Low AMH and GnRH-antagonist strategies

28 05 2009

To the Editor:

We read with interest the case report by Tocci reporting a live birth in a woman with a negligible anti-Mullerian hormone (AMH) as defined by an AMH of <3.5 pmol/L (1).  We have previously reported a prospective cohort of 61 women with a median AMH of 3.0 (IQR 2.0 -3.8) pmol/L, where use of antagonist cycles without preprogramming achieved a clinical pregnancy rate of 14.7% per cycle started and a trend towards higher pregnancy rates as compared to agonist cycles [adjusted OR 2.89 (95% CI 0.88 -9.50); p=0.08](2).  Specifically, in this cohort there were 47 treatment cycles in 35 women with AMH <3.5pmol/L, of whom 6 (12.7% per cycle) achieved a clinical pregnancy.  Subsequent follow up of these women demonstrated that all 6 achieved a live birth. 

Notably pre-programming of cycles was not used during this prospective approach.  However, pre-programming was deployed subsequently, in a cohort of 153 cycles in women with AMH <3.5.  The clinical pregnancy rate (11.1%) in this cohort was similar to that achieved without pre-programming, suggesting no clinical advantage from this tactical aspect.

Consistent with the successful protocol reported by Tocci, GnRH antagonists were utilised in keeping with our previous recommendations (3).  The current case report strengthens our case for the use of GnRH antagonist control of ovarian stimulation in women with a low ovarian reserve as determined by AMH (2, 3).

This debate begins to explore aspects of assisted conception in which a combination of ovarian reserve and age can be deployed to provide realistic assessments of patient options.  The requirement of reliable assays for AMH is now in place, although variability at these low concentrations needs further clarification. Prospective comparative trials can now be undertaken based upon the specific requirements of better defined populations.

Scott M Nelson, Ph.D.a
Richard Fleming. Ph.D.a,b
aReproductive & Maternal Medicine

Faculty of Medicine
University of Glasgow
Glasgow, United Kingdom

bGlasgow Centre for Reproductive Medicine
Glasgow, United Kingdom

References
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.

2. Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M et al. Anti-Mullerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod 2009:den480.

3. Nelson SM, Yates RW, Fleming R. Serum anti-Mullerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles implications for individualization of therapy. Hum Reprod 2007;22:2414-21.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.05.056

The Authors Respond:

We thank Dr. Nelson and Dr. Fleming for their interest in our paper (1) and comments.

They presented unpublished follow-up data on live births following GnRh antagonist cycles in patients with negligible levels of anti-mullerian hormone (AMH): in the absence of cycle pre-programming, treatment results in a 12.7% live birth rate per cycle in a cohort of 35 patients younger than 40 years old (2; Nelson & Fleming’s letter to the Editor).

The new interesting data reported by Nelson and Fleming strengthen our reported birth of a normal boy following an uneventful pregnancy in a patient with isolated negligible AMH values <3.6 pmol/L undergoing a modified minimal stimulation protocol using rFSH and GnRh antagonist (1).

We appreciate that a decrease of AMH to negligible levels can be an epiphenomenon of complex associated conditions, including impending premature ovarian failure (POF), which may occur in a substantial number of patients aged < 40 years who display impaired ovarian response to high dose gonadotropin controlled ovarian hyper-stimulation (COH). Some of these patients experience spontaneous pregnancy, including those with overt POF who still display a 5-10% chance to conceive (3,4). The etiology of these sometimes transient conditions is presently unknown and possibly based on patients’ genetic, chromosomal, environmental or auto-immune background; all these conditions, particularly those transient, may bear different pregnancy outcomes compared to that expressed by negligible levels of AMH.

Notably, in our study we provided a full laboratory evaluation for impending POF and other possible associated and transient conditions in a patient with negligible AMH: laboratory testing showed no abnormalities for any of the parameters investigated (1).

This approach let us deal with a patient with isolated very low AMH levels thus minimizing other possible confounding factors explaining her severely decreased response to COH. Therefore, in our case, a correlation between treatment outcome and AMH levels may be inferred.

We agree with Nelson and Fleming on the need for a better definition of the study populations. We feel that a selection of patients based on negligible levels of AMH as an isolated finding, in the absence of other possible confounding conditions, may avoid possible pooling of patients with similar AMH levels and ages but potentially different clinical characteristics.

In their letter, Nelson and Fleming also reported on a larger cohort of similar patients undergoing pre-programming, suggesting no advantage of this strategy to increase clinical pregnancy rates.

We are not able to ascertain if pre-programming is a successful strategy for increasing live birth rates in these patients. We suggested a rationale for this approach, inferring that in our case pituitary desensitization from three previous long agonist treatment may have resulted in a transient increase of AMH levels leading to hyper-stimulation. Similarly, we are not able to confirm the value of oral contraceptive pre-treatment before deploying a modified minimal stimulation protocol. In the absence of controlled randomized studies these issues remain elusive.

Angelo Tocci MD, PhD
Clinical Director Reproductive Medicine
Nuova Villa Claudia Clinic
Rome, Italy

Department of Reproductive Medicine
European Hospital Clinic
Rome, Italy

References
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. Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M, Mitchell P, Ambrose P, Fleming R. Anti-Mullerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod 2009; 24: 867-75.

3. Anasti JN. Premature ovarian failure: un update. Fertil Steril 1998; 70: 1-5

4. 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.2009.05.073

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