Yoshiharu Morimoto1
(1)
Department of Obstetrics and Gynecology, IVF Namba Clinic, Kansai Medical University, 1-17-28, Minami-horie, Nishi-ku, Osaka 550-0015, Japan
Yoshiharu Morimoto
Email: ivfceo@gmail.com
Abstract
Polycystic ovary syndrome (PCOS) has been implicated as a main endocrine disorder that can cause oligo- or anovulation. PCOS has been studied for a long period and was first described by Stein and Leventhal in 1935.
A consensus between the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) defined the diagnosis criteria for PCOS as oligo- and/or anovulation, hyperandrogenism (clinical and/or biochemical), and the appearance of polycystic ovaries on ultrasound. Most PCOS cases can be diagnosed using these criteria; however, there are some variant phenotypes, and the diagnosis is often difficult. Although PCOS has been well studied, an optimal treatment to achieve pregnancy remains unclear. In this chapter, the current status of PCOS and management methods of the disorder are discussed. Furthermore, how to control ovarian hyperstimulation syndrome (OHSS), the most troublesome side effect of PCOS during ovarian stimulation, is discussed.
Keywords
Polycystic ovaryOvarian stