Editorial
tive in
Anti-Müllerian hormone is all you need: an assisted reproductive technology perspective in diagnosing polycystic ovary syndrome “...levels of anti-Müllerian hormone alone are strongly related to polycystic ovary syndrome as a cause of anovulation and can also give insight into a woman’s potential to respond to fertility treatment.” First draft submitted: 15 January 2016; Accepted for publication: 25 January 2016; Published online: 11 May 2016 Keywords: anovulatory infertility • anti-Müllerian hormone • assisted reproductive technology • hyperandrogenism • polycystic ovarian morphology • polycystic ovarian syndrome • Rotterdam criteria • subfertility
Many different groups of medical specialists provide care to women with polycystic ovary syndrome (PCOS). These include general practitioners, endocrinologists, gynecologists and fertility specialists. The condition is believed to be widespread, with 5–10% of women of childbearing age affected [1–3] . However, PCOS is a heterogenous syndrome encompassing a wide clinical spectrum from mild ovulatory dysfunction to severe metabolic disturbance and infertility [4] . A syndrome is merely a collection of clinical signs and symptoms rather than a specific diagnosis, so it is not surprising that PCOS has many different facets that are recognized and approached differently by specialists of different disciplines depending on the intended outcomes of treatment [1] . A fertility specialist sees PCOS as a different phenomenon to that seen by a specialist in metabolic medicine or endocrinology. While the unmasking of previously undiagnosed PCOS following investigation of anovular infertility can have lifelong consequences for the patient concerned [5] , the immediate results of this diagnosis pertain only to the management of treatment for induction of ovulation and/or superovulation for IVF. Improvements in quality and availability of easy to run assays for anti-Müllerian hormone (AMH) have led to increased interest
10.2217/whe-2016-0005 © 2016 Future Medicine Ltd
in the use of AMH measurement for diagnosis of PCOS [6] . Currently, a diagnosis of PCOS is made using the Rotterdam criteria, which requires two out of three features of clinical or biochemical hyperandrogenism, oligo/anovulation and/or polycystic ovaries on ultrasound [1] . Patients fall into various phenotypes ranging from a woman with only asymptomatic oligomenorrhea and slightly elevated testosterone to a woman with hirsutism, acne, amenorrhea and polycystic ovarian morphology [1] . When patients with anovulation present to fertility specialists for treatment, a full suite of hormonal, imaging and sometimes surgical investigations are carried out, often at great financial and time cost to the woman [1] . Although AMH measurement is not yet a standard diagnostic test for PCOS, levels of AMH alone are strongly related to PCOS as a cause of anovulation and can also give insight into a woman’s potential to respond to fertility treatment [7] . AMH is produced by granulosa cells primarily of preantral and antral ovarian follicles and may negatively feedback to regulate the growth of follicles by decreasing their sensitivity to FSH [4,7] . Thus, elevated AMH may inhibit the development and maturation of follicles, which contributes to both polycystic ovarian morphology and anovulation associated with PCOS [4,7] . In normally
Womens Health (2016) 12(3), 263–265
Kate McCullough Nepean Clinical School, University of Sydney, Australia
William Ledger Author for correspondence: School of Women’s & Children’s Health, University of NSW, Australia [email protected]
part of
ISSN 1745-5057
263
Editorial McCullough & Ledger cycling women, production of AMH by smaller antral follicles falls as the dominant follicle emerges [7] . However in PCOS the larger number of small antral follicles results in production of excessive AMH, which disrupts follicle selection and hence inhibits ovulation [7] . The higher the AMH, the more severe the clinical symptoms and the more antral follicles per ovary [4] . The elevated AMH may therefore be both a diagnostic marker of ongoing anovulatory cycles in PCOS as well as having a pathogenic role itself in continuing impaired folliculogenesis [7] . Studies concerning the usefulness of AMH in PCOS diagnosis are numerous and inconsistent. One recent study [8] reported that AMH measurement was only useful as a diagnostic adjunct in anovulatory women, with follicle number per ovary being a more sensitive measure and one that is useful across all PCOS phenotypes. Others have reported a greater utility for AMH over ultrasound criteria in diagnosis of PCOS [9] . There has also been concern over accuracy and reproducibility of existing AMH assays, making the development of a standardized normal range quite challenging. However, increased AMH is directly and independently related to increased ovarian volume [4] , increased antral follicle count [3] , amenorrhea [7] and hyperandrogenism [4] . Thus increased AMH is linked to all three Rotterdam criteria and AMH increases with severity of symptoms in PCOS [7] .
