GnRH antagonists for treatment of polycystic ovarian syndrome

FERTILITY AND STERILITY威 VOL. 80, SUPPL. 1, JULY 2003 Copyright ©2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.

GnRH antagonists for treatment of polycystic ovarian syndrome Vito S. Cardone, M.D. Fertility Center of New England, Reading, Massachusetts

Objective: To review treatment options for women with polycystic ovary syndrome (PCOS) seeking relief from infertility. Design: Review article and case studies. Results: Treatment options for women with PCOS include lifestyle modification, treatment with insulinsensitizing agents, ovulation induction with clomiphene citrate (CC), FSH preparations, and possibly, GnRH antagonists. Conclusions: The GnRH antagonists provide a new treatment option for women with PCOS. When the goal is to restore normal ovulation, the use of GnRH antagonists is limited to the prevention of LH surges. When undertaking controlled ovarian hyperstimulation (COH) in women with PCOS, a GnRH antagonist protocol should be the protocol of choice. (Fertil Steril威 2003;80(Suppl 1):S25–31. ©2003 by American Society for Reproductive Medicine.) Key Words: Ganirelix, GnRH antagonist, PCOS, treatment options

Received April 15, 2003; revised and accepted April 15, 2003. Presented at the symposium, “Real-Life Clinical Applications of GnRH Antagonists: Individualization of Fertility Treatment,” Seattle, Washington, October 16, 2002 in conjunction with the American Society for Reproductive Medicine 2002 annual meeting. Supported by an unrestricted educational grant from Organon Inc. Reprints requests: Dr. Vito S. Cardone, Fertility Center of New England, 20 Pond Meadow Drive, Suite 101, Reading, Massachussetts 01865. (FAX: 781-9427200; E-mail: cardonevi@ fertilitycenter.com). 0015-0282/03/$30.00 doi:10.1016/S0015-0282(03) 00763-5

When I was asked to present on the use of GnRH antagonists, especially in relation to the treatment of women with polycystic ovarian syndrome (PCOS), the first thing I did was a Medline search. I found only one abstract, which was presented by Karen Elkind-Hirsch at the Pacific Coast meeting in April 2002 (1). At this ASRM meeting, there was another abstract by Bracero et al. (2), which is a retrospective study. The first abstract (1) is a prospective study on the use of ganirelix with recombinant FSH for IUI in women with PCOS. However, the two studies, in total, only involved treatment of approximately 35 patients. The limited material available did not allow me to do a meta-analysis on the literature. This is our recent experience with the use of GnRH antagonists in the PCOS patient. Previous to that, there will be a very brief review of PCOS and the treatment options available. The pathophysiology of PCOS will not be discussed because, although it was first described almost 70 years ago (3), there is still no consensus on precisely how to define the syndrome (4, 5). What is important is that women with PCOS represent a large part of our ovulation-induc-

tion (OI) patient population. It is very important not to define PCOS too strictly because in clinical practice, it is not very useful and just eliminates some women whom you can probably help.

CHARACTERISTICS OF PCOS Polycystic ovarian syndrome is a very heterogenous disorder with a wide spectrum of clinical and biochemical manifestations (5). One of the things that reproductive endocrinologists commonly see is menstrual dysfunction. All of these patients have some degree of menstrual dysfunction, either oligomenorrhea or amenorrhea. They come to our clinics for infertility treatment and that infertility is basically due to anovulation. Many of them are obese and some have hirsutism. Some people believe that you need to have some form of ultrasonic or histologic evidence of PCOS, as that is how it was originally described (the rosary-bead type of ovaries). However, Legros et al. (6) refute that theory and discount its importance. Many non-PCOS patients have polycystic ovaries and some patients with PCOS do not have polycystic ovaries. Ultrasound evidence of polycystic ovaries is definitely not pathognomonic. S25

