Ovulation Induction versus Controlled Ovarian Hyperstimulation

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Ovulation Induction versus Controlled Ovarian Hyperstimulation

Ben J. Cohlen

Introduction

Chronic anovulation is a common feature in infertile couples. It is unknown how many couples suffer from anovulation in the general population, but estimates vary between 5% and 15%. Being a sign rather than a disease, chronic anovulation is treated in various ways, depending on the underlying cause.

Although with ovulation induction, treatment is started to regain monthly mono-ovulation, the aim of treatment in controlled ovarian hyperstimulation is the development and ovulation of at least two dominant follicles to improve pregnancy chances in an ovulatory patient. However, two very different treatment strategies, ovulation induction (OI) and controlled ovarian hyperstimulation (COH), are often mixed up, which might result in unnecessary complications (Chapters 23 through 26).

In this chapter, both treatment modalities are defined and discussed.

Definitions

The WHO-ICMART committees defined ovulation induction as follows: pharmacologic treatment of women with anovulation or oligo-ovulation with the intention of inducing normal ovulatory cycles (1). From this definition, we can conclude that the intention of OI is the release of one oocyte per cycle, resembling normal ovulatory cycles. Thus, the goal of OI should be monthly mono-follicular development and mono-ovulation.

Controlled ovarian hyperstimulation in NON-ART cycles (the WHO calls it controlled ovarian stimulation) is defined by the WHO-ICMART as pharmacologic treatment for women in which the ovaries are stimulated to ovulate more than one oocyte. Thus, the goal of COH in NON-ART should be (monthly) multi-follicular development and multiple ovulations. In this definition, NON-ART stands for hyper-stimulated cycles besides IVF or ICSI.

Existing Evidence in COH for NON-ART

Why should we stress this difference in approach between COH and OI? Regaining normal ovulatory cycles in women with anovulation, patent tubes, and a partner with normal sperm parameters restores almost normal fertility. Cumulative live birth rates of up to 70% in two years in anovulatory women have been reported (2), almost resembling normal fertility rates. Furthermore, a successful outcome in fertility treatment is defined as the live birth of a healthy singleton. Mono-ovulation is a requirement to achieve this goal.

In COH cycles, the goal is the same: the live birth of a healthy singleton. However, one tries to enhance fertility by releasing two to three oocytes in couples with often a period of unsuccessful mono-ovulation combined with intercourse (unexplained or mild male subfertility, minimal to mild endometriosis) (3) (LOE 1a). Multi-follicular development is one of the keystones for success. It is even questionable whether mono-follicular development in COH cycles increases pregnancy rates. With this strategy, however, one incorporates the chance of achieving a multiple pregnancy, and couples should be informed about these chances beforehand.

Treatment of anovulation with ovulation induction is the subject of Chapters 14 through 21 and will not further be discussed in this chapter.

When to Start COH?

It is obvious that COH is applied in IVF or ICSI cycles. In couples with mild male or unexplained subfertility, it is hypothesized that the subfertility of the couple is related to the subfertility of the woman, and COH in combination with IUI is the most cost-effective first-line treatment option when spontaneous changes are low (4,5) (LOE 1b). By applying COH, one increases the number of available oocytes, improves timing of insemination, and one might correct subtle hormonal imbalances and luteinized unruptured follicle cycles.

But what should we offer couples after 12 ovulatory but unsuccessful OI cycles? What has been proven the most cost-effective treatment option in couples with minimal to mild endometriosis? When should we apply COH in (lesbian) couples or single women using donor sperm?

A large Dutch randomized trial currently investigates whether switching after six ovulatory OI cycles to either IUI of FSH-stimulated cycles improves treatment outcome (M-OVIN study, Netherlands Trial register NTR1449). But further large prospective studies are lacking.

Many centers offer COH (in combination with IUI) after 12 unsuccessful ovulatory cycles suggesting that subfertility is “unexplained” after these 12 cycles. This strategy has not been proven effective, and chances of obtaining a multiple pregnancy are enhanced. On the hand, couples become unmotivated to prolong an unsuccessful treatment option and are often glad to move on. IVF remains their last option but is often not needed.