“Ovarian hyperstimulation remains the greatest threat to the health of women undergoing IVF treatment.” AMH is widely used as a marker of ovarian reserve, and generally decreases after age 25 years [3,7] . Serum AMH concentrations correlate with quantitative and qualitative measures of fertility treatment success including response to ovarian stimulation, pregnancy rates and life birth rates regardless of the woman’s age [7] and AMH is also strongly linked to the risk of developing ovarian hyperstimulation syndrome (OHSS) during fertility treatment, particularly so when the level becomes very elevated [7] . So in women who have anovulatory infertility with PCOS, AMH measurement can allow for planning of safe treatment. Furthermore, even in women without diagnosed PCOS, elevated AMH concentration is still predictive of increased risk of OHSS [4] . Such cases of ‘occult’ or hidden PCOS are at particularly high risk of overstimulation since the conventional ‘Rotterdam’ criteria are not met, deluding the clinician into a false sense of security and frequently leading to use of a ‘long protocol’ with gonadotropin-releasing hormone (GnRH) agonists, high doses of gonadotropins and subsequent moderate or severe OHSS. Women with a very elevated
264
Womens Health (2016) 12(3)
AMH have triple the risk of developing OHSS than those with a normal or borderline high level regardless of otherwise diagnosable PCOS, so potential for identifying these women and reducing their risk of fertility treatment complications is significant [7] . Ovarian hyperstimulation remains the greatest threat to the health of women undergoing IVF treatment [10] . Developing this potentially fatal condition can cause vascular hyperpermeability and severe third-spacing of fluid, particularly as ascites, and significant ovarian enlargement leading to risk of torsion [11] . Other sequelae of OHSS can include pleural effusions, thromboembolic events, hypovolemia and acute kidney injury, all of which have the potential to be catastrophic in otherwise well women undergoing fertility treatment [10] . Risks of OHSS have fallen in recent years, due in part to use of lower doses of gonadotropins for ovarian stimulation but, more recently by introduction of GnRH antagonist protocols for avoidance of premature luteinizing hormone (LH) surges. The use of a GnRH antagonist allows for an agonist ‘trigger’ to be used to stimulate final oocyte maturation before oocyte collection. Subsequent cryopreservation of embryos without a fresh embryo transfer has been shown in many studies to reduce risk of OHSS to almost zero [11] . Efficient cryopreservation using blastocyst vitrification maintains high pregnancy rates while removing the threat of OHSS [12,13] . It may be that in a few years time, all IVF treatments will employ an agonist trigger with cryopreservation of embryos. However, this is not the case in 2016. Many women prefer a fresh embryo transfer as this avoids delay and prolongation of treatment and not all laboratories are able to run successful vitrification programs. Current practice is to use pretreatment predictors of ovarian response to gonadotropin stimulation to determine the dose to be used and to decide whether strategies including a GnRH agonist trigger and ‘freeze-all’ embryos should be recommended to the woman. While both AMH and ultrasound-based tests, mainly antral follicle count, have been proposed as useful markers of possible high ovarian response to gonadotropins and risk of OHSS, AMH measurement has emerged as the more reliable and reproducible test, particularly now that automated assays are available [14] . Regardless of the underlying cause of infertility, IVF specialists’ aim is to help patients achieve a healthy pregnancy with minimal complications and side effects. A diagnosis of PCOS may have lifelong ramifications for women, but in those undergoing IVF, more importantly it is a significant contributor to OHSS risk. Hence, when diagnosing PCOS in the context of managing safe superovulation, AMH is all you need [15] .
future science group
AMH is all you need: an ART perspective in diagnosing PCOS
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employ-
Carmina E, Campagna AM, Fruzzetti F, Lobo RA. AMH measurement versus ovarian ultrasound in the diagnosis of polycystic ovary syndrome (PCOS) in different phenotypes. Endocr. Pract. 22(3), 287–293 (2015).
9
Lauritsen MP, Pinborg A, Loft A et al. Revised criteria for PCOS in WHO Group II anovulatory infertility – a revival of hypothalamic amenorrhoea? Clin. Endocrinol. (Oxf.) 82(4), 584–591 (2015).
10
Lie Fong S, Visser JA, Welt CK et al. Serum anti-Müllerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood. J. Clin. Endocrinol. Metab. 97(12), 4650–4655 (2012).
Carter R, Petrie K, Sadighi A, Skene H. Ovarian hyperstimulation syndrome on the acute medical unit: a problem-based review. Acute Med. 14(1), 21–27 (2015).
11
Rosenfield RL, Wroblewski K, Padmanabhan V, Littlejohn E, Mortensen M, Ehrmann DA. Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries. Fertil. Steril. 98(1), 242–249 (2012).
