To the Editor:
We read with interest the reports of Fraisse et al. (2008) (1) and Tocci et al. (2009) (2) published in Fertility Sterility on a total of three cases of pregnancies despite undetectable serum anti-muellerian hormone (AMH) levels. Herein we report a similar case, which we would like to bring to the attention of our colleagues.
A 40-year-old female patient with a history of secondary infertility for two years presented at our department. In 2004 the definite diagnosis of premature ovarian failure had already been established by her gynecologist based on undetectable AMH levels, yet the patient conceived shortly thereafter by timed intercourse in a first cycle of clomifene treatment.
In 2009, when the patient presented at our department, the patient had already tried to conceive for 2 years, but suffered from oligomenorrhoea and showed follicle-stimulating-hormone (FSH) elevation to 26.0 mIU/ml. The serum AMH level measured by active MIS/AMH ELISA (Beckman Coulter) was below the detection limit (<3.6 pmol/l or <0.05 ng/ml). Antral follicle count in early follicular phase was two. In a first treatment trial, the patient was administered clomifene 50mg as performed previously (resulting in live birth in 2005), but estradiol remained low (peak level 18 pg/ml) and no follicular development was observed.
A second treatment cycle was performed with daily 75 IU of menopausal gonadotrophin stimulation. Two follicles developed with a pre-ovulatory estradiol level of 174 pg/ml, and ovulation induction was performed with 5,000 IU hCG on cycle day ten. The couple had timed intercourse resulting in a pregnancy which is ongoing in the third trimester at the time of writing.
Although it may be correct that that AMH may provide an accurate assessment of the size of the follicular pool in hypergonadotropic women with cycle disturbances not fulfilling the POF diagnostic criteria (3) and thus may provide a good measure of the response to ovarian stimulation, it is important to acknowledge that AMH cannot reliably predict present fecundity. This, together with a recent report on the relative insufficiency of AMH levels to predict pregnancy in IUI cycles (4) casts a doubt on the usefulness of AMH measurements for fast-tracking aging patients to IVF rather than to low intervention treatment options.
Tim Cordes, M.D.
Askan Schultze-Mosgau, M.D.
Klaus Diedrich, M.D.
Georg Griesinger, M.D., M.Sc.
Department of Gynecology and Obstetrics
University Hospital of Schleswig-Holstein, Campus Luebeck
1. Fraisse T, Ibecheole V, Streuli I, Bischof P, de Ziegler D. Undetectable serum anti-Müllerian hormone levels and occurrence of ongoing pregnancy. Fertil Steril. 2008 Mar;89(3):723.e9-11.
2. Tocci A, Ferrero S, Iacobelli M, Greco E. Negligible serum anti-müllerian hormone: pregnancy and birth after a 1-month course of an oral contraceptive, ovarian hyperstimulation, and intracytoplasmic sperm injection. Fertil Steril. 2009 Jul;92(1):395.e9-395.e12.
3. Knauff EA, Eijkemans MJ, Lambalk CB, ten Kate-Booij MJ, Hoek A, Beerendonk CC, Laven JS, Goverde AJ, Broekmans FJ, Themmen AP, de Jong FH, Fauser BC; Dutch Premature Ovarian Failure Consortium. Anti-Mullerian hormone, inhibin B, and antral follicle count in young women with ovarian failure. J Clin Endocrinol Metab. 2009 Mar;94(3):786-92. Epub 2008 Dec 9. Erratum in: J Clin Endocrinol Metab. 2010 Jan;95(1):465
4. Li HW, Biu Yeung WS, Lan Lau EY, Ho PC, Ng EH. Evaluating the performance of serum antimullerian hormone concentration in predicting the live birth rate of controlled ovarian stimulation and intrauterine insemination. Fertil Steril. 2010 Feb 18. [Epub ahead of print] PubMed PMID: 20171627
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.06.073
The Authors Respond (Fraisse et al.):
We warmly thank Cordes et al. (1) for adding one new case to our original report that first flashed the possibility of ongoing pregnancies in women whose AMH is undetectable (2). On our end, we identified 10 other similar cases since our first report was published, including 4 in non-infertile women.
