- Email: [email protected]
Ovulation induction in women with polycystic ovary syndrome
Steroids 78 (2013) 767–772
Contents lists available at SciVerse ScienceDirect
Steroids journal homepage: www.elsevier.com/locate/steroids
Ovulation induction in women with polycystic ovary syndrome Alfredo Perales-Puchalt 1, Richard S. Legro ⇑ Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA, USA
a r t i c l e
i n f o
Article history: Received 22 April 2013 Received in revised form 30 April 2013 Accepted 30 April 2013 Available online 21 May 2013 Keywords: Ovulation induction Polycystic ovary syndrome Anovulation Infertility
a b s t r a c t Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. There are multiple ways to induce ovulation in PCOS patients, which will eventually provide a successful live birth. Each of these treatments varies in aggressiveness and effectiveness. Ranging from lifestyle modifications, through insulin-sensitizing agents, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, to laparoscopic ovarian drilling and assisted reproductive techniques, each method achieves ovulation induction through different mechanisms of action. This review provides a description and specific characteristics of the different methods used for ovulation induction which can help to design a personalized approach to each PCOS patient, and a general stepwise approach to ovulation induction in these patients. Ó 2013 Elsevier Inc. All rights reserved.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ovulation induction in PCOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Weight loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Insulin-sensitizing agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Clomiphene citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Combination of metformin and clomiphene citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Aromatase inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Gonadotropins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Laparoscopic ovarian drilling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Assisted reproductive techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Polycystic ovary syndrome (PCOS) is the most common disorder in women of reproductive age and the primary cause of anovulatory infertility. Its prevalence ranges between 6% and 8% in the general population [1,2]. Despite multiple publications from experts, there is no clear consensus on its specific definition [3,4]. ⇑ Corresponding author. Address: 500 University Drive, H103, Hershey, PA 17033, USA. Tel.: +1 (717) 531 8478; fax: +1 (717) 531 0701. E-mail address: [email protected] (R.S. Legro). 1 Present address: The Wistar Institute, Philadelphia, PA, USA. 0039-128X/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.steroids.2013.05.005
767 768 768 768 769 769 769 769 770 770 770 770
However, all of the diagnostic criteria include some combination of oligo-anovulation, androgen excess and polycystic ovaries. Infertility is one of the most common complaints in women with PCOS. There are multiple ways of treating the anovulatory infertility of these women, ranging from simpler interventions, such as lifestyle modification, to more aggressive ones, such as assisted reproductive techniques (ART) or laparoscopic ovarian drilling. Due to the fact that anovulatory infertility can often be treated by low resource and cost effective methods, it is important to elaborate a stepwise approach in which less invasive therapies can be used first, leaving the least number of patients to the more aggressive ones (Fig. 1).
768
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
In this review, we will address the different approaches to ovulation induction for the treatment of infertility in patients with PCOS, discussing its mechanisms of action (Fig. 2), effectiveness, advantages and disadvantages. 2. Ovulation induction in PCOS 2.1. Weight loss Weight loss is considered as the first-line therapy for infertility in overweight and obese patients with PCOS [5]. Obesity can potentially affect fertility by acting at different points of the hypothalamic–pituitary–ovarian axis. Obesity is often accompanied by hyperinsulinemia, which has a co-gonadotropin action in the ovary to stimulate androgen production [6]. There also seems to be a direct action of insulin resistance or hyperinsulinemia on the hypothalamus that affects gonadotropin secretion [7]. High leptin levels directly inhibit basal and follicle stimulating hormone (FSH)-stimulated estradiol and progesterone production in ovarian granulosa cells, showing a clinical reduced ovarian responsiveness after FSH stimulation [8–10]. Besides, adipose tissue expresses aromatase, which can mediate an increase in circulating estrogens from the androgens [11], further exacerbating inappropriate hypothalamic–pituitary feedback. Weight loss is associated with an improvement in menstrual cyclicity [12,13], ovulation [14,15] and reports of pregnancy [16,17] in PCOS patients. However, the studies that support this concept have limitations such as low sample sizes, inappropriate or lacking control groups, or lack of randomization [18]. Weight loss alone, has shown to have a limited benefit for achieving pregnancy [18], so we think that this approach should be time-limited and dependent on the age of the patient. Multiple options are available for weight loss: lifestyle changes (diet and exercise), drug therapy and bariatric surgery. However, there are no appropriate studies to guide the best choice to achieve pregnancy. The most rapid and sustained weight loss can be obtained through bariatric surgery. Bariatric surgery has been able to restore regular menstrual cycles and ovulation in morbidly obese patients with PCOS [19]. It is also able to restore fertility and sexual function in an unselected obese population [20,21]. An important drawback from this approach, apart from being an invasive therapy with potential surgical complications, is the previous recommendation of a 1–2 year time interval between bariatric surgery and a attempts at conception [22], often an unacceptably long interval for the woman seeking pregnancy. However, this recommendation is controversial, and the ACOG itself has removed it from its latest committee opinion [23,24]. 2.2. Insulin-sensitizing agents Metformin and thiazolidinediones have been suggested to be useful agents for ovulation induction in small RCT and observational studies [25–28]. The proposed mechanisms of action, similar to those of weight loss, are an insulin lowering effect, which may indirectly decrease ovarian androgen production, and a potential direct effect on the hypothalamus. Metformin is a biguanide, mainly used as an antihyperglycemic agent. It is an oral agent used in doses of 1500–2000 mg in divided daily doses. Its most common adverse effects are nausea, vomiting and diarrhea, which can be avoided or diminished by a gradual dose escalation. In a recent meta-analysis, metformin showed no improvement in live birth rate compared to no treatment, although it improved the clinical pregnancy rate [29]. The Pregnancy in Polycystic Ovary Syndrome I (PPCOS I) trial, a large multi-center
Fig. 1. Algorithm for ovulation induction in the PCOS patient. Weight loss is the first step in ovulation induction for obese and overweight women with PCOS. It can help to both resume ovulation and assist with subsequent ovulation induction methods. Ovulation induction with clomiphene citrate is the first-line pharmacological therapy for PCOS. If no ovulation is achieved after up to 3 cycles (clomiphene resistance) or no pregnancy after up to 6 ovulatory cycles (clomiphene citrate failure), further steps should be considered. Physician and patient must then discuss gonadotropin therapy versus laparoscopic ovarian drilling, taking into account advantages and disadvantages of each method. If no pregnancy is achieved, or if other infertility-related conditions coexist, ART can be employed. FSH: follicle stimulating hormone; ART: assisted reproductive techniques.
Fig. 2. Mechanism of action of the different methods of ovulation induction. The main mechanisms of action in ovulation induction are a(an): (1) decrease in insulin levels, (2) reduction in ovarian androgen production, (3) decrease in aromatase and (4) increase in hypothalamic–pituitary FSH secretion. A further benefit is an increase in circulating sex hormone binding globulin levels, which decreases bioavailable androgens. FSH: follicle stimulating hormone; E2: estradiol; ART: assisted reproductive techniques.