Fatemi HM, Garcia-Velasco J. Avoiding ovarian hyperstimulation syndrome with the use of gonadotropinreleasing hormone agonist trigger. Fertil. Steril. 103(4), 870–873 (2015).
12
Ledger WL, Atkin S, Sathyapalan T. Long term consequences of polycystic ovary syndrome. In: RCOG Guideline 33 (3rd Edition). Royal College of Obstetricians and Gynaecologists, London, UK (2014).
Atkinson P, Koch J, Susic D, Ledger WL. GnRH agonist triggers and their use in assisted reproductive technology: the past, the present and the future. Womens Health (Lond.) 10(3), 267–276 (2014).
13
Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum. Reprod. 26(10), 2593–2597 (2011).
14
Nelson SM, Pastuszek E, Kloss G et al. Two new automated, compared with two enzyme-linked immunosorbent, antimüllerian hormone assays. Fertil. Steril. 104(4), 1016. e6–1021.e6 (2015).
15
Nelson SM, Klein BM, Arce JC. Comparison of antimüllerian hormone levels and antral follicle count as predictor of ovarian response to controlled ovarian stimulation in good-prognosis patients at individual fertility clinics in two multicenter trials. Fertil. Steril. 103(4), 923.e1–930.e1 (2015).
1
Pasquali R, Gambineri A. A comprehensive approach in diagnosing the polycystic ovary syndrome. Womens Health (Lond.) 11(4), 501–512 (2015).
2
Crisosto N, Echiburú B, Maliqueo M et al. Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters. Fertil. Steril. 97(1), 218–224 (2012).
3
4
5
ment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 8
References
6
Anderson RA, Anckaert E, Bosch E et al. Prospective study into the value of the automated Elecsys antimüllerian hormone assay for the assessment of the ovarian growing follicle pool. Fertil. Steril. 103(4), 1074–1080 (2015).
7
Tal R, Seifer DB, Khanimov M, Malter HE, Grazi RV, Leader B. Characterization of women with elevated antimüllerian hormone levels (AMH): correlation of AMH with polycystic ovarian syndrome phenotypes and assisted reproductive technology outcomes. Am. J. Obstet. Gynecol. 211(1), 59.e1–59.e8 (2014).
future science group
Editorial
www.futuremedicine.com
265
tive in
Anti-Müllerian hormone is all you need: an assisted reproductive technology perspective in diagnosing polycystic ovary syndrome “...levels of anti-Müllerian hormone alone are strongly related to polycystic ovary syndrome as a cause of anovulation and can also give insight into a woman’s potential to respond to fertility treatment.” First draft submitted: 15 January 2016; Accepted for publication: 25 January 2016; Published online: 11 May 2016 Keywords: anovulatory infertility • anti-Müllerian hormone • assisted reproductive technology • hyperandrogenism • polycystic ovarian morphology • polycystic ovarian syndrome • Rotterdam criteria • subfertility
Many different groups of medical specialists provide care to women with polycystic ovary syndrome (PCOS). These include general practitioners, endocrinologists, gynecologists and fertility specialists. The condition is believed to be widespread, with 5–10% of women of childbearing age affected [1–3] . However, PCOS is a heterogenous syndrome encompassing a wide clinical spectrum from mild ovulatory dysfunction to severe metabolic disturbance and infertility [4] . A syndrome is merely a collection of clinical signs and symptoms rather than a specific diagnosis, so it is not surprising that PCOS has many different facets that are recognized and approached differently by specialists of different disciplines depending on the intended outcomes of treatment [1] . A fertility specialist sees PCOS as a different phenomenon to that seen by a specialist in metabolic medicine or endocrinology. While the unmasking of previously undiagnosed PCOS following investigation of anovular infertility can have lifelong consequences for the patient concerned [5] , the immediate results of this diagnosis pertain only to the management of treatment for induction of ovulation and/or superovulation for IVF. Improvements in quality and availability of easy to run assays for anti-Müllerian hormone (AMH) have led to increased interest
10.2217/whe-2016-0005 © 2016 Future Medicine Ltd
in the use of AMH measurement for diagnosis of PCOS [6] . Currently, a diagnosis of PCOS is made using the Rotterdam criteria, which requires two out of three features of clinical or biochemical hyperandrogenism, oligo/anovulation and/or polycystic ovaries on ultrasound [1] . Patients fall into various phenotypes ranging from a woman with only asymptomatic oligomenorrhea and slightly elevated testosterone to a woman with hirsutism, acne, amenorrhea and polycystic ovarian morphology [1] . When patients with anovulation present to fertility specialists for treatment, a full suite of hormonal, imaging and sometimes surgical investigations are carried out, often at great financial and time cost to the woman [1] . Although AMH measurement is not yet a standard diagnostic test for PCOS, levels of AMH alone are strongly related to PCOS as a cause of anovulation and can also give insight into a woman’s potential to respond to fertility treatment [7] . AMH is produced by granulosa cells primarily of preantral and antral ovarian follicles and may negatively feedback to regulate the growth of follicles by decreasing their sensitivity to FSH [4,7] . Thus, elevated AMH may inhibit the development and maturation of follicles, which contributes to both polycystic ovarian morphology and anovulation associated with PCOS [4,7] . In normally
Womens Health (2016) 12(3), 263–265
Kate McCullough Nepean Clinical School, University of Sydney, Australia