The number of ovarian follicles susceptible to being stimulated in ART decreases with age, a phenomenon which commonly becomes overt by 37 years of age. Logically, this process was seen to parallel the known dwindling in women fecundity that debuts at approximately the same age. It was thus tempting to associate the quantity of ovarian follicles – as assessed by AMH and other markers – with the chances of conceiving in ART or even, naturally.
But recent data revealed that there is no independent link between the number of ovarian follicles available and pregnancy chances in ART (3). Indeed, Broekmans et al. reported that in ART, AMH levels adequately predict the magnitude of responses to controlled ovarian hyperstimulation (COH), but not pregnancies (3).
Reeling from Broekmans’ analysis (3), we understand therefore that AMH – like day-3 FSH and antral follicle count (AFC) – is a quantitative, not qualitative, marker of ovarian follicles. This sobering message certainly tempered the initial enthusiasm for AMH originally portrayed as the Holy Grail of ovarian function and flawless predictor of fecundity (4). Now that we better understand the differences between ovarian follicles quantity – AMH is a marker of – and quality, pregnancies in women with undetectable AMH levels are seen as lesser oddities.
In our eyes however, the lack of pregnancy prediction is not a reason for not measuring AMH when caring for infertile women. Indeed, aside from helping select the better COH protocol and initial FSH dose in ART, AMH measurements may help determining the relative urgency for ART. This is particularly the case in women whose infertility is seemingly unexplained. In these women, an unexpectedly low level of AMH should lead to suspicion that ovarian aging might play a part in infertility. In such cases, therefore, low AMH levels will – together with other elements of the infertility workup – weigh in favor of undertaking ART earlier rather than later.
Conversely, we do not follow the quest of Cordes et al. (1) for identifying the perfect candidate for non-ART ovarian stimulations, with or without intrauterine insemination. This is because, in most infertile women – in those who normally ovulate, notably – these middle-line treatments, which are not effective (5) let alone cost-effective (6), should not be undertaken.
Isabelle Streuli, M.D.a
Victoria Ibecheole, M.D.a
Timothée Fraisse, M.D.b
Paul Bischof, Ph.D.a
Dominique de Ziegler, M.D.c
aDepartment of Obstetrics and Gynecology, University Hospital Geneva, Geneva, Switzerland.
bMcKinzey & Company, Geneva, Switzerand.
cDivision of and Reproductive Endocrinology and Infertility,Department of Obstetrics and Gynecology II, Université Paris Descartes – Assistance Publique Hôpitaux de Paris, CHU Cochin, Paris, France.
1. Cordes T, Schultze-Mosgau A, Diedrich K, Griesinger G. Ongoing pregnancy in a 40 year old woman with undetectable AMH levels. Fertil Steril, in press.
2. Fraisse T, Ibecheole V, Streuli I, Bischof P, de Ziegler D. Undetectable serum anti-Müllerian hormone levels and occurrence of ongoing pregnancy. Fertil Steril. 2008;89:729-11.
3. Broekmans FJ, Soules MR, Fauser BC. Ovarian Aging: Mechanisms and Clinical Consequences. Endocr Reviews 2009,30:465–93.
4. Hazout A, Bouchard P, Seifer DB, Aussage P, Junca AM, Cohen-Bacrie P. Serum antimüllerian hormone/müllerian-inhibiting substance appears to be a more discriminatory marker of assisted reproductive technology outcome than follicle-stimulating hormone, inhibin B, or estradiol. Fertil Steril. 2004;82:1323-9.
5. Steures P, van der Steeg JW, Hompes PG, Habbema JD, Eijkemans MJ, Broekmans FJ, Verhoeve HR, Bossuyt PM, van der Veen F, Mol BW. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet. 2006;368:216-21.