RCT that evaluated the use of metformin versus clomiphene versus both combined, shows a significantly lower live birth rate with metformin compared to clomiphene, only offering an advantage when added to clomiphene in women with BMI over 35 kg/m2 [30]. Thiazolidinediones are selective peroxisome proliferator-activated receptor-c (PPARc) agonists [31] that act by increasing the peripheral response to insulin. Apart from reducing insulin action on ovarian sex steroid production, they also seem to exert direct ef-
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
fects on ovarian steroidogenesis by decreasing the activity of ovarian 3b-hydroxysteroid dehydrogenase, inhibiting estradiol and testosterone production and increasing the production of progesterone and IGFBP-1. Besides, they decrease the ovarian production of TNFa [32–35]. Rosiglitazone has shown improved ovulation rates compared to placebo [26]. However, there are no studies addressing pregnancy and live birth rate. Thiazolidinediones have been less studied as infertility therapy for PCOS, most likely because they are in a more concerning FDA category C risk for pregnancy, and have been associated with weight gain and more serious adverse events, such as hepatotoxicity (troglitazone, now removed from the market), cardiovascular events (rosiglitazone), and bladder cancer (pioglitazone). Therefore, although useful in very specific settings, the effect of insulin sensitizing agents in ovulation induction is very limited, and they should not be routinely considered in the early steps of ovulation induction.
769
should be performed in order to confirm this novel finding and try to elucidate its mechanism of action. 2.4. Combination of metformin and clomiphene citrate The combination of metformin and clomiphene has been extensively studied for the treatment of infertility in PCOS. There is controversy about the possibility of achieving a higher rate of ovulation and pregnancy after this combined therapy than after clomiphene citrate alone. However, there are no differences in the live birth rate [30,42,43]. Subgroup analyses have found a possible role of this pharmacological combination in PCOS patients who are clomiphene citrate resistant [44] and those individuals with a BMI >35 kg/m2 and low hirsutism [30], but these associations should be further studied. The potential benefits of metformin as an adjuvant therapy to other infertility treatments (including clomiphene) in obese women was recently underscored in a multi-center Scandinavian trial [45].
2.3. Clomiphene citrate
2.5. Aromatase inhibitors
Clomiphene citrate is an oral selective estrogen receptor modulator (SERM). It is generally considered the first-line pharmacological therapy for ovulation induction in women with PCOS [30]. Its mechanism of action is inhibition of estrogen negative feedback on the hypothalamus by estrogen receptor blockade. As a result, a secondary increase in circulating FSH levels stimulates follicular development and ovulation [36]. Among its adverse effects are antiestrogenic effects on endometrial development and cervical mucus production, both of which have been implicated in a low pregnancy rate despite a relatively high ovulation rate with the use of this drug [37,38]. Another adverse effect is a higher rate of multiple pregnancies compared to a natural cycle, due to reduced estrogen negative feedback on the hypothalamus from the long half-life of the drug, resulting in exaggerated FSH release and multi-follicular development [39]. The reported rate of multiple pregnancies with clomiphene citrate is 4–8% [30,40]. While this is relatively low compared to gonadotropins and ART therapy, the increased utilization of clomiphene citrate as first line therapy by many practitioners (Ob/Gyn, Internal Medicine, Family Practice, etc.) may make this drug the single largest contributor to iatrogenic multiple pregnancy in the United States. Other side effects of clomiphene citrate include hot flashes, headaches, mood changes, temporary visual disturbances and very rarely, ovarian hyperstimulation syndrome (OHSS). The rates of ovulation, pregnancy and live birth over a six cycle treatment period are 49%, 30% and 23%, respectively, according to the PPCOS trial I, the only RCT adequately powered to study live birth rate up to date [30]. The method of clomiphene administration is 50 mg starting on the 2nd to 5th day after the onset of menses, for five days. If ovulation doesn’t occur, the dose should be increased in 50 mg increments until 150 mg/d or ovulation is achieved. When the patient ovulates, that dosing can be repeated for 6 ovulatory cycles or until pregnancy is achieved in one cycle. After 6 cycles, a more aggressive approach is recommended [5]. There has been controversy about when to begin the clomiphene stimulation in anovulatory cycles. Traditionally, ovulation induction was preceded by an endometrial shedding provoked by the administration of a progestin. However, in a recent secondary analysis of the PPCOS I data, the pregnancy and live birth rates were higher when ovulation induction was started without a withdrawal bleeding, even though ovulation rate was higher in those cycles preceded by endometrial shedding [41]. However, a randomized controlled trial primarily focused on the effect of endometrial shedding before starting the ovulation induction cycle
As a member of the P450 enzyme family, aromatase catalyzes the conversion of testosterone and androstenedione to estradiol and estrone, respectively. Thus, aromatase inhibitors produce an anti-estrogenic effect which decreases the negative feedback of estrogens in the hypothalamus, subsequently increasing the circulating concentration of FSH [46]. The most widely used aromatase inhibitor for ovulation induction is letrozole. It is an oral agent usually administered for 5 days starting on day 3 of the menstrual cycle, in doses between 2.5 and 7.5 mg per day [47]. Anastrazole has also been studied as an ovulation induction agent in women with PCOS, but Phase II studies showed that anastrazole was inferior to clomiphene in both ovulation and pregnancy rates, and further industry sponsored development of the drug was discontinued [48,49]. Aromatase inhibitors have been proposed to replace clomiphene as first-line pharmacological step in ovulation induction in PCOS patients [50]. Potentially, aromatase inhibitors have multiple advantages over clomiphene, including absence of an anti-estrogenic effect on the endometrium [51]. However, clinical trials have failed to find a difference in endometrial thickness comparing women receiving letrozole or clomiphene with non-stimulated cycles [52,53]. Other advantages are its short half-life, approximately 45 h versus a 2-week half-life of clomiphene citrate, and a higher rate of mono-follicular ovulation, and thus, a lower rate of multiple pregnancy [46]. Despite these potential advantages, clinical trials to date have failed to show a superiority of aromatase inhibitors in ovulation induction compared to clomiphene. A recent meta-analysis shows only a significant increase in ovulation rate per patient, but no increase in pregnancy or live birth rates [54]. We are looking forward to assessing the live birth results in women with PCOS from the PPCOS II trial, a randomized trial of clomiphene versus letrozole for anovulatory infertility in women with PCOS [55]; as well as determining the risk of multiple intrauterine gestation from an ovarian stimulation (AMIGOS) trial, a RCT designed and powered to study the rate of multiple pregnancies comparing clomiphene, letrozole and gonadotropins [56]. Both of these trials will provide useful data to assess the rates of ovulation, pregnancy and live birth with a homogeneity lacking in meta-analyses of smaller trials. 2.6. Gonadotropins Ovarian stimulation with gonadotropins is considered a secondline treatment for the PCOS patients with infertility. The main rea-