William Ledger Author for correspondence: School of Women’s & Children’s Health, University of NSW, Australia [email protected]
part of
ISSN 1745-5057
263
Editorial McCullough & Ledger cycling women, production of AMH by smaller antral follicles falls as the dominant follicle emerges [7] . However in PCOS the larger number of small antral follicles results in production of excessive AMH, which disrupts follicle selection and hence inhibits ovulation [7] . The higher the AMH, the more severe the clinical symptoms and the more antral follicles per ovary [4] . The elevated AMH may therefore be both a diagnostic marker of ongoing anovulatory cycles in PCOS as well as having a pathogenic role itself in continuing impaired folliculogenesis [7] . Studies concerning the usefulness of AMH in PCOS diagnosis are numerous and inconsistent. One recent study [8] reported that AMH measurement was only useful as a diagnostic adjunct in anovulatory women, with follicle number per ovary being a more sensitive measure and one that is useful across all PCOS phenotypes. Others have reported a greater utility for AMH over ultrasound criteria in diagnosis of PCOS [9] . There has also been concern over accuracy and reproducibility of existing AMH assays, making the development of a standardized normal range quite challenging. However, increased AMH is directly and independently related to increased ovarian volume [4] , increased antral follicle count [3] , amenorrhea [7] and hyperandrogenism [4] . Thus increased AMH is linked to all three Rotterdam criteria and AMH increases with severity of symptoms in PCOS [7] .
“Ovarian hyperstimulation remains the greatest threat to the health of women undergoing IVF treatment.” AMH is widely used as a marker of ovarian reserve, and generally decreases after age 25 years [3,7] . Serum AMH concentrations correlate with quantitative and qualitative measures of fertility treatment success including response to ovarian stimulation, pregnancy rates and life birth rates regardless of the woman’s age [7] and AMH is also strongly linked to the risk of developing ovarian hyperstimulation syndrome (OHSS) during fertility treatment, particularly so when the level becomes very elevated [7] . So in women who have anovulatory infertility with PCOS, AMH measurement can allow for planning of safe treatment. Furthermore, even in women without diagnosed PCOS, elevated AMH concentration is still predictive of increased risk of OHSS [4] . Such cases of ‘occult’ or hidden PCOS are at particularly high risk of overstimulation since the conventional ‘Rotterdam’ criteria are not met, deluding the clinician into a false sense of security and frequently leading to use of a ‘long protocol’ with gonadotropin-releasing hormone (GnRH) agonists, high doses of gonadotropins and subsequent moderate or severe OHSS. Women with a very elevated
264
Womens Health (2016) 12(3)
AMH have triple the risk of developing OHSS than those with a normal or borderline high level regardless of otherwise diagnosable PCOS, so potential for identifying these women and reducing their risk of fertility treatment complications is significant [7] . Ovarian hyperstimulation remains the greatest threat to the health of women undergoing IVF treatment [10] . Developing this potentially fatal condition can cause vascular hyperpermeability and severe third-spacing of fluid, particularly as ascites, and significant ovarian enlargement leading to risk of torsion [11] . Other sequelae of OHSS can include pleural effusions, thromboembolic events, hypovolemia and acute kidney injury, all of which have the potential to be catastrophic in otherwise well women undergoing fertility treatment [10] . Risks of OHSS have fallen in recent years, due in part to use of lower doses of gonadotropins for ovarian stimulation but, more recently by introduction of GnRH antagonist protocols for avoidance of premature luteinizing hormone (LH) surges. The use of a GnRH antagonist allows for an agonist ‘trigger’ to be used to stimulate final oocyte maturation before oocyte collection. Subsequent cryopreservation of embryos without a fresh embryo transfer has been shown in many studies to reduce risk of OHSS to almost zero [11] . Efficient cryopreservation using blastocyst vitrification maintains high pregnancy rates while removing the threat of OHSS [12,13] . It may be that in a few years time, all IVF treatments will employ an agonist trigger with cryopreservation of embryos. However, this is not the case in 2016. Many women prefer a fresh embryo transfer as this avoids delay and prolongation of treatment and not all laboratories are able to run successful vitrification programs. Current practice is to use pretreatment predictors of ovarian response to gonadotropin stimulation to determine the dose to be used and to decide whether strategies including a GnRH agonist trigger and ‘freeze-all’ embryos should be recommended to the woman. While both AMH and ultrasound-based tests, mainly antral follicle count, have been proposed as useful markers of possible high ovarian response to gonadotropins and risk of OHSS, AMH measurement has emerged as the more reliable and reproducible test, particularly now that automated assays are available [14] . Regardless of the underlying cause of infertility, IVF specialists’ aim is to help patients achieve a healthy pregnancy with minimal complications and side effects. A diagnosis of PCOS may have lifelong ramifications for women, but in those undergoing IVF, more importantly it is a significant contributor to OHSS risk. Hence, when diagnosing PCOS in the context of managing safe superovulation, AMH is all you need [15] .
