Ovarian hyperstimulation

Ovarian hyperstimulation (also called controlled ovarian hyperstimulation^[1]) is where a regimen of fertility medications are used to stimulate the development of multiple follicles of the ovaries in one single cycle, resulting in superovulation (release of a larger-than-normal number of eggs)^[2]. It may be used as a part of in vitro fertilization. Treatment cycles are typically started on the third day of menstruation.

In contrast, when referring to the reversal of oligoovulation or anovulation, the preferred term is rather ovulation induction.^[3]

Procedure

Medications used

In most patients injectable gonadotropins are used, usually FSH analogues. A meta-analysis came to the result that the optimal daily recombinant FSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF.^[4] Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy rates and embryo cryopreservation rates.^[4] There is a concomitant monitoring, including frequently checking the estradiol level and, by means of gynecologic ultrasonography, follicular growth. Typically approximately 10 days of injections will be necessary. Concomitantly administering recombinant hCG has no significant beneficial effect.^[5] Spontaneous ovulation during the cycle is typically prevented by the use of GnRH agonists or GnRH antagonists, which block the natural surge of luteinising hormone (LH).

Tracking

Tracking or supervising the maturation of follicles is performed in order to timely schedule oocyte retrieval. Two-dimensional ultrasound is conventionally used. Automated follicle tracking does not appear to improve the clinical outcome of assisted reproduction treatment.^[6]

Retrieval

When used in conjunction with in vitro fertilization (IVF), ovarian hyperstimulation may be followed by ovulation induction using human chorionic gonadotropin (hCG). hCH makes the follicles perform their final maturation. A transvaginal oocyte retrieval is then performed just prior to when the follicles would rupture. Alternatively, coasting may be performed, which is ovarian hyperstimulation in IVF without hCG administration. Coasting radically decreases the risk of ovarian hyperstimulation syndrome (OHSS), with a study of high risk patients showing no incidence of OHSS in 21 patients, versus ~20% in the control group.^[7] On the other hand, live birth rate may be slightly decreased, with the same study resulting in 38% in coasting vs. 45% among controls, as well as decreased cumulative live birth rate (52% vs. 59%),^[7] presumably because of more difficulty in timing oocyte retrieval with full maturation. However, there appears to be no significantly decreased birth rate among high responder patients, in the associated study defined as those having at least 20 follicles, each measuring ≥10 mm in diameter with ≥20% of them of diameter ≥15 mm.^[8]

Response predictors

Antral follicle count

The response to gonadotropins may be roughly approximated by antral follicle count (AFC), estimated by vaginal ultrasound, which in turn reflects how many primordial follicles there are in reserve in the ovary.^[9]

Patients may be classified by response as low responders, normal or average responders or high responders.^[9]

Antral follicle count	Classification	Approximate expected response	Risks	Pregnancy rates	Recommendation
Less than 4	Extremely low	Very poor or none	Cancelled cycle expected	Lower than average	Not attempt IVF
4-7	Low	Possibly/probably poor response	Higher than average rate of IVF cycle cancellation		High doses of gonadotropin likely
8-10	Reduced	Lower than average	Higher than average rate of IVF cycle cancellation	Slightly reduced
11-14	Normal (but intermediate)	Sometimes low, but usually adequate	Slight increased risk for IVF cycle cancellation	Slightly reduced compared to the "best" group
15-30	Normal (good)	Excellent	Very low risk for IVF cycle cancellation. Some risk for ovarian overstimulation	Best overall as a group	Low doses of gonadotropins
More than 30	High	Likely high	Overstimulation and ovarian hyperstimulation syndrome	Very good overall as a group, but potential egg quality issues	Low doses of gonadotropins
Unless else specified in boxes, then reference is [9]

Other

• Elevated basal Follicle stimulating hormone (FSH) levels imply a need of more ampoules of gonadotropins for stimulation, and have a higher cancellation rate because of poor response.^[10]

• Circulating Anti-Müllerian hormone (AMH) can predict excessive and poor response to ovarian stimulation. For predicting an excessive response, AMH is has a sensitivity and specificity of 82% and 76%, respectively.^[11] Overall it may be superior to AFC and basal FSH.^[12]

• Advanced maternal age causes decreased success rates in ovarian hyperstimulation. In ovarian hyperstimulation combined with IUI, women aged 38–39 years appear to have reasonable success during the first two cycles, with an overall live birth rate of 6.1% per cycle.^[13] However, for women aged ≥40 years, the overall live birth rate is 2.0% per cycle, and there appears to be no benefit after a single cycle of COH/IUI.^[13] It is therefore recommended to consider in vitro fertilization after one failed COH/IUI cycle for women aged ≥40 years.^[13]

Risks

There doesn't seem to be a substantial risk of invasive ovarian cancer with ovarian stimulation. However, a stronger association between fertility drug use and the relatively harmless borderline tumors of the ovary has been observed.^[14]

Alternative

In vitro maturation is letting ovarian follicles mature in vitro, and with this technique ovarian hyperstimulation isn't essential. Rather, oocytes can mature outside the body prior to IVF. Hence, no (or at least a lower dose of) gonadotropins have to be injected in the body.^[15] However, there still isn't enough evidence to prove the effectiveness and security of the technique.^[15]