770
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
sons for this are the lack of an oral formulation, their high price, and their potentially serious adverse effects, especially multiple pregnancy and OHSS. Besides, they require close monitoring with ultrasound and determination of estradiol levels. In gonadotropin stimulation for PCOS patients, FSH is administered beginning with a dose of 37.5 and 75 IU/day (low-dose protocol). The rationale is to achieve an increase in FSH levels enough to allow the development of, ideally, a single follicle. For that purpose, the most appropriate regime is the step-up protocol, in which the FSH dose is gradually increased (in 7–14 day increments) until follicular development is observed, and then maintained until follicular selection is achieved [57]. This step should not exceed 6 ovulatory cycles. The Thessaloniki consensus defined a maximal stimulation as the presence of no more than two follicles P16 mm or one follicle P16 mm and two additional follicles P14 mm [5]. As above mentioned, obesity has been associated with a lower response to FSH so it has been suggested that obese patients should start ovarian stimulation with a 75 IU/day dose [58]. An ovarian stimulation of clomiphene followed by gonadotropins in case of clomiphene resistance or failure in PCOS patients showed a cumulative singleton live birth rate of 60% after a year of treatment and 78% after two years [59]. A recent RCT evaluates the clinical outcome of using gonadotropin versus clomiphene stimulation as first line therapy for ovulation induction in PCOS, showing a higher pregnancy and live birth rate with low-dose FSH. However, they acknowledge that using clomiphene as a first line therapy is a more convenient and cost-effective approach [60]. Women with PCOS have a higher risk of OHSS per se [61]. The use of supraphysiological levels of FSH can induce OHSS; however, this risk has been decreased due to the use of low-dose FSH protocols for ovulation induction in patients with PCOS [62]. The higher risk of OHSS has been associated to the larger cohort of FSH sensitive small antral follicles present in the women with PCOS, rather than a different threshold to FSH [63]. Besides, despite showing no effect on pregnancy or live birth rates, the addition of metformin during gonadotropin stimulation has been associated with a lower risk of OHSS [64]. Multiple pregnancy is considered as another adverse event of reproductive techniques. Although higher after IVF procedures, ovulation induction with FSH has also shown an increase in multifollicular development and multiple pregnancy [62]. As with OHSS, low-dose FSH protocols have helped to decrease the rate of multiple pregnancy to <6% [60]. 2.7. Laparoscopic ovarian drilling Ovarian drilling is the perforation of multiple holes in the surface and stroma of the ovary. It’s mechanism of action is thought to be a decrease in the production of androgens and their peripheral conversion to estrogens due to disruption of the ovarian tissue. Another potential mechanism is the conversion of the adverse androgenic follicular microenvironment to a more estrogenic one [65]. A third mechanism may be disruption of the ovarian capsule and dense stroma, allowing space for follicular expansion. As with gonadotropin therapy, laparoscopic ovarian drilling is considered a second-line approach for clomiphene citrate-resistant PCOS patients. This technique is preferred especially when other surgical indications coexist in the patient or when frequent follow up, as needed for FSH therapy, is impractical. The main concerns of ovarian drilling are the possibility of surgical complications, postsurgical adhesions [66] and iatrogenic premature ovarian failure [67]. As advantages with respect to gonadotropin therapy, it shows a significantly lower multiple pregnancy rate and no OHSS [68]. A recent meta-analysis showed no differences in pregnancy or live birth rate between ovarian drilling versus ovulation induction with
gonadotropins [68]. After surgery, if no ovulation is detected, clomiphene can be used again, since response has been observed in previously clomiphene citrate resistant patients [69,70]. 2.8. Assisted reproductive techniques Assisted reproductive techniques (ART) are those that include the direct manipulation of oocytes and sperm to achieve pregnancy. It requires several days of treatment with gonadotropin releasing hormone (GnRH) analogs or antagonists to inhibit the midcycle LH surge, gonadotropin therapy for achieving a multifollicular ovarian stimulation and human chorionic gonadotropin (hCG) administration to trigger ovulation. Afterwards, the gametes are fertilized in vitro and the resulting embryos are transferred to the uterus or frozen for future embryo transfer. Assisted reproductive techniques should be considered the last option for infertile PCOS patients, or for those individuals at great risk of multiple pregnancy by gonadotropin therapy or with coexisting indications for ART (i.e. tubal damage, endometriosis or male factor infertility). The pregnancy and live birth rate per cycle in patients with PCOS is not different to non-PCOS patients [71]. As with gonadotropin therapy, the most important adverse effects of ART are multiple pregnancy and OHSS. Multiple pregnancy can be controlled with elective single embryo transfer. Despite having shown a lower birth rate when compared to double embryo transfer after the fresh transfer, the addition of a subsequent transfer of a single frozen-thawed embryo makes the difference no longer significant [72]. However, to the best of our knowledge, no there are no studies that address elective single-embryo transfer in the PCOS population. With respect to the higher risk of OHSS in PCOS patients, lower doses of FSH should be used, and there is a higher risk of cycle cancellation [71]. In vitro oocyte maturation has been proposed for some women with PCOS due to their higher risk of OHSS [73]. Other advantages of in vitro oocyte maturation are a less frequent monitoring and a lower economic cost. However, it has been shown less effective than conventional in vitro fertilization [74,75] and there is still not quality evidence to recommend it in a systematic way. 3. Conclusions Following a stepwise approach in the treatment of infertility will provide the majority of PCOS patients with the opportunity of achieving pregnancy and live birth, while avoiding more expensive and invasive therapies whenever possible. It is likely that many patients will benefit from weight loss alone, both as an ‘‘ovulation induction’’ method itself and as an adjuvant to concomitant ovulation induction therapies. Following lifestyle modifications, clomiphene citrate has been the most efficient and most studied method to overcome infertility in PCOS patients. The potential benefits of aromatase inhibitors may replace the use of clomiphene as first-line pharmacological therapy. However, up to date, clinical trials have not yet shown a practical superiority over clomiphene. A more personalized approach is necessary for the patients who need second-line therapy, when the physician and patient have to carefully balance the advantages and disadvantages of ovulation induction with gonadotropins versus laparoscopic ovarian drilling. Finally, if all other resources have been unsuccessful or if other infertility-related conditions exist, ART can be used to attain a high rate of pregnancy in women with PCOS. References [1] Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004;89:2745–9.