6. Reindollar RH, Regan MM, Neumann PJ, Levine BS, Thornton KL, Alper MM, Goldman MB. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril. 2009 Jun 16., Epub ahead of print.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.06.072
The Authors Respond (Tocci):
We thank Dr. Cordes and Dr. Griesinger for their interest in our paper (1).
They present a case of a 40-year-old hypergonadotropic patient with secondary infertility who achieved pregnancy by slight controlled ovarian hyperstimulation (COH) and timed intercourse in the presence of undetectable levels of anti-mullerian hormone (AMH) (2).
In the opinion of Cordes and Griesinger, their case corroborates the hypotheses that undetectable AMH levels are not able to predict fecundity and should not imply the use of in vitro fertilization (IVF) as a first option.
However, the case reported by Cordes and Griesinger is different in many respect from the case described by my group. In our case, the young patient with primary (prevalently male) infertility was not hypergonadotropic and undetectable AMH levels were found as an isolated finding in the absence of any other sign of impending premature ovarian failure apart from a low antral follicles count (1); also, our patient displayed hyperstimulation with 6 recruited follicles and four metaphase II oocytes retrieved.
These findings, together with the verified quality of oocytes and embryos and the genetic-chromosomal competence of at least one embryo obtained in vitro raised interest of other colleagues in our case (3).
In this respect, the case described by Cordes and Griesinger is more similar to one of the two cases described by Fraisse et al. (4) that report on an hypergonadotropic patient with secondary infertility who spontaneously conceived in the presence of undetectable AMH levels. The second normogonadotropic patient described by Fraisse et al. raises doubts on the accuracy of AMH dosage, as the antral follicle count was normal at 12. In our opinion, the case described by Cordes and Griesinger should also be considered as a spontaneous conception, as it is unlikely that the use of a slight COH with human menopausal gonadotropin may have affected the folliculogenesis in the presence of basal FSH at 26 mIU/mL. We should also notice that, at the reported levels of basal FSH, the patient described by Cordes and Griesinger could not have been enrolled for IVF.
Therefore, in our opinion, in the cases described by the colleagues (2,4), the finding of undetectable AMH levels was an incidental, as well as an obvious finding given the impending premature ovarian failure with hypergonadotropism. Instead, the cases reported by Cordes and Fraisse should be interpreted more cautiously as the occurrence of spontaneous pregnancies, a phenomenon incidentally observed also in patients with overt premature ovarian failure who still display a 5-10 % chance to conceive (5).
In conclusion, we think that the usefulness of AMH measurements in counseling aged patients deserves more attention.
Angelo Tocci, M.D., Ph.D.
Reproductive Medicine Unit
Nuova Villa Claudia Clinic
1. Tocci A, Ferrero S, Iacobelli M, Greco E. Negligible serum anti-Mullerian hormone: pregnancy and birth after a 1-month course of an oral contraceptive, ovarian hyperstimulation, and intracytoplasmic sperm injection. Fertil Steril 2009; Apr 30.
2. Cordes T, Schultze-Mosgau A, Diedrich K, Griesinger G. Ongoing pregnancy after hMG stimulation and timed-intercourse in a 40 year old woman with undetectable AMH levels. Letter to the Editor of Fertility and Sterility, 2010.
3. Nelson SM, Fleming R.Low AMH and GnRH-antagonist strategies. Fertil Steril. 2009 Aug;92(2):e40; author reply e41. Epub 2009 Jul 5.
4. Fraisse T, Ibecheole V, Streuli I, Bischof P, de Ziegler D. Undetectable serum anti-Mullerian hormone levels and occurrence of ongoing pregnancy. Fertil Steril. 2008 Mar;89(3):723 e9-11.
5. Kalantaridou SN, Davis SR, Nelson LM. Premature ovarian failure. Endocrinol Metab Clin North Am 1998; 27: 989-1006
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.06.074