Serum concentrations of E2 (both total and free) usually fall within the normal ranges for the early follicular and midfollicular phases of the cycle. However, the pattern of secretion is abnormal because there is no preovulatory or midluteal increase in E2 levels (7). Polycystic ovarian syndrome is an androgenic syndrome. In fact, the syndrome is sometimes referred to as hyperandrogenic chronic anovulation (8). There is a lot of androgen floating around, particularly T and androstenedione (A). Also, the effective levels of androgens are further increased by a decrease in sex hormone-binding globulin (SHBG) caused by hyperinsulinemia (9). Classically, there is also hypersecretion of LH but with low-to-normal levels of FSH resulting in an LH/FSH ratio favoring LH (10). It is important to remember that PCOS is also a syndrome of exclusion. One has to be very careful to eliminate the other endocrine disorders that can mimic PCOS. Thyroid dysfunction, adrenal dysfunction, and hyperprolactinemia are the most frequent of these disorders and should definitely be eliminated. It is increasingly apparent that women with PCOS are at increased risk of developing some very significant diseases (11, 12). Endometrial cancer has been known for many years to be associated with chronic anovulation. Adam Balen (13) presented a review that showed that even breast cancer is possibly increased in these patients. Women with PCOS have increased risk of developing cardiovascular disease and diabetes. In recent years, a lot of work has been done on the association of these risks and the incidence of insulin resistance, especially in the overweight PCOS patient (14 –16).

TREATMENT OPTIONS In patients with insulin resistance, we have a lot of experience now with metformin (15, 16) and in patients intolerant to metformin, perhaps it will be possible to use rosiglitazone (17). Something else that we have known for years is that a small-to-moderate weight loss can restore menstrual cycles, achieve ovulation, achieve pregnancy, and also decrease insulin resistance and, most likely, other health risks (18). This was clearly shown by Clark et al. (19), who presented a 6-month follow-up on patients who were put through a lifestyle modification program. Of the 67 patients who followed the program, 60 ovulated and 52 became pregnant, compared with none in the reference group. Furthermore, there was a reduction in miscarriage rates (75% preintervention to 18% postintervention). At the Fertility Center of New England, before OI or other therapy is recommended for the patients with PCOS, we believe that it is very important to try to change their lifestyle if they are overweight or if there is insulin resistance. We have established a website for our patients (with support from a nutritionist and a personal trainer) to help S26

Cardone

GnRH antagonists for treatment of PCOS

TABLE 1 Sequence of interventions used to treat patients with PCOS. Lifestyle modification Nutrition and exercise to achieve ideal BMI If insulin resistance Metformin (Glucophage威) Troglitazone (Rezulin威)a Rosiglitazone (Avandia威) Ovulation induction In vitro fertilization Retrieval of immature oocytes and in vitro maturation Ovarian surgery a

No longer available in the United States.

Cardone. GnRH antagonists for treatment of PCOS. Fertil Steril 2003.

patients with lifestyle modifications. The first is an interactive web site coined “PCOS success” (www.pcossuccess.com). This site was established about 6 months ago and we already have very nice results, which I hope to present one day. An additional website is available (www.pcossupport. com) that provides the patients with information and is basically a support group for these patients. Many women with PCOS need a lot of encouragement. The sequence of interventions that we use after reaching the diagnosis is listed in Table 1. First, we try to modify their lifestyle. If that fails and the patient is insulin resistant, one of the insulin-sensitizing agents is tried. If that still fails, OI is tried next. In vitro fertilization is used only for patients in whom we have not been able to control the number of follicles produced with OI or if they still fail to establish a successful pregnancy after repeated presumptive ovulations. I, personally, have very little experience with retrieval of immature oocytes and in vitro maturization. However, Tan et al. have presented papers on this (20 –22) and seem to be doing extremely well. With regard to ovarian surgery, apart from the wedge resection that I did when I was in residency, I have very little experience. Because I practice in a state that mandates coverage of infertility treatment by health insurance plans (Massachusetts), we have access to fertility treatments without costs. I think, however, that ovarian surgery/ovarian drilling (23, 24) may be useful in states where you have no infertility coverage—it could be cost effective.

OVULATION INDUCTION There are two reasons to do OI in the patient with PCOS. One is to restore normal ovulation, with the goal being a single follicle for timed intercourse. The other is to obtain multiple follicles through controlled ovarian hyperstimulation (COH), for IVF/intracytoplasmic sperm injection Vol. 80, Suppl 1, July 2003

the patients are reported to have evidence of ovulation but only 30%–50% of them become pregnant. One of the reasons why a lot of these patients do not become pregnant with simple clomiphene is because they have premature LH surges, although there seems to be a biphasic temperature chart, a positive LH predictor kit result, or luteal phase P increases.