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772 [2] Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85:2434–8. [3] Rotterdam EA-SPCWG. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25. [4] Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456–88. [5] Thessaloniki EA-SPCWG. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008;89:505–22. [6] Willis D, Franks S. Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 1995;80:3788–90. [7] Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 1981;108:1441–9. [8] Butzow TL, Moilanen JM, Lehtovirta M, Tuomi T, Hovatta O, Siegberg R, et al. Serum and follicular fluid leptin during in vitro fertilization: relationship among leptin increase, body fat mass, and reduced ovarian response. J Clin Endocrinol Metab 1999;84:3135–9. [9] Greisen S, Ledet T, Moller N, Jorgensen JO, Christiansen JS, Petersen K, et al. Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells. Acta Obstet Gynecol Scand 2000;79:931–5. [10] Gurbuz B, Yalti S, Ficicioglu C, Tasdemir S. The relation of serum and follicular fluid leptin and ovarian steroid levels in response to induction of ovulation in in vitro fertilization cycles. Eur J Obstet Gynecol Reprod Biol 2005;118:214–8. [11] Wake DJ, Strand M, Rask E, Westerbacka J, Livingstone DE, Soderberg S, et al. Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol (Oxf) 2007;66:440–6. [12] Moran LJ, Noakes M, Clifton PM, Wittert GA, Williams G, Norman RJ. Shortterm meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome. Am J Clin Nutr 2006;84:77–87. [13] Moran LJ, Noakes M, Clifton PM, Tomlinson L, Galletly C, Norman RJ. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:812–9. [14] Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994;61:598–604. [15] Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:1470–4. [16] Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995;10:2705–12. [17] 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;13:1502–5. [18] Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011:CD007506. [19] Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005;90:6364–9. [20] Musella M, Milone M, Bellini M, Sosa Fernandez LM, Leongito M, Milone F. Effect of bariatric surgery on obesity-related infertility. Surg Obes Relat Dis 2012;8:445–9. [21] Legro RS, Dodson WC, Gnatuk CL, Estes SJ, Kunselman AR, Meadows JW, et al. Effects of gastric bypass surgery on female reproductive function. J Clin Endocrinol Metab 2012;97:4540–8. [22] Maggard MA, Yermilov I, Li Z, Maglione M, Newberry S, Suttorp M, et al. Pregnancy and fertility following bariatric surgery: a systematic review. JAMA 2008;300:2286–96. [23] ACOG Committee Opinion No. 315. Obesity in pregnancy. Obstet Gynecol 2005;106:671–5. [24] ACOG Committee Opinion No. 549. Obesity in pregnancy. Obstet Gynecol 2013;121:213–7. [25] Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RW. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 2003;79:562–6. [26] Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 2004;82:893–902. [27] Carmina E, Lobo RA. Does metformin induce ovulation in normoandrogenic anovulatory women? Am J Obstet Gynecol 2004;191:1580–4. [28] Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876–80. [29] Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with
[30]
[31]
[32]
[33]
[34]
[35]
[36] [37]
[38]
[39]
[40] [41]
[42]
[43]
[44] [45]
[46]
[47] [48]
[49]
[50] [51] [52]
[53]
[54]
[55]
771
polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev 2012;5:CD003053. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270:12953–6. Gasic S, Nagamani M, Green A, Urban RJ. Troglitazone is a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase enzyme in the ovary. Am J Obstet Gynecol 2001;184:575–9. Komar CM. Peroxisome proliferator-activated receptors (PPARs) and ovarian function–implications for regulating steroidogenesis, differentiation, and tissue remodeling. Reprod Biol Endocrinol 2005;3:41. Chen Q, Sun X, Chen J, Cheng L, Wang J, Wang Y, et al. Direct rosiglitazone action on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells. Reprod Biol Endocrinol 2009;7:147. Seto-Young D, Paliou M, Schlosser J, Avtanski D, Park A, Patel P, et al. Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production. J Clin Endocrinol Metab 2005;90:6099–105. Adashi EY. Clomiphene citrate: mechanism(s) and site(s) of action – a hypothesis revisited. Fertil Steril 1984;42:331–44. Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson ME. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 1989;73:187–90. Massai MR, de Ziegler D, Lesobre V, Bergeron C, Frydman R, Bouchard P. Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment. Fertil Steril 1993;59:1179–86. MacDougall MJ, Tan SL, Hall V, Balen A, Mason BA, Jacobs HS. Comparison of natural with clomiphene citrate-stimulated cycles in in vitro fertilization: a prospective, randomized trial. Fertil Steril 1994;61:1052–7. Asch RH, Greenblatt RB. Update on the safety and efficacy of clomiphene citrate as a therapeutic agent. J Reprod Med 1976;17:175–80. Diamond MP, Kruger M, Santoro N, Zhang H, Casson P, Schlaff W, et al. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet Gynecol 2012;119:902–8. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006;332:1485. Johnson NP, Stewart AW, Falkiner J, Farquhar CM, Milsom S, Singh VP, et al. PCOSMIC: a multi-centre randomized trial in women with polycystic ovary syndrome evaluating metformin for infertility with clomiphene. Hum Reprod 2010;25:1675–83. Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007;13:527–37. Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippelainen M, Perheentupa A, et al. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab 2012;97:1492–500. Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clin Obstet Gynecol 2011;54:685–95. Pritts EA. Letrozole for ovulation induction and controlled ovarian hyperstimulation. Curr Opin Obstet Gynecol 2010;22:289–94. Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole singledose protocol in women with oligo- or anovulatory infertility: results of a randomized phase II dose-response study. Fertil Steril 2011;95:1725–9 [e1–8]. Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study. Fertil Steril 2011;95:1720–4 [e1–8]. Casper RF, Mitwally MF. Review: aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab 2006;91:760–71. Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil Steril 2006;85:277–84. Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002;78:280–5. Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fertil Steril 2009;92:1355–9. Misso ML, Wong JL, Teede HJ, Hart R, Rombauts L, Melder AM, et al. Aromatase inhibitors for PCOS: a systematic review and meta-analysis. Hum Reprod Update 2012;18:301–12. Legro RS, Kunselman AR, Brzyski RG, Casson PR, Diamond MP, Schlaff WD, et al. The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 2012;33:470–81.
772
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
[56] Diamond MP, Mitwally M, Casper R, Ager J, Legro RS, Brzyski R, et al. Estimating rates of multiple gestation pregnancies: sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial. Contemp Clin Trials 2011;32:902–8. [57] Christin-Maitre S, Hugues JN, Recombinant FSHSG. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod 2003;18:1626–31. [58] Yildizhan R, Adali E, Kolusari A, Kurdoglu M, Yildizhan B, Sahin HG, et al. Ovarian stimulation in obese and non-obese polycystic ovary syndrome using a low-dose step-up regimen with two different starting doses of recombinant follicle-stimulating hormone. J Int Med Res 2008;36:1197–204. [59] Veltman-Verhulst SM, Fauser BC, Eijkemans MJ. High singleton live birth rate confirmed after ovulation induction in women with anovulatory polycystic ovary syndrome: validation of a prediction model for clinical practice. Fertil Steril 2012;98:761–8 [e1]. [60] Homburg R, Hendriks ML, Konig TE, Anderson RA, Balen AH, Brincat M, et al. Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study. Hum Reprod 2012;27:468–73. [61] Swanton A, Storey L, McVeigh E, Child T. IVF outcome in women with PCOS, PCO and normal ovarian morphology. Eur J Obstet Gynecol Reprod Biol 2010;149:68–71. [62] Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update 1999;5:493–9. [63] Van Der Meer M, Hompes PG, De Boer JA, Schats R, Schoemaker J. Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:423–6. [64] Palomba S, Falbo A, La Sala GB. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and metaanalysis of randomised controlled trials. BJOG 2013;120:267–76.
[65] Aakvaag A, Gjonnaess H. Hormonal response to electrocautery of the ovary in patients with polycystic ovarian disease. Br J Obstet Gynaecol 1985;92:1258–64. [66] Mercorio F, Mercorio A, Di Spiezio Sardo A, Barba GV, Pellicano M, Nappi C. Evaluation of ovarian adhesion formation after laparoscopic ovarian drilling by second-look minilaparoscopy. Fertil Steril 2008;89:1229–33. [67] Kandil M, Selim M. Hormonal and sonographic assessment of ovarian reserve before and after laparoscopic ovarian drilling in polycystic ovary syndrome. BJOG 2005;112:1427–30. [68] Farquhar C, Brown J, Marjoribanks J. Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2012;6:CD001122. [69] Gjonnaess H. Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope. Fertil Steril 1984;41:20–5. [70] Bayram N, van Wely M, Kaaijk EM, Bossuyt PM, van der Veen F. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial. BMJ 2004;328:192. [71] Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006;12:13–21. [72] Thurin A, Hausken J, Hillensjo T, Jablonowska B, Pinborg A, Strandell A, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392–402. [73] Chian RC. In-vitro maturation of immature oocytes for infertile women with PCOS. Reprod Biomed Online 2004;8:547–52. [74] Child TJ, Phillips SJ, Abdul-Jalil AK, Gulekli B, Tan SL. A comparison of in vitro maturation and in vitro fertilization for women with polycystic ovaries. Obstet Gynecol 2002;100:665–70. [75] Gremeau AS, Andreadis N, Fatum M, Craig J, Turner K, McVeigh E, et al. In vitro maturation or in vitro fertilization for women with polycystic ovaries? A casecontrol study of 194 treatment cycles. Fertil Steril 2012;98:355–60.
