Published Research >
E.A.J. Ryan, S. Blanco Mejia, M. Maroleanu, M. Moruzanu, E.A. Claessens. An analysis of the effects of exogenous androgen administration on fertility rates in different age groups and with different adjunctive treatments. Meeting of the Canadian Fertility and Andrology Society, Vancouver, Canada. September 2010
30 Sep 2010
INTRODUCTION: Since Casson et al in 2000 first published a small number of patients (7) who seemed to benefit in their fertility quest using Dehydroepiandrosterone (DHEA) , many other authors from at least 5 countries have published more extensive information. Since 2005. Drs Gleicher and Barad from the C.H.R in New York were the leaders in this aspect of a “new “ innovative treatment. We have had some of our own data and some in combination with Gleicher et al published at ASRM 2008 and 2009, CFAS 2009, RB and E 2009 and I.F.G.I Florence 2010. As we have been using DHEA in many patients with diminished ovarian reserve (DOR ) since Feb, 2006 we have accumulated a large number of patients and treatment cycles and modalities and herein share our most recent findings with you.
MATERIAL AND METHODS: From February 2006 to April 2010 we started 347 patients whom we put on DHEA and were available for follow up and analysis. Our definition for DOR or poor ovarian responders is in keeping with current day accepted criteria of increased day 3 F.S.H., decreased A.M.H., decreased A.F.C. and previous poor response to ovarian stimulation or prolonged days of gonadotrophin stimulation using high doses. Our standard office policy in such cases is to give detailed information both from published data and from sites like WWW.DHEA.COM and have the patients sign an informed consent before starting DHEA. Any side effects are documented and DHEA is discontinued if these are significant. All pregnancies were followed to delivery to document any major or minor congenital defects.
If the patient fulfilled the definition of D.O.R, then she would start on 25 mgs micronized DHEA t.i.d. and after one or two months would start on an aromatase inhibitor either as 2.5 mgs daily for days 3-7 of the cycle or the step up Letrozole protocol. If pregnancy failed to occur with properly timed intercourse by 3 cycles then we progressed to COH-IUI in most cases. If pregnancy did not occur within 3 cycles of this regimen, IVF with ICSI was advised .The average number of treatment cycles for groups a,b,and c was 3.
66 PATIENTS LESS THAN 35 YR ( Aver. age 31.9yrs) WERE TREATED IN THE MANNER DESCRIBED AND RESULTED IN THE FOLLOWING CUMULATIVE PREGNANCY RATES
A: 7 OF 12 (58.3%) GOT PREGNANT ON DHEA ALONE
B: 4 OF 5 (80%) GOT PREGNANT ON LETROZOLE + DHEA
C: 6 OF 8 (75%) GOT PREGNANT ON C.O.H. -I.U.I. + DHEA
D: 14 OF 41 (34.1%) GOT PREGNANT, ONE CYCLE, WITH I.V.F./ I.C.S.I. + DHEA. Average age 31.9. Pregnancy loss rate 12.2% with one ectopic included. Multiple preg. rate of 28.57 %. Cycle cancellation rate was 8.3%.
142 PATIENTS WERE AGED 35 TO 39 INCLUSIVE.( Aver age 37 yrs)
A: 14 OF 34 (41.1%) GOT PREGNANT ON DHEA ALONE.
B: 9 OF 16 (56.2%) GOT PREGNANT ON LETROZOLE + DHEA (2 WITH ADDITION OF I.U.I.)
C: 22 OF 28 (78.5%) GOT PREGNANT ON C.O.H.- I.U.I. + DHEA, average of 3 cycles /patient )
D: 35 OF 64 PTS (54.7%) GOT PREGNANT, ONE CYCLE, WITH I.V.F./I.C.S.I. + DHEA..Pregnancy loss rate 15.6% (includes one termination at 20 wks for multiple congenital abnormalities). Multiple preg.rate of 29.41%. Cycle cancellation rate 9.3%.
139 PATIENTS WERE OVER 40 YRS
A: 8 OF 39 (20.5 %) PATIENTS GOT PREGNANT ON DHEA ALONE.
B: 12 OF 18 (66.6 %) GOT PREGNANT ON LETROZOLE + DHEA AND TIMED INTERCOURSE (1 HAD T.D.I.). 3 cycles average.
C: 14 OF 24 (58.3%) GOT PREGNANT ON C.O.H.- I.U.I. + DHEA (2/24 PATIENTS HAD TIMED INTERCOURSE, FROM WHICH NONE GOT PREGNANT)
D: 19 OF 58 (32.8%) ( Aver age 41.6yrs ) GOT PREGNANT WITH I.V.F./I.C.S.I.( ONE CYCLE ), Preg. Loss rate 13.8%, Cycle cancellation rate 22.1%
N.B. ALL PREGNANCIES ARE STATED AS POSITIVE WITH A DOUBLING OF THE H.C.G. FROM 14 DAYS POST I.U.I. OR EMBRYO TRANSFER OR ULTRASOUND VERIFIED OVULATION.
How DHEA seems to increase the quantity and more importantly the quality of class 1 to 5 primordial follicles and allow them to go through proper folliculogenesis is unknown. Effect may be mediated through the activation of IGF-1 by the increase in intra-ovarian and intra-follicular testosterone levels. Modification to mitochondrial function via alterations in the LASY system or changes to Caps 3 and 9, altering the polarity of the inner mitochondrial membrane, altering the production of ATP by the mitochondria, thereby influencing calcium homeostasis, cytoplasmic exostosis and various other proposed mitochondrial changes may be involved ( Bentov etal personal communication).
These beneficial effects seem to improve the function of the chromosomal spindle leading to a significant reduction in aneuploidy which would account for the reduced pregnancy loss rate we have reported before (ASRM San Francisco) and is shown again here in the very low pregnancy loss rates in this normally high loss rate group, namely D.O.R. and older patients. This reduction in aneuploidy has been shown in first polar body biopsy of IVF created eggs in women >40 Y.O. if on DHEA compared to age matched women NOT on DHEA (Dr. N. Gleicher, personal communication 2010). We have documented a pregnancy loss rate in most women on DHEA up to age 38 of 15 to 16 % and at age 42+, a 25% loss versus the expected 50%+ from the literature.
From our analysis of the 347 patients in our ongoing study it seems reasonable to proceed with DHEA using the above progression of treatment modalities, as an effective and affordable alternative to early IVF intervention. These IVF stats are from Feb 2006 to Sept 2010 and all other groups are from Feb 2006 to 1st April 2010. We note in particular , the poor performance of those women under 35 yrs who required IVF. This group acts more like the over 40 yrs olds except for a higher cancellation rate in the latter group.