TABLE 2 Patient 1. Clomiphene and Premature LH Surge Day # CC FSH LH E2 P4 US

2 100 4 15 52 1.0

3

4

5

6

100

100

100

100

7

8

9

21 105 0.9 L10 ⬍10 R12 ⬍10

10

CASE STUDIES

58 215 2.1 L11 L11 L10 ⬍10 R15 ⬍10

As shown in Table 2, this patient (Patient 1) has a good response in terms of her estrogen (E) levels rising from 52 pg/mL on day 2 to 105 pg/mL on day 8 and 215 pg/mL on day 10. However, by day 10, she has evidence of an LH surge with levels of 58 ng/mL and an increase in P to 2.1 ng/mL. By most of the conventional ways of documenting ovulation, it would be assumed that she ovulated, but as you can see by looking at the ultrasound results, she has really not developed any mature follicles (maximum size, 11 mm) that could lead to pregnancy.

Cardone. GnRH antagonists for treatment of PCOS. Fertil Steril 2003.

(ICSI). Obviously, you should not start with the same approach in these two groups.

In these circumstances, where patients either do not respond to clomiphene or have this type of situation, we have had a lot of experience through the past 15 years with a low-dose FSH protocol. We start with the clomiphene and add FSH very late in the cycle. In our hands, at least, it has maximized the ovulation frequency and pregnancy rate and also reduced the number of follicles.

For OI, where the goal is a single egg, the first task is to stabilize the patients’ metabolism. You need to take care of their insulin resistance. You need to try hard to persuade them to change their lifestyle. If you are successful, not only will it often restore ovulation but it may be the only thing that they need to become pregnant. Even if you have to progress to OI, there is more and more evidence now that weight loss or use of insulin-sensitizing agents will improve the response to OI, ultimately resulting in better pregnancy rates (25, 26). Furthermore, the miscarriage rate in PCOS can be quite high. The only interventions that have been shown to reduce this are the use of insulin-sensitizing agents (27, 28) or weight control (19).

In Table 3, there is a subsequent cycle of the same patient (Patient 1). Again, we started with clomiphene (100 mg/day) beginning on day 2. The patient had an E2 increase to 122 pg/mL by day 7 but no mature follicles (all ⬍10 mm). The blood work was repeated on day 9 and her E2 was actually starting to decrease (102 pg/mL). This is one of the reasons why we do not have success with simple clomiphene. We started adding a very low dose of FSH (75 IU/day) and had

For OI, we start with clomiphene, which is a common approach. In the literature (29), approximately 80%–90% of

TABLE 3 Patient 1: subsequent cycle. Clomiphene gonadotropin (low dose) and ganirelix Day # CC FSH LH E2 P4 US

2

3

4

5

6

100

100

100

100

100

7

18 122 0.9 R10 ⬍10 L15 ⬍10

8

9

1 20 102 0.0

10

1

11

12

13

14

Ganirelix 2 20 182 0.8 R10 ⬍10 L15 ⬍10 L10 L12

Ganirelix 2 6 215 1.2

Ganirelix 2 1.8 385 1.1 R10 ⬍10 L15 ⬍10 L10 L10 L10 L16 L13

hCG 0.9 638 0.8

Cardone. GnRH antagonists for treatment of PCOS. Fertil Steril 2003.

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better protocol compared with the agonist protocol, which tends to result in very high numbers of follicles with an associated higher risk of multiples and requires a lot more medication.

TABLE 4 Patient 2. Gonadotropin without antagonist Day # FSH LH E2 P4 US

2

3

4

5

6

7

8

1 18 15 10.8 R20 ⬍10 L10 ⬍10

1

1

1

1

1.5 22 103 1.1 R20 ⬍10 L10 ⬍10

1.5

62

9

55 348 2.8 R20 ⬍10 R12 L10 ⬍10

Cardone. GnRH antagonists for treatment of PCOS. Fertil Steril 2003.

her come back 2 days later. On day 11, the LH level was still rather high (20 IU/L). The levels of E were finally going back up (182 pg/mL). We added the ganirelix (250 ␮g/day) at that point, although her follicles were still quite small (one follicle was 12 mm; the rest were ⬍10 mm). There was some follicle activity. The FSH was gradually increased (150 IU/day from day 11). This patient developed very nice follicles on day 13 and on day 14 we triggered ovulation with hCG. This patient became pregnant on this slightly more complicated but still very easy protocol. When this fails, pure gonadotropin is used, mostly to relieve the possible effects of the clomiphene on the endometrium, which could possibly be the other reason why some of these women do not get pregnant. We usually use a step-up protocol with FSH and we only use the gonadotropin with the GnRH antagonist if we have a premature LH surge. We have found that this is definitely a