Contents lists available at SciVerse ScienceDirect
Steroids journal homepage: www.elsevier.com/locate/steroids
Ovulation induction in women with polycystic ovary syndrome Alfredo Perales-Puchalt 1, Richard S. Legro ⇑ Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA, USA
a r t i c l e
i n f o
Article history: Received 22 April 2013 Received in revised form 30 April 2013 Accepted 30 April 2013 Available online 21 May 2013 Keywords: Ovulation induction Polycystic ovary syndrome Anovulation Infertility
a b s t r a c t Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. There are multiple ways to induce ovulation in PCOS patients, which will eventually provide a successful live birth. Each of these treatments varies in aggressiveness and effectiveness. Ranging from lifestyle modifications, through insulin-sensitizing agents, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, to laparoscopic ovarian drilling and assisted reproductive techniques, each method achieves ovulation induction through different mechanisms of action. This review provides a description and specific characteristics of the different methods used for ovulation induction which can help to design a personalized approach to each PCOS patient, and a general stepwise approach to ovulation induction in these patients. Ó 2013 Elsevier Inc. All rights reserved.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ovulation induction in PCOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Weight loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Insulin-sensitizing agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Clomiphene citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Combination of metformin and clomiphene citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Aromatase inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Gonadotropins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Laparoscopic ovarian drilling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Assisted reproductive techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Polycystic ovary syndrome (PCOS) is the most common disorder in women of reproductive age and the primary cause of anovulatory infertility. Its prevalence ranges between 6% and 8% in the general population [1,2]. Despite multiple publications from experts, there is no clear consensus on its specific definition [3,4]. ⇑ Corresponding author. Address: 500 University Drive, H103, Hershey, PA 17033, USA. Tel.: +1 (717) 531 8478; fax: +1 (717) 531 0701. E-mail address: [email protected] (R.S. Legro). 1 Present address: The Wistar Institute, Philadelphia, PA, USA. 0039-128X/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.steroids.2013.05.005
767 768 768 768 769 769 769 769 770 770 770 770
However, all of the diagnostic criteria include some combination of oligo-anovulation, androgen excess and polycystic ovaries. Infertility is one of the most common complaints in women with PCOS. There are multiple ways of treating the anovulatory infertility of these women, ranging from simpler interventions, such as lifestyle modification, to more aggressive ones, such as assisted reproductive techniques (ART) or laparoscopic ovarian drilling. Due to the fact that anovulatory infertility can often be treated by low resource and cost effective methods, it is important to elaborate a stepwise approach in which less invasive therapies can be used first, leaving the least number of patients to the more aggressive ones (Fig. 1).
768
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
In this review, we will address the different approaches to ovulation induction for the treatment of infertility in patients with PCOS, discussing its mechanisms of action (Fig. 2), effectiveness, advantages and disadvantages. 2. Ovulation induction in PCOS 2.1. Weight loss Weight loss is considered as the first-line therapy for infertility in overweight and obese patients with PCOS [5]. Obesity can potentially affect fertility by acting at different points of the hypothalamic–pituitary–ovarian axis. Obesity is often accompanied by hyperinsulinemia, which has a co-gonadotropin action in the ovary to stimulate androgen production [6]. There also seems to be a direct action of insulin resistance or hyperinsulinemia on the hypothalamus that affects gonadotropin secretion [7]. High leptin levels directly inhibit basal and follicle stimulating hormone (FSH)-stimulated estradiol and progesterone production in ovarian granulosa cells, showing a clinical reduced ovarian responsiveness after FSH stimulation [8–10]. Besides, adipose tissue expresses aromatase, which can mediate an increase in circulating estrogens from the androgens [11], further exacerbating inappropriate hypothalamic–pituitary feedback. Weight loss is associated with an improvement in menstrual cyclicity [12,13], ovulation [14,15] and reports of pregnancy [16,17] in PCOS patients. However, the studies that support this concept have limitations such as low sample sizes, inappropriate or lacking control groups, or lack of randomization [18]. Weight loss alone, has shown to have a limited benefit for achieving pregnancy [18], so we think that this approach should be time-limited and dependent on the age of the patient. Multiple options are available for weight loss: lifestyle changes (diet and exercise), drug therapy and bariatric surgery. However, there are no appropriate studies to guide the best choice to achieve pregnancy. The most rapid and sustained weight loss can be obtained through bariatric surgery. Bariatric surgery has been able to restore regular menstrual cycles and ovulation in morbidly obese patients with PCOS [19]. It is also able to restore fertility and sexual function in an unselected obese population [20,21]. An important drawback from this approach, apart from being an invasive therapy with potential surgical complications, is the previous recommendation of a 1–2 year time interval between bariatric surgery and a attempts at conception [22], often an unacceptably long interval for the woman seeking pregnancy. However, this recommendation is controversial, and the ACOG itself has removed it from its latest committee opinion [23,24]. 2.2. Insulin-sensitizing agents Metformin and thiazolidinediones have been suggested to be useful agents for ovulation induction in small RCT and observational studies [25–28]. The proposed mechanisms of action, similar to those of weight loss, are an insulin lowering effect, which may indirectly decrease ovarian androgen production, and a potential direct effect on the hypothalamus. Metformin is a biguanide, mainly used as an antihyperglycemic agent. It is an oral agent used in doses of 1500–2000 mg in divided daily doses. Its most common adverse effects are nausea, vomiting and diarrhea, which can be avoided or diminished by a gradual dose escalation. In a recent meta-analysis, metformin showed no improvement in live birth rate compared to no treatment, although it improved the clinical pregnancy rate [29]. The Pregnancy in Polycystic Ovary Syndrome I (PPCOS I) trial, a large multi-center
Fig. 1. Algorithm for ovulation induction in the PCOS patient. Weight loss is the first step in ovulation induction for obese and overweight women with PCOS. It can help to both resume ovulation and assist with subsequent ovulation induction methods. Ovulation induction with clomiphene citrate is the first-line pharmacological therapy for PCOS. If no ovulation is achieved after up to 3 cycles (clomiphene resistance) or no pregnancy after up to 6 ovulatory cycles (clomiphene citrate failure), further steps should be considered. Physician and patient must then discuss gonadotropin therapy versus laparoscopic ovarian drilling, taking into account advantages and disadvantages of each method. If no pregnancy is achieved, or if other infertility-related conditions coexist, ART can be employed. FSH: follicle stimulating hormone; ART: assisted reproductive techniques.
Fig. 2. Mechanism of action of the different methods of ovulation induction. The main mechanisms of action in ovulation induction are a(an): (1) decrease in insulin levels, (2) reduction in ovarian androgen production, (3) decrease in aromatase and (4) increase in hypothalamic–pituitary FSH secretion. A further benefit is an increase in circulating sex hormone binding globulin levels, which decreases bioavailable androgens. FSH: follicle stimulating hormone; E2: estradiol; ART: assisted reproductive techniques.
RCT that evaluated the use of metformin versus clomiphene versus both combined, shows a significantly lower live birth rate with metformin compared to clomiphene, only offering an advantage when added to clomiphene in women with BMI over 35 kg/m2 [30]. Thiazolidinediones are selective peroxisome proliferator-activated receptor-c (PPARc) agonists [31] that act by increasing the peripheral response to insulin. Apart from reducing insulin action on ovarian sex steroid production, they also seem to exert direct ef-
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
fects on ovarian steroidogenesis by decreasing the activity of ovarian 3b-hydroxysteroid dehydrogenase, inhibiting estradiol and testosterone production and increasing the production of progesterone and IGFBP-1. Besides, they decrease the ovarian production of TNFa [32–35]. Rosiglitazone has shown improved ovulation rates compared to placebo [26]. However, there are no studies addressing pregnancy and live birth rate. Thiazolidinediones have been less studied as infertility therapy for PCOS, most likely because they are in a more concerning FDA category C risk for pregnancy, and have been associated with weight gain and more serious adverse events, such as hepatotoxicity (troglitazone, now removed from the market), cardiovascular events (rosiglitazone), and bladder cancer (pioglitazone). Therefore, although useful in very specific settings, the effect of insulin sensitizing agents in ovulation induction is very limited, and they should not be routinely considered in the early steps of ovulation induction.
769
should be performed in order to confirm this novel finding and try to elucidate its mechanism of action. 2.4. Combination of metformin and clomiphene citrate The combination of metformin and clomiphene has been extensively studied for the treatment of infertility in PCOS. There is controversy about the possibility of achieving a higher rate of ovulation and pregnancy after this combined therapy than after clomiphene citrate alone. However, there are no differences in the live birth rate [30,42,43]. Subgroup analyses have found a possible role of this pharmacological combination in PCOS patients who are clomiphene citrate resistant [44] and those individuals with a BMI >35 kg/m2 and low hirsutism [30], but these associations should be further studied. The potential benefits of metformin as an adjuvant therapy to other infertility treatments (including clomiphene) in obese women was recently underscored in a multi-center Scandinavian trial [45].
2.3. Clomiphene citrate
2.5. Aromatase inhibitors
Clomiphene citrate is an oral selective estrogen receptor modulator (SERM). It is generally considered the first-line pharmacological therapy for ovulation induction in women with PCOS [30]. Its mechanism of action is inhibition of estrogen negative feedback on the hypothalamus by estrogen receptor blockade. As a result, a secondary increase in circulating FSH levels stimulates follicular development and ovulation [36]. Among its adverse effects are antiestrogenic effects on endometrial development and cervical mucus production, both of which have been implicated in a low pregnancy rate despite a relatively high ovulation rate with the use of this drug [37,38]. Another adverse effect is a higher rate of multiple pregnancies compared to a natural cycle, due to reduced estrogen negative feedback on the hypothalamus from the long half-life of the drug, resulting in exaggerated FSH release and multi-follicular development [39]. The reported rate of multiple pregnancies with clomiphene citrate is 4–8% [30,40]. While this is relatively low compared to gonadotropins and ART therapy, the increased utilization of clomiphene citrate as first line therapy by many practitioners (Ob/Gyn, Internal Medicine, Family Practice, etc.) may make this drug the single largest contributor to iatrogenic multiple pregnancy in the United States. Other side effects of clomiphene citrate include hot flashes, headaches, mood changes, temporary visual disturbances and very rarely, ovarian hyperstimulation syndrome (OHSS). The rates of ovulation, pregnancy and live birth over a six cycle treatment period are 49%, 30% and 23%, respectively, according to the PPCOS trial I, the only RCT adequately powered to study live birth rate up to date [30]. The method of clomiphene administration is 50 mg starting on the 2nd to 5th day after the onset of menses, for five days. If ovulation doesn’t occur, the dose should be increased in 50 mg increments until 150 mg/d or ovulation is achieved. When the patient ovulates, that dosing can be repeated for 6 ovulatory cycles or until pregnancy is achieved in one cycle. After 6 cycles, a more aggressive approach is recommended [5]. There has been controversy about when to begin the clomiphene stimulation in anovulatory cycles. Traditionally, ovulation induction was preceded by an endometrial shedding provoked by the administration of a progestin. However, in a recent secondary analysis of the PPCOS I data, the pregnancy and live birth rates were higher when ovulation induction was started without a withdrawal bleeding, even though ovulation rate was higher in those cycles preceded by endometrial shedding [41]. However, a randomized controlled trial primarily focused on the effect of endometrial shedding before starting the ovulation induction cycle
As a member of the P450 enzyme family, aromatase catalyzes the conversion of testosterone and androstenedione to estradiol and estrone, respectively. Thus, aromatase inhibitors produce an anti-estrogenic effect which decreases the negative feedback of estrogens in the hypothalamus, subsequently increasing the circulating concentration of FSH [46]. The most widely used aromatase inhibitor for ovulation induction is letrozole. It is an oral agent usually administered for 5 days starting on day 3 of the menstrual cycle, in doses between 2.5 and 7.5 mg per day [47]. Anastrazole has also been studied as an ovulation induction agent in women with PCOS, but Phase II studies showed that anastrazole was inferior to clomiphene in both ovulation and pregnancy rates, and further industry sponsored development of the drug was discontinued [48,49]. Aromatase inhibitors have been proposed to replace clomiphene as first-line pharmacological step in ovulation induction in PCOS patients [50]. Potentially, aromatase inhibitors have multiple advantages over clomiphene, including absence of an anti-estrogenic effect on the endometrium [51]. However, clinical trials have failed to find a difference in endometrial thickness comparing women receiving letrozole or clomiphene with non-stimulated cycles [52,53]. Other advantages are its short half-life, approximately 45 h versus a 2-week half-life of clomiphene citrate, and a higher rate of mono-follicular ovulation, and thus, a lower rate of multiple pregnancy [46]. Despite these potential advantages, clinical trials to date have failed to show a superiority of aromatase inhibitors in ovulation induction compared to clomiphene. A recent meta-analysis shows only a significant increase in ovulation rate per patient, but no increase in pregnancy or live birth rates [54]. We are looking forward to assessing the live birth results in women with PCOS from the PPCOS II trial, a randomized trial of clomiphene versus letrozole for anovulatory infertility in women with PCOS [55]; as well as determining the risk of multiple intrauterine gestation from an ovarian stimulation (AMIGOS) trial, a RCT designed and powered to study the rate of multiple pregnancies comparing clomiphene, letrozole and gonadotropins [56]. Both of these trials will provide useful data to assess the rates of ovulation, pregnancy and live birth with a homogeneity lacking in meta-analyses of smaller trials. 2.6. Gonadotropins Ovarian stimulation with gonadotropins is considered a secondline treatment for the PCOS patients with infertility. The main rea-
