Hum. Reprod. Advance Access published online on September 5, 2008
Human Reproduction, doi:10.1093/humrep/den320
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Letter to the Editor |
Reply: Androgen priming before ovarian stimulation for IVF
1 The Fertility Clinic, Section 4071, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark 2 Laboratory of Reproductive Biology, Section 5712, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark
3 Correspondence address. E-mail: kristine.loessl{at}rh.dk
We thank N. Gleicher and D.H. Barad for their interest in our newly published study (Lossl et al., 2008
). We both share the same interest in exploring elevated androgen levels as a mean to improve the outcome of infertility treatment. The concept is that androgens may augment FSH-receptor expression and stimulate granulosa cell proliferation. This could potentially increase oocyte yield, by increasing the number of follicles responding to exogenous FSH administration and by improving the quality and pregnancy potential of the retrieved oocytes.
Whereas Gleicher and Barad have mainly focused on administrating androgens systemically, through the use of the relative week androgen DHEA, we have focused on increasing the ‘local’ intraovarian androgen levels, without affecting circulating levels, by giving an aromatase inhibitor (AI) to prevent conversion of androgens into estrogens, and hCG to stimulate local androgen synthesis within the theca cells (Lossl et al., 2006, 2008; Yding Andersen and Lossl, 2008). The other main differences between the studies performed by the two groups are the patient selection and the duration of treatment. Gleicher and Barad treated poor responder patients with long-term (months) administration of DHEA (Barad and Gleicher, 2005, 2006), whereas we used short-term (days) androgen priming in patients with a presumable normal ovarian reserve.
First of all, we do agree that the use of androgens for priming purposes remains an attractive possibility to improve the ovarian response, probably both in low and normal responders. In our point of view, the overall goal is to create a ‘temporary reversible PCO-like condition’ with an enhanced follicular response to gonadotrophins. The protocol, as used in our recent prospective randomized study, does, however, need adjustments (Lossl et al., 2008), but with the many drugs presently available including GnRH analogues, androgens, AI, recombinant LH/hCG and FSH preparations, although being a challenge, it may be possible.
Although we failed to find an increased number of embryos in the androgen primed group, it is correctly stated by Gleicher and Barad that we observed a higher peak estradiol level and a higher estradiol level per follicle, and that this usually correlates with oocyte quality and ultimately pregnancy potential. This was, however, accompanied by a lower fertilization rate in the androgen primed group when compared with the control group. We believe that this is due to a dual action of androgens during the follicular development (Yding Andersen and Lossl, 2008). We think that we actually did obtain an increased responsiveness of the follicles by the androgen priming of the small antral follicles, but that a prolonged exposure to high androgen levels in the late follicular phase created unfavourable intrafollicular conditions, which reduced the fertilization potential of the retrieved oocytes from the large pre-ovulatory follicles. This was substantiated by the significantly increased levels of androgens found in the pre-ovulatory follicular fluid at oocyte retrieval, which was an unexpected finding, since AI administration was withdrawn almost 12 days earlier.
In contrast, we did not find differences in the systemic levels of androgen during the period of androgen priming and ovarian stimulation. This is probably one of the main differences between the ‘systemic’ approach by Gleicher and Barad and our ‘local’ approach. To create increased intrafollicular levels of androgens capable of stimulating the androgen receptor to a degree that results in an increased FSH-expression may require high amounts of biological active substances like testosterone or prolonged systemic administration of weaker androgens like DHEA.
We used a modified antagonist protocol, and combined the ‘priming’ with the use of high-dose antagonist in order to prevent follicular growth during the ‘priming’. Indeed, early follicular-phase antagonist administration is not an established option. However, as an extension of our first pilot study (Lossl et al., 2006), we also pilot-tested the priming concept in a standard long agonist protocol including an extra week of agonist administration and androgen priming from Day 35, when down-regulation was achieved, until initiation of ovarian stimulation with exogenous HP-hMG on Day 42. The results are presented in Table I. It is seen that the number of oocytes retrieved, the fertilization rate and the number of embryos were not increased in the agonist protocol compared with the 1 week of priming in the modified antagonist protocol. Still the pregnancy rate was all right.
|
Gleischer and Barad have used the concept of androgen priming on primarily low-responder patients. We have chosen to study normal-responder patients, as we believe that androgen priming is general phenomenon. The animal studies that demonstrated increased number of pre-antral and small antral follicles, increased granulosa and theca cell proliferation, and increased granulosa cell FSH receptor mRNA level, after 3–10 days of androgen exposure, were performed on presumable ‘normal responder’ animals (Vendola et al., 1998
; Weil et al., 1999; Luo and Wiltbank, 2006). Where the target of short-term androgen priming is the cohort of antral follicles ready for secondary recruitment, the target of long-term androgen priming may be pre-antral follicles at earlier stages, where androgens may exert proliferate effects independent of FSH. We do recognize that low-responder patients are likely to benefit the most once an effective protocol has developed, and still find that the interesting concept of androgen priming is far from fully exploited, but we do find that randomized controlled trials are needed before firm conclusions of the clinical relevance of androgen priming can be drawn, recognizing the difficulties in recruiting certain relevant patient groups.
References
Andersen CY, Lossl K. Increased intrafollicular androgen levels affect human granulosa cell secretion of anti-Müllerian hormone and inhibin-B. Fertil Steril (2008) 89:1760–1765.[CrossRef][Web of Science][Medline]
Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod (2006) 21:2845–2849.
Barad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril (2005) 84:756.[Medline]
Lossl K, Andersen AN, Loft A, Freiesleben NL, Bangsboll S, Andersen CY. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols. Hum Reprod (2006) 21:2593–2600.
Lossl K, Andersen CY, Loft A, Freiesleben NL, Bangsboll S, Andersen AN. Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial. Hum Reprod (2008) 23:1820–1829.
Luo W, Wiltbank MC. Distinct regulation by steroids of messenger RNAs for FSHR and CYP19A1 in bovine granulosa cells. Biol Reprod (2006) 75:217–225.
Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest (1998) 101:2622–2629.[Web of Science][Medline]
Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab (1999) 84:2951–2956.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||