Here is another example of a similar patient (Table 4, Patient 2). We started off with the low-dose FSH protocol. We see that she did well with E levels increasing from 15 pg/mL on day 2 to 62 pg/mL on day 5 and to 103 pg/mL on day 7. However, the patient started having an LH surge (55 IU/L LH and 2.8 ng/mL P4 on day 9) while her follicles were still very small (one 12 mm follicle and the rest ⬍10 mm). Her stimulation was repeated with, again, a very small dose of FSH and ganirelix was administered (Table 5). The starting dose was75 IU/day FSH. On day 7, the dose of FSH was increased to 112.5 IU/day. The E2 levels were doing fine (increasing from 58 pg/mL on day 2 to 84 pg/mL on day 5 and 125 pg/mL on day 7). Her LH level was 28 IU/L, so ganirelix was started. We sometimes increase (a little bit) the FSH dose when we start the ganirelix. The next day she did okay. Her LH went down to 8 IU/L. The following day (day 9), her LH was very low (1.2 IU/L) and we saw a plateauing of the E2 levels (125 pg/mL on day 7, 140 pg/mL on day 8, and135 pg/mL on day 9). When we saw this, we added back some LH. In some patients, if we do not add back a little bit of LH, either as hMG or the recombinant LH, there is a significant decrease in E2. We do not like to see a decrease in E2 in the later part of the cycles. The patient has now developed at least one dominant follicle (20 mm on the right ovary) and a few smaller ones that are probably mature (two 15-mm follicles). Again, these are success stories—this patient also became pregnant. Should the GnRH antagonist be used on every PCOS patient where we want to restore normal ovulation? The

TABLE 5 Patient 2: subsequent cycle. Gonadotropin with antagonist Day #

2

3

4

5

6

7

8

9

10

FSH hMG

1

1

1

1

1

1.5

1.5

1

1 1 Ganirelix 1.5 320 1

LH E2 P4 US

20 58 0.8 R15 ⬍10 L15 ⬍10

84

Ganirelix 28 125 1.2 R12 R15 ⬍10 L15 ⬍10

Ganirelix 8 140 1

Ganirelix 1.2 135 1 R15 R12 R10 R15 ⬍10 L10 L11 L15 ⬍10

11

12

hCG 2 540 1.1 R20 R15 R12 R15 ⬍10 L15 L12 L15 ⬍10

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TABLE 6 Outcome measures in patients administered concurrent ganirelix–follitropin ␤ according to insulin sensitivity. Variable BMI Mean duration Mean # vials Pregnancy (%) Ongoing pregnancy (%)

Group I (IR) FG/I ⬍5 (n ⫽ 9)

Group II (NIR) FG/I ⬎5 (n ⫽ 9)

Total (n ⫽ 18)

45.1 ⫾ 9.7 15.1 ⫾ 3.6 31.4 ⫾ 10.6 4 (44.4%) 2 (22.2%)

26.1 ⫾ 5.6 11.9 ⫾ 2.8a 20.8 ⫾ 9.0b 4 (44.4%) 3 (33.3%)

33.8 ⫾ 11.2 13.5 ⫾ 3.6 26.1 ⫾ 11.2 8 (44.4%) 5 (27.8%)

Note: Values are means ⫾ SD. a P ⫽ .024. bP ⫽ .04. IR ⫽ insulin resistant; NIR ⫽ noninsulin resistant; FG/I ⫽ fasting glucose-to-insulin ratio. Adapted from Elkind-Hirsch KE, et al. Fertil Steril 2002;77:(Suppl 3):59. Cardone. GnRH antagonists for treatment of PCOS. Fertil Steril 2003.

answer is definitely no. We need to start with the simpler protocols. However, if premature luteinization occurs, we need to add it, which is a way to control these cycles more effectively.