Once couples are fully informed about chances of success and risks, a balanced decision can be made, a decision, regretfully, not supported by evidence-based guidelines.

Luteal Support?

In COH cycles, using a GNRH agonist or antagonist luteal support is mandatory. But is luteal support also beneficial in OI or non-IVF COH cycles? Lately, there has been a discussion going on regarding luteal support in COH-IUI cycles. The first randomized trials published showed a significant effect of luteal support when gonadotropins are used for COH (LOE 1a) (6). A recent RCT, however, showed no significant effect; thus the end of this discussion has not been reached (LOE 1b) (7). In OI cycles, there seems to be less interest in this subject: Large randomized trials comparing luteal support with placebo on no luteal support in CC cycles are lacking. It has been suggested that the need for luteal support in mono-ovulatory cycles is less pronounced compared to multi-ovulatory cycles (8).

Discussion

It should be clear for both patients and physicians that OI and COH are two different treatment modalities with different goals. Ovulation induction should aim to achieve mono-ovulation and chances to obtain a multiple pregnancy are low. In COH, the ovulation of two to three follicles should be the goal, and multiple pregnancy rates of about 10% are described when strict cancellation criteria are used (5).

Both CC as gonadotropins can be used for OI and COH. In IUI programs, COH with gonadotropins seems more successful (9). Luteal support in mono-ovulatory cycles has not been investigated in randomized trials, and discussion remains ongoing whether luteal support should be advocated in cycles with two to three dominant follicles. Starting support based on small favorable trials only does not seem a cost-effective strategy.

TABLE 12.1

Level of Evidence of Statements

TABLE 12.2

Grade of Strength for Recommendations

REFERENCES

1. Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, Sullivan E, van der Poel S. International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod. 2009 Nov; 24(11):2683–7.

2. Eijkemans MJ, Imani B, Mulders AG, Habbema JD, Fauser BC. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2). Hum Reprod. 2003 Nov; 18(11):2357–62.

3. van Rumste MM, Custers IM, van der Veen F, van Wely M, Evers JL, Mol BW. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: A meta-analysis. Hum Reprod Update. 2008 Nov-Dec; 14(6):563–70.

4. Cohlen BJ, te Velde ER, van Kooij RJ, Looman CW, Habbema JD. Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: A controlled study. Hum Reprod. 1998 Jun; 13(6):1553–8.

5. Bensdorp AJ, Tjon-Kon-Fat RI, Bossuyt PM, Koks CA, Oosterhuis GJ, Hoek A et al. Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: Randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation. BMJ. 2015 Jan 9;350:g7771.

6. Miralpeix E, González-Comadran M, Solà I, Manau D, Carreras R, Checa MA. Efficacy of luteal phase support with vaginal progesterone in intrauterine insemination: A systematic review and meta-analysis. J Assist Reprod Genet. 2014 Jan; 31(1):89–100.

7. Hossein Rashidi B, Davari Tanha F, Rahmanpour H, Ghazizadeh M. Luteal phase support in the intrauterine insemination (IUI) cycles: A randomized double blind, placebo controlled study. J Family Reprod Health. 2014 Dec; 8(4):149–53.

8. Seckin B, Turkcapar F, Yildiz Y, Senturk B, Yilmaz N, Gulerman C. Effect of luteal phase support with vaginal progesterone in intrauterine insemination cycles with regard to follicular response: A prospective randomized study. J Reprod Med. 2014 May-Jun; 59(5–6):260–6.

9. Cantineau AE, Cohlen BJ, Heineman MJ. Ovarian stimulation protocols (anti-estrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility. Cochrane Database Syst Rev. 2007 Apr 18; (2):CD005356.

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Classification of Anovulation Causes of Anovulation: WHO Type 2: Polycystic Ovary Syndrome Causes of Anovulation: WHO Class 1 Predicting Outcome of Treating Anovulation Summary: Levels of Evidence of Statements Complications of Ovarian Stimulation: Multiple Pregnancies

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