770
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
sons for this are the lack of an oral formulation, their high price, and their potentially serious adverse effects, especially multiple pregnancy and OHSS. Besides, they require close monitoring with ultrasound and determination of estradiol levels. In gonadotropin stimulation for PCOS patients, FSH is administered beginning with a dose of 37.5 and 75 IU/day (low-dose protocol). The rationale is to achieve an increase in FSH levels enough to allow the development of, ideally, a single follicle. For that purpose, the most appropriate regime is the step-up protocol, in which the FSH dose is gradually increased (in 7–14 day increments) until follicular development is observed, and then maintained until follicular selection is achieved [57]. This step should not exceed 6 ovulatory cycles. The Thessaloniki consensus defined a maximal stimulation as the presence of no more than two follicles P16 mm or one follicle P16 mm and two additional follicles P14 mm [5]. As above mentioned, obesity has been associated with a lower response to FSH so it has been suggested that obese patients should start ovarian stimulation with a 75 IU/day dose [58]. An ovarian stimulation of clomiphene followed by gonadotropins in case of clomiphene resistance or failure in PCOS patients showed a cumulative singleton live birth rate of 60% after a year of treatment and 78% after two years [59]. A recent RCT evaluates the clinical outcome of using gonadotropin versus clomiphene stimulation as first line therapy for ovulation induction in PCOS, showing a higher pregnancy and live birth rate with low-dose FSH. However, they acknowledge that using clomiphene as a first line therapy is a more convenient and cost-effective approach [60]. Women with PCOS have a higher risk of OHSS per se [61]. The use of supraphysiological levels of FSH can induce OHSS; however, this risk has been decreased due to the use of low-dose FSH protocols for ovulation induction in patients with PCOS [62]. The higher risk of OHSS has been associated to the larger cohort of FSH sensitive small antral follicles present in the women with PCOS, rather than a different threshold to FSH [63]. Besides, despite showing no effect on pregnancy or live birth rates, the addition of metformin during gonadotropin stimulation has been associated with a lower risk of OHSS [64]. Multiple pregnancy is considered as another adverse event of reproductive techniques. Although higher after IVF procedures, ovulation induction with FSH has also shown an increase in multifollicular development and multiple pregnancy [62]. As with OHSS, low-dose FSH protocols have helped to decrease the rate of multiple pregnancy to <6% [60]. 2.7. Laparoscopic ovarian drilling Ovarian drilling is the perforation of multiple holes in the surface and stroma of the ovary. It’s mechanism of action is thought to be a decrease in the production of androgens and their peripheral conversion to estrogens due to disruption of the ovarian tissue. Another potential mechanism is the conversion of the adverse androgenic follicular microenvironment to a more estrogenic one [65]. A third mechanism may be disruption of the ovarian capsule and dense stroma, allowing space for follicular expansion. As with gonadotropin therapy, laparoscopic ovarian drilling is considered a second-line approach for clomiphene citrate-resistant PCOS patients. This technique is preferred especially when other surgical indications coexist in the patient or when frequent follow up, as needed for FSH therapy, is impractical. The main concerns of ovarian drilling are the possibility of surgical complications, postsurgical adhesions [66] and iatrogenic premature ovarian failure [67]. As advantages with respect to gonadotropin therapy, it shows a significantly lower multiple pregnancy rate and no OHSS [68]. A recent meta-analysis showed no differences in pregnancy or live birth rate between ovarian drilling versus ovulation induction with
gonadotropins [68]. After surgery, if no ovulation is detected, clomiphene can be used again, since response has been observed in previously clomiphene citrate resistant patients [69,70]. 2.8. Assisted reproductive techniques Assisted reproductive techniques (ART) are those that include the direct manipulation of oocytes and sperm to achieve pregnancy. It requires several days of treatment with gonadotropin releasing hormone (GnRH) analogs or antagonists to inhibit the midcycle LH surge, gonadotropin therapy for achieving a multifollicular ovarian stimulation and human chorionic gonadotropin (hCG) administration to trigger ovulation. Afterwards, the gametes are fertilized in vitro and the resulting embryos are transferred to the uterus or frozen for future embryo transfer. Assisted reproductive techniques should be considered the last option for infertile PCOS patients, or for those individuals at great risk of multiple pregnancy by gonadotropin therapy or with coexisting indications for ART (i.e. tubal damage, endometriosis or male factor infertility). The pregnancy and live birth rate per cycle in patients with PCOS is not different to non-PCOS patients [71]. As with gonadotropin therapy, the most important adverse effects of ART are multiple pregnancy and OHSS. Multiple pregnancy can be controlled with elective single embryo transfer. Despite having shown a lower birth rate when compared to double embryo transfer after the fresh transfer, the addition of a subsequent transfer of a single frozen-thawed embryo makes the difference no longer significant [72]. However, to the best of our knowledge, no there are no studies that address elective single-embryo transfer in the PCOS population. With respect to the higher risk of OHSS in PCOS patients, lower doses of FSH should be used, and there is a higher risk of cycle cancellation [71]. In vitro oocyte maturation has been proposed for some women with PCOS due to their higher risk of OHSS [73]. Other advantages of in vitro oocyte maturation are a less frequent monitoring and a lower economic cost. However, it has been shown less effective than conventional in vitro fertilization [74,75] and there is still not quality evidence to recommend it in a systematic way. 3. Conclusions Following a stepwise approach in the treatment of infertility will provide the majority of PCOS patients with the opportunity of achieving pregnancy and live birth, while avoiding more expensive and invasive therapies whenever possible. It is likely that many patients will benefit from weight loss alone, both as an ‘‘ovulation induction’’ method itself and as an adjuvant to concomitant ovulation induction therapies. Following lifestyle modifications, clomiphene citrate has been the most efficient and most studied method to overcome infertility in PCOS patients. The potential benefits of aromatase inhibitors may replace the use of clomiphene as first-line pharmacological therapy. However, up to date, clinical trials have not yet shown a practical superiority over clomiphene. A more personalized approach is necessary for the patients who need second-line therapy, when the physician and patient have to carefully balance the advantages and disadvantages of ovulation induction with gonadotropins versus laparoscopic ovarian drilling. Finally, if all other resources have been unsuccessful or if other infertility-related conditions exist, ART can be used to attain a high rate of pregnancy in women with PCOS. References [1] Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004;89:2745–9.