References

1. ^ TheFreeDictionary --> controlled ovarian hyperstimulation Retrieved on October 3, 2009
2. ^ Webster's New World College Dictionary » superovulation Retrieved on October 3, 2009
3. ^ Ovulation Problems and Infertility: Treatment of ovulation problems with Clomid and other fertility drugs. Advanced Fertility Center of Chicago. Gurnee & Crystal Lake, Illinois. Retrieved on Mars 7, 2010
4. ^ ^{a b} Sterrenburg, M. D.; Veltman-Verhulst, S. M.; Eijkemans, M. J. C.; Hughes, E. G.; MacKlon, N. S.; Broekmans, F. J.; Fauser, B. C. J. M. (2010). "Clinical outcomes in relation to the daily dose of recombinant follicle-stimulating hormone for ovarian stimulation in in vitro fertilization in presumed normal responders younger than 39 years: a meta-analysis". Human Reproduction Update 17 (2): 184. doi:10.1093/humupd/dmq041. PMID 20843965.  edit
5. ^ Cavagna, M.; Maldonado, L.; De Souza Bonetti, T.; de Almeida Ferreira Braga DP; Iaconelli Jr, A.; Borges Jr, E. (2010). "Supplementation with a recombinant human chorionic gonadotropin microdose leads to similar outcomes in ovarian stimulation with recombinant follicle-stimulating hormone using either a gonadotropin-releasing hormone agonist or antagonist for pituitary suppression". Fertility and sterility 94 (1): 167–172. doi:10.1016/j.fertnstert.2009.02.075. PMID 19342035.  edit
6. ^ Raine-Fenning, N.; Deb, S.; Jayaprakasan, K.; Clewes, J.; Hopkisson, J.; Campbell, B. (2010). "Timing of oocyte maturation and egg collection during controlled ovarian stimulation: a randomized controlled trial evaluating manual and automated measurements of follicle diameter". Fertility and sterility 94 (1): 184–188. doi:10.1016/j.fertnstert.2009.02.063. PMID 19342014.  edit
7. ^ ^{a b} Gera, P.; Tatpati, L.; Allemand, M.; Wentworth, M.; Coddington, C. (2010). "Ovarian hyperstimulation syndrome: steps to maximize success and minimize effect for assisted reproductive outcome". Fertility and sterility 94 (1): 173–178. doi:10.1016/j.fertnstert.2009.02.049. PMID 19356753.  edit
8. ^ Yilmaz, N.; Uygur, D.; Ozgu, E.; Batioglu, S. (2010). "Does coasting, a procedure to avoid ovarian hyperstimulation syndrome, affect assisted reproduction cycle outcome?". Fertility and sterility 94 (1): 189–193. doi:10.1016/j.fertnstert.2009.02.090. PMID 19376515.  edit
9. ^ ^{a b c} Antral Follicle Counts, Resting Follicles, Ovarian Volume and Ovarian Reserve. Testing of egg supply and predicting response to ovarian stimulation drugs Advanced Fertility Center of Chicago. Retrieved on October 2, 2009
10. ^ ]http://content.karger.com/ProdukteDB/produkte.asp?Doi=52939 Useful Predictors of Ovarian Stimulation Response in Women Undergoing in vitro Fertilization.] Jolande G. van der Stegea, Paul J.Q. van der Lindenb. Gynecol Obstet Invest 2001;52:43-46 (DOI: 10.1159/000052939)
11. ^ Broer, S. L.; Dolleman, M.; Opmeer, B. C.; Fauser, B. C.; Mol, B. W.; Broekmans, F. J. M. (2010). "AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis". Human Reproduction Update 17 (1): 46. doi:10.1093/humupd/dmq034. PMID 20667894.  edit
12. ^ Circulating basal anti-Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization. Luciano G. Nardo, M.D.a, Tarek A. Gelbaya, M.D.a, Hannah Wilkinson, MB.ChB.a, Stephen A. Roberts, Ph.D.b, Allen Yates, Ph.D.c, Phil Pemberton, B.A.c, Ian Laing, Ph.D.c. Fertility and Sterility. Volume 92, Issue 5, Pages 1586-1593 (November 2009)
13. ^ ^{a b c} Harris, I.; Missmer, S.; Hornstein, M. (2010). "Poor success of gonadotropin-induced controlled ovarian hyperstimulation and intrauterine insemination for older women". Fertility and sterility 94 (1): 144–148. doi:10.1016/j.fertnstert.2009.02.040. PMID 19394605.  edit
14. ^ Mahdavi A, Pejovic T, Nezhat F (April 2006). "Induction of ovulation and ovarian cancer: a critical review of the literature". Fertil. Steril. 85 (4): 819–26. doi:10.1016/j.fertnstert.2005.08.061. PMID 16580355. 
15. ^ ^{a b} Vejledning om kunstig befrugtning 2006 (Danish)

External links

• Antral Follicle Counts, Resting Follicles, Ovarian Volume and Ovarian Reserve Advanced Fertility Center of Chicago.