future science group
AMH is all you need: an ART perspective in diagnosing PCOS
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employ-
Carmina E, Campagna AM, Fruzzetti F, Lobo RA. AMH measurement versus ovarian ultrasound in the diagnosis of polycystic ovary syndrome (PCOS) in different phenotypes. Endocr. Pract. 22(3), 287–293 (2015).
9
Lauritsen MP, Pinborg A, Loft A et al. Revised criteria for PCOS in WHO Group II anovulatory infertility – a revival of hypothalamic amenorrhoea? Clin. Endocrinol. (Oxf.) 82(4), 584–591 (2015).
10
Lie Fong S, Visser JA, Welt CK et al. Serum anti-Müllerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood. J. Clin. Endocrinol. Metab. 97(12), 4650–4655 (2012).
Carter R, Petrie K, Sadighi A, Skene H. Ovarian hyperstimulation syndrome on the acute medical unit: a problem-based review. Acute Med. 14(1), 21–27 (2015).
11
Rosenfield RL, Wroblewski K, Padmanabhan V, Littlejohn E, Mortensen M, Ehrmann DA. Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries. Fertil. Steril. 98(1), 242–249 (2012).
Fatemi HM, Garcia-Velasco J. Avoiding ovarian hyperstimulation syndrome with the use of gonadotropinreleasing hormone agonist trigger. Fertil. Steril. 103(4), 870–873 (2015).
12
Ledger WL, Atkin S, Sathyapalan T. Long term consequences of polycystic ovary syndrome. In: RCOG Guideline 33 (3rd Edition). Royal College of Obstetricians and Gynaecologists, London, UK (2014).
Atkinson P, Koch J, Susic D, Ledger WL. GnRH agonist triggers and their use in assisted reproductive technology: the past, the present and the future. Womens Health (Lond.) 10(3), 267–276 (2014).
13
Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum. Reprod. 26(10), 2593–2597 (2011).
14
Nelson SM, Pastuszek E, Kloss G et al. Two new automated, compared with two enzyme-linked immunosorbent, antimüllerian hormone assays. Fertil. Steril. 104(4), 1016. e6–1021.e6 (2015).
15
Nelson SM, Klein BM, Arce JC. Comparison of antimüllerian hormone levels and antral follicle count as predictor of ovarian response to controlled ovarian stimulation in good-prognosis patients at individual fertility clinics in two multicenter trials. Fertil. Steril. 103(4), 923.e1–930.e1 (2015).
1
Pasquali R, Gambineri A. A comprehensive approach in diagnosing the polycystic ovary syndrome. Womens Health (Lond.) 11(4), 501–512 (2015).
2
Crisosto N, Echiburú B, Maliqueo M et al. Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters. Fertil. Steril. 97(1), 218–224 (2012).
3
4
5
ment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 8
References
6
Anderson RA, Anckaert E, Bosch E et al. Prospective study into the value of the automated Elecsys antimüllerian hormone assay for the assessment of the ovarian growing follicle pool. Fertil. Steril. 103(4), 1074–1080 (2015).
7
Tal R, Seifer DB, Khanimov M, Malter HE, Grazi RV, Leader B. Characterization of women with elevated antimüllerian hormone levels (AMH): correlation of AMH with polycystic ovarian syndrome phenotypes and assisted reproductive technology outcomes. Am. J. Obstet. Gynecol. 211(1), 59.e1–59.e8 (2014).
future science group
Editorial
www.futuremedicine.com
265