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772 [2] Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85:2434–8. [3] Rotterdam EA-SPCWG. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25. [4] Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456–88. [5] Thessaloniki EA-SPCWG. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008;89:505–22. [6] Willis D, Franks S. Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 1995;80:3788–90. [7] Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 1981;108:1441–9. [8] Butzow TL, Moilanen JM, Lehtovirta M, Tuomi T, Hovatta O, Siegberg R, et al. Serum and follicular fluid leptin during in vitro fertilization: relationship among leptin increase, body fat mass, and reduced ovarian response. J Clin Endocrinol Metab 1999;84:3135–9. [9] Greisen S, Ledet T, Moller N, Jorgensen JO, Christiansen JS, Petersen K, et al. Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells. Acta Obstet Gynecol Scand 2000;79:931–5. [10] Gurbuz B, Yalti S, Ficicioglu C, Tasdemir S. The relation of serum and follicular fluid leptin and ovarian steroid levels in response to induction of ovulation in in vitro fertilization cycles. Eur J Obstet Gynecol Reprod Biol 2005;118:214–8. [11] Wake DJ, Strand M, Rask E, Westerbacka J, Livingstone DE, Soderberg S, et al. Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol (Oxf) 2007;66:440–6. [12] Moran LJ, Noakes M, Clifton PM, Wittert GA, Williams G, Norman RJ. Shortterm meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome. Am J Clin Nutr 2006;84:77–87. [13] Moran LJ, Noakes M, Clifton PM, Tomlinson L, Galletly C, Norman RJ. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:812–9. [14] Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994;61:598–604. [15] Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:1470–4. [16] Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995;10:2705–12. [17] 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;13:1502–5. [18] Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011:CD007506. [19] Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005;90:6364–9. [20] Musella M, Milone M, Bellini M, Sosa Fernandez LM, Leongito M, Milone F. Effect of bariatric surgery on obesity-related infertility. Surg Obes Relat Dis 2012;8:445–9. [21] Legro RS, Dodson WC, Gnatuk CL, Estes SJ, Kunselman AR, Meadows JW, et al. Effects of gastric bypass surgery on female reproductive function. J Clin Endocrinol Metab 2012;97:4540–8. [22] Maggard MA, Yermilov I, Li Z, Maglione M, Newberry S, Suttorp M, et al. Pregnancy and fertility following bariatric surgery: a systematic review. JAMA 2008;300:2286–96. [23] ACOG Committee Opinion No. 315. Obesity in pregnancy. Obstet Gynecol 2005;106:671–5. [24] ACOG Committee Opinion No. 549. Obesity in pregnancy. Obstet Gynecol 2013;121:213–7. [25] Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RW. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 2003;79:562–6. [26] Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 2004;82:893–902. [27] Carmina E, Lobo RA. Does metformin induce ovulation in normoandrogenic anovulatory women? Am J Obstet Gynecol 2004;191:1580–4. [28] Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876–80. [29] Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with
[30]
[31]
[32]
[33]
[34]
[35]
[36] [37]
[38]
[39]
[40] [41]
[42]
[43]
[44] [45]
[46]
[47] [48]
[49]
[50] [51] [52]
[53]
[54]
[55]
771
polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev 2012;5:CD003053. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270:12953–6. Gasic S, Nagamani M, Green A, Urban RJ. Troglitazone is a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase enzyme in the ovary. Am J Obstet Gynecol 2001;184:575–9. Komar CM. Peroxisome proliferator-activated receptors (PPARs) and ovarian function–implications for regulating steroidogenesis, differentiation, and tissue remodeling. Reprod Biol Endocrinol 2005;3:41. Chen Q, Sun X, Chen J, Cheng L, Wang J, Wang Y, et al. Direct rosiglitazone action on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells. Reprod Biol Endocrinol 2009;7:147. Seto-Young D, Paliou M, Schlosser J, Avtanski D, Park A, Patel P, et al. Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production. J Clin Endocrinol Metab 2005;90:6099–105. Adashi EY. Clomiphene citrate: mechanism(s) and site(s) of action – a hypothesis revisited. Fertil Steril 1984;42:331–44. Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson ME. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 1989;73:187–90. Massai MR, de Ziegler D, Lesobre V, Bergeron C, Frydman R, Bouchard P. Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment. Fertil Steril 1993;59:1179–86. MacDougall MJ, Tan SL, Hall V, Balen A, Mason BA, Jacobs HS. Comparison of natural with clomiphene citrate-stimulated cycles in in vitro fertilization: a prospective, randomized trial. Fertil Steril 1994;61:1052–7. Asch RH, Greenblatt RB. Update on the safety and efficacy of clomiphene citrate as a therapeutic agent. J Reprod Med 1976;17:175–80. Diamond MP, Kruger M, Santoro N, Zhang H, Casson P, Schlaff W, et al. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet Gynecol 2012;119:902–8. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006;332:1485. Johnson NP, Stewart AW, Falkiner J, Farquhar CM, Milsom S, Singh VP, et al. PCOSMIC: a multi-centre randomized trial in women with polycystic ovary syndrome evaluating metformin for infertility with clomiphene. Hum Reprod 2010;25:1675–83. Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007;13:527–37. Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippelainen M, Perheentupa A, et al. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab 2012;97:1492–500. Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clin Obstet Gynecol 2011;54:685–95. Pritts EA. Letrozole for ovulation induction and controlled ovarian hyperstimulation. Curr Opin Obstet Gynecol 2010;22:289–94. Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole singledose protocol in women with oligo- or anovulatory infertility: results of a randomized phase II dose-response study. Fertil Steril 2011;95:1725–9 [e1–8]. Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study. Fertil Steril 2011;95:1720–4 [e1–8]. Casper RF, Mitwally MF. Review: aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab 2006;91:760–71. Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil Steril 2006;85:277–84. Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002;78:280–5. Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fertil Steril 2009;92:1355–9. Misso ML, Wong JL, Teede HJ, Hart R, Rombauts L, Melder AM, et al. Aromatase inhibitors for PCOS: a systematic review and meta-analysis. Hum Reprod Update 2012;18:301–12. Legro RS, Kunselman AR, Brzyski RG, Casson PR, Diamond MP, Schlaff WD, et al. The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials 2012;33:470–81.
772
A. Perales-Puchalt, R.S. Legro / Steroids 78 (2013) 767–772
[56] Diamond MP, Mitwally M, Casper R, Ager J, Legro RS, Brzyski R, et al. Estimating rates of multiple gestation pregnancies: sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial. Contemp Clin Trials 2011;32:902–8. [57] Christin-Maitre S, Hugues JN, Recombinant FSHSG. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod 2003;18:1626–31. [58] Yildizhan R, Adali E, Kolusari A, Kurdoglu M, Yildizhan B, Sahin HG, et al. Ovarian stimulation in obese and non-obese polycystic ovary syndrome using a low-dose step-up regimen with two different starting doses of recombinant follicle-stimulating hormone. J Int Med Res 2008;36:1197–204. [59] Veltman-Verhulst SM, Fauser BC, Eijkemans MJ. High singleton live birth rate confirmed after ovulation induction in women with anovulatory polycystic ovary syndrome: validation of a prediction model for clinical practice. Fertil Steril 2012;98:761–8 [e1]. [60] Homburg R, Hendriks ML, Konig TE, Anderson RA, Balen AH, Brincat M, et al. Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study. Hum Reprod 2012;27:468–73. [61] Swanton A, Storey L, McVeigh E, Child T. IVF outcome in women with PCOS, PCO and normal ovarian morphology. Eur J Obstet Gynecol Reprod Biol 2010;149:68–71. [62] Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update 1999;5:493–9. [63] Van Der Meer M, Hompes PG, De Boer JA, Schats R, Schoemaker J. Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:423–6. [64] Palomba S, Falbo A, La Sala GB. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and metaanalysis of randomised controlled trials. BJOG 2013;120:267–76.
[65] Aakvaag A, Gjonnaess H. Hormonal response to electrocautery of the ovary in patients with polycystic ovarian disease. Br J Obstet Gynaecol 1985;92:1258–64. [66] Mercorio F, Mercorio A, Di Spiezio Sardo A, Barba GV, Pellicano M, Nappi C. Evaluation of ovarian adhesion formation after laparoscopic ovarian drilling by second-look minilaparoscopy. Fertil Steril 2008;89:1229–33. [67] Kandil M, Selim M. Hormonal and sonographic assessment of ovarian reserve before and after laparoscopic ovarian drilling in polycystic ovary syndrome. BJOG 2005;112:1427–30. [68] Farquhar C, Brown J, Marjoribanks J. Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2012;6:CD001122. [69] Gjonnaess H. Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope. Fertil Steril 1984;41:20–5. [70] Bayram N, van Wely M, Kaaijk EM, Bossuyt PM, van der Veen F. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial. BMJ 2004;328:192. [71] Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006;12:13–21. [72] Thurin A, Hausken J, Hillensjo T, Jablonowska B, Pinborg A, Strandell A, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392–402. [73] Chian RC. In-vitro maturation of immature oocytes for infertile women with PCOS. Reprod Biomed Online 2004;8:547–52. [74] Child TJ, Phillips SJ, Abdul-Jalil AK, Gulekli B, Tan SL. A comparison of in vitro maturation and in vitro fertilization for women with polycystic ovaries. Obstet Gynecol 2002;100:665–70. [75] Gremeau AS, Andreadis N, Fatum M, Craig J, Turner K, McVeigh E, et al. In vitro maturation or in vitro fertilization for women with polycystic ovaries? A casecontrol study of 194 treatment cycles. Fertil Steril 2012;98:355–60.