COH For patients who need COH, there are basically three choices: [1] FSH with a GnRH antagonist; [2] clomiphene/ FSH with the GnRH antagonist; or [3] the long course GnRH agonist protocol. We normally start with either the FSH with a GnRH antagonist or the clomiphene/FSH with the GnRH antagonist protocol in our group. Because I learned my OI and IVF skills in Europe, I like the clomiphene plus FSH protocol advocated by Frydman et al. (30). Before going into our preferred stimulation protocols, I will review a recent study that suggests that PCOS is treatable with ganirelix (1). In this small but prospective study, two groups of women with PCOS (with or without insulin resistance) were treated with ganirelix concurrently from the start of the stimulation. The results presented in Table 6 show that the pregnancy rate actually seems to be identical. Why should the antagonists be used rather than the agonists? Basically, there are three reasons. One, I do not believe that there is any question in anybody’s mind who has used simpler protocols, either with clomiphene, hMG/FSH, or the FSH protocol (with or without the antagonist) that significantly less gonadotropin is required. Also, I think that we have better compliance due to the number of injections that these patients have to take— ours is approximately 4 to 5 days of injections with the GnRH antagonist compared with anywhere between 21 to 25 days with the GnRH agonist. Another challenge in treating women with PCOS is their high risk of developing ovarian hyperstimulation FERTILITY & STERILITY威

syndrome (OHSS). I believe that this is the reason why we should all convert to the antagonist in PCOS as a firstchoice treatment. It definitely decreases the risk of OHSS. Those who know what that could involve really appreciate this benefit. We had a few patients who had OHSS. You need to prevent it, especially now that it seems that a few papers have presented the use of the GnRH agonist to trigger ovulation. When you use the antagonist, as Dr. Shapiro mentioned in the introduction, you can use a GnRH agonist to trigger ovulation (31, 32). With this type of protocol, you can probably reduce the risk of OHSS even further. However, there is no real prospective study that has shown that yet. Some pitfalls— one of the things that I have to mention is that unfortunately, many women with PCOS have an increased body mass index (BMI). Hardy et al. (33) presented an abstract at this meeting last year showing the increased risk of LH elevations in patients on the antagonists who had increased BMI. In that small study, there was a 37% incidence of premature LH surges in patients who had a BMI ⬎35. In these circumstances, our protocol is to increase the antagonist to twice a day. Table 7 shows what I think the ideal protocol should look like. Use clomiphene on days 2–5 and add some FSH. The dose of FSH should be titrated to the individual patient (75–150 IU/d is usually sufficient). It is either given every day or every other day. It is monitored. Anywhere between 4 and 5 days of ganirelix is given. If you have a high number of follicles, I believe that using a GnRH agonist to trigger ovulation is the ideal way to go. If you follow the different steps as mentioned, the amount of medication can still be minimized. The patient also has to give herself fewer shots, therefore, compliance is higher. An additional benefit is that you reduce the risk of multiples, especially when you try to obtain a single egg to restore normal ovulation. The OHSS and superovulation are reduced also. Cancellation rate in our hands S29

TABLE 7 Ideal protocol for COH for IVF. Day #

2

3

4

5

6

7

8

9

Ganirelix

Ganirelix

Ganirelix

1 or 2

1 or 2 1 or 2 X X X X

1 or 2 1 or 2

Provera/OCP GnRH agonist CC FSH hMG LH E2 P4 US

10

11

0.2 q 12 h 100 1 or 2

100 1 or 2

100 1 or 2

100 1 or 2

100 1 or 2

X

X X X X

OCP ⫽ oral contraceptive pill. Cardone. GnRH antagonists for treatment of PCOS. Fertil Steril 2003.

