tingthanatikul, Y., Wansumrith, S., 1399 bs_bs_query
1341
bs_bs_query bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29, 181– Leelaphiwat, S., 2007. and Jultanmas R. Ovarian reserve in women 1400 bs_bs_query
1342
bs_bs_query 191. with polycystic ovary syndrome who underwent laparoscopic 1401 bs_bs_query
1343
bs_bs_query Streuli, I., Fraisse, T., Chapron, C., Bijaoui, G., Bischof, P., de Ziegler, ovarian drilling. Gynecol. Endocrinol. 23, 455–460. 1402 bs_bs_query
1344
bs_bs_query D., 2009. Clinical uses of anti-Mullerian hormone assays: pitfalls Weil, S., Vendola, K., Zhou, J., Bondy, C.A., 1999. Androgen and 1403 bs_bs_query
1345
bs_bs_query and promises. Fertil. Steril. 91, 226–230. follicle-stimulating hormone interactions in primate ovarian fol- 1404 bs_bs_query
1346
bs_bs_query Stubbs, S.A., Hardy, K., Da Silva-Buttkus, P., Stark, J., Webber, L.J., licle development. J. Clin. Endocrinol. Metab. 84, 2951–2956. 1405 bs_bs_query
1347
bs_bs_query Flanagan, A.M., Themmen, A.P., Visser, J.A., Groome, N.P., Wilson, C.A., di Clemente, N., Ehrenfels, C., Pepinsky, R.B., Josso, 1406 bs_bs_query
1348
bs_bs_query Franks, S., 2005. Anti-mullerian hormone protein expression is N., Vigier, B., Cate, R.L., 1993. Mullerian inhibiting substance 1407 bs_bs_query
1349
bs_bs_query reduced during the initial stages of follicle development in human requires its N-terminal domain for maintenance of biological 1408 bs_bs_query
1350
bs_bs_query polycystic ovaries. J. Clin. Endocrinol. Metab. 90, 5536–5543. activity, a novel finding within the transforming growth factor- 1409 bs_bs_query
1351
bs_bs_query Tal, R., Seifer, D.B., Khanimov, M., Malter, H.E., Grazi, R.V., Leader, beta superfamily. Mol. Endocrinol. 7, 247–257. 1410 bs_bs_query
1352
bs_bs_query B., 2014. Characterization of women with elevated antimullerian Xi, W., Gong, F., Lu, G., 2012. Correlation of serum Anti-Mullerian 1411 bs_bs_query
1353
bs_bs_query hormone levels (AMH): correlation of AMH with polycystic ovarian hormone concentrations on day 3 of the in vitro fertilization stimu- 1412 bs_bs_query
1354
bs_bs_query syndrome phenotypes and assisted reproductive technology out- lation cycle with assisted reproduction outcome in polycystic ovary 1413 bs_bs_query
1355
bs_bs_query comes. Am. J. Obstet. Gynecol. 211, 59, e51-58. syndrome patients. J. Assist. Reprod. Genet. 29, 397–402. 1414 bs_bs_query
1356
bs_bs_query Tal, R., Tal, O., Seifer, B.J., Seifer, D.B., 2015. Antimullerian hormone
1415
as predictor of implantation and clinical pregnancy after as-
bs_bs_query
1357
bs_bs_query
1358
bs_bs_query sisted conception: a systematic review and meta-analysis. Fertil. Declaration: The authors report no financial or commercial con- 1416 bs_bs_query
1359
bs_bs_query Steril. 103, 119–130, e113. flicts of interests. 1417 bs_bs_query
1360
bs_bs_query Thomson, R.L., Buckley, J.D., Moran, L.J., Noakes, M., Clifton, P.M.,
1418
Norman, R.J., Brinkworth, G.D., 2009. The effect of weight loss
bs_bs_query
1361
bs_bs_query
1362
bs_bs_query on anti-Mullerian hormone levels in overweight and obese women Received 3 January 2016; refereed 3 April 2016; accepted 4 April 2016. 1419 bs_bs_query
(2016), doi: 10.1016/j.rbmo.2016.04.007

The Role of AMH in The Pathophysiology of

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Role of AMH in The Pathophysiology of

Uploaded by

Copyright:

Available Formats

ARTICLE IN PRESS

Reproductive BioMedicine Online (2016) ■■, ■■–■■

3 bs_bs_query The role of AMH in the pathophysiology of

39 bs_bs_query Introduction AMH and ovarian physiology 99 bs_bs_query

40 bs_bs_query 100 bs_bs_query

Primordial Preantral Small Antral Large Antral Pre ovulatory

172 bs_bs_query strated to result in decreased aromatase mRNA expression and

Increased Elevated Elevated AGEs Genetic Factors?

Decreased aromatase Decreased FSH

(2013). In addition to direct inhibitory effects of AMH on granu- 392 bs_bs_query

losa cell aromatase expression/activity leading to increased 393 bs_bs_query

a paracrine effect on theca interna cells given the presence 395

of AMHRII in these cells, leading to theca cell dysregulation 396 bs_bs_query

364 Androgens are produced in theca interna cells and con-

365 verted to oestrogens in granulosa cells by the action

366 of aromatase (Erickson et al., 1979). LH stimulates

367 steroidonegenesis by producing androgens from theca interna

368 cells. Elevated serum AMH concentration in PCOS has been

369 shown to be positively associated with androgen levels such

370 as serum testosterone and androstenedione (Carlsen et al.,

373 ute to the development of hyperandrogenism in women with

374 PCOS. While the speciﬁc mechanism/s of action of AMH leading

375 to hyperandrogensim in PCOS has not yet been fully eluci-

376 dated, such effect may be mediated by the reduction in

377 aromatase activity in granulosa cells of polycystic ovaries

458 bs_bs_query women, Pigny et al. found no signiﬁcant correlation between

800 women who underwent ovarian laser evaporation but not

1033 bs_bs_query ovary. Endocrinology 142, 4891–4899. 1083. 1101

1087 bs_bs_query 11 P687. mAb 12G4. MAbs 6, 1314–1326. 1155

You might also like