has been quite low. If you stabilize the patients’ metabolism, you will have a definite decreased risk of miscarriage. In conclusion, when the goal is restoring normal ovulation, the antagonist has limited use to prevent LH surge. It is basically used to prevent an unwanted LH surge. It should not be the first protocol used. However, for superovulation, I believe it is the protocol of choice. References 1. Elkind-Hirsch KE, Webster BW, Brown C, Vernon MW. Concurrent Antagon and Follistim therapy for ovulation induction in women with polycystic ovary syndrome (PCOS). Fertil Steril 2002;77(Suppl 3):S9. 2. Bracero N, Jurema M, Vlahos N, Kolp L, Garcia J. Polycystic ovarian syndrome (PCOS) patients have a favorable response to ganirelix acetate during controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF)-embryo transfer (ET). Fertil Steril 2002;78(Suppl 3):S149 –50. 3. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gyn 1935;29:181–91. 4. Homburg R. What is polycystic ovarian syndrome? A proposal for a consensus on the definition and diagnosis of polycystic ovarian syndrome. Hum Reprod 2002;17:2495–9. 5. Balen A, Michelmore K. What is polycystic ovary syndrome? Are national views important? Hum Reprod 2002;17:2219 –27. 6. Legro RS, Chiu P, Kunselman A, Demers LM, Dodson WC, Dunaif A. The polycystic ovary is full of sound and fury but signifies nothing. Fertil Steril 2002;78(Suppl 1):S34 –5. 7. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853–61. 8. Fauser BCJM. Classification of chronic hyperandrogenic anovulation. In: Coelingh Bennink HJ, Vemer HM, van Keep PA, eds. Chronic hyperandrogenic anovulation. New Jersey: The Parthenon Publishing Group, 1989:13–7. 9. Nestler JE. Insulin regulation of human ovarian androgens. Hum Reprod 1997;12(Suppl 1):53–62. 10. Goldzieher JW. Polycystic ovarian disease. Fertil Steril 1981;35:371– 94. 11. Lobo RA, Carmina E. The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med 2000;132:989 –93. 12. Wild RA. Polycystic ovary syndrome: a risk for coronary artery disease? Am J Obstet Gynecol 2002;186:35–43. 13. Balen A. Polycystic ovary syndrome and cancer. Hum Reprod Update 2001;7:522–5. 14. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774 – 800. 15. Nestler JE. Should patients with polycystic ovarian syndrome be treated with metformin? An enthusiastic endorsement. Hum Reprod 2002;17: 1950 –3.

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16. Homburg R. Should patients with polycystic ovarian syndrome be treated with metformin? A note of cautious optimism. Hum Reprod 2002;17:853–6. 17. Cataldo NA, Abbasi F, McLaughlin TL, Lamendola C, Reaven GM. Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone. Fertil Steril 2001;76:1057–9. 18. Norman RJ, Davies MJ, Lord J, Moran LJ. The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 2002;13:251–7. 19. Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13: 502–5. 20. Chian RC, Gulekli B, Buckett WM, Tan SL. Pregnancy and delivery after cryopreservation of zygotes produced by in-vitro matured oocytes retrieved from a woman with polycystic ovarian syndrome. Hum Reprod 2001;16:1700 –2. 21. Child TJ, Abdul-Jalil AK, Gulekli B, Tan SL. In vitro maturation and fertilization of oocytes from unstimulated normal ovaries, polycystic ovaries, and women with polycystic ovary syndrome. Fertil Steril 2001;76:936 –42. 22. Gosden RG, Mullan J, Picton HM, Yin H, Tan S-L. Current perspective on primordial follicle cryopreservation and culture for reproductive medicine. Hum Reprod Update 2002;8:105–10. 23. Farquhar CM, Williamson K, Gudex G, Johnson NP, Garland J, Sadler L. A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome. Fertil Steril 2002;78:404 –11. 24. Amer SAKS, Banu Z, Li TC, Cooke ID. Long-term follow-up of patients with polycystic ovary syndrome after laparoscopic ovarian drilling: endocrine and ultrasonographic outcomes. Hum Reprod 2002; 17:2851–7. 25. De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999;72:282–5. 26. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SC, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001;75: 310 –5. 27. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002;17:2858 –64. 28. Seli E, Duleba AJ. Should patients with polycystic ovarian syndrome be treated with metformin? Proven and potential benefits. Hum Reprod 2002;17:2230 –6. 29. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996;2:483– 506. 30. Frydman R, Bellaisch-Allart J, Fries N, Hazout A, Glissant A, Testart J. An obstetric assessment of the first 100 births from the in vitro fertilization program at Clamart, France. Am J Obstet Gynecol 1986; 154:550 –5.

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31. Olivennes F, Fanchin R, Bouchard P, Taieb J, Frydman R. Triggering of ovulation by a gonadotropin-releasing hormone (GnRH) agonist in patients pretreated with a GnRH antagonist. Fertil Steril 1986;66: 151–3. 32. Itskovitz-Eldor J, Kol S, Mannaerts B. Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted repro-

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duction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report. Short communication. Hum Reprod 2000;15:1965–8 . 33. Hardy RI, Tummon IS, Hosseinzadeh M, Cardone VR, Seibel M, Lee M. Luteinizing hormone (LH) surge on ganirelix (Antagon) is related to increased body mass index (BMI). Fertil Steril 2001;76(Suppl 1): S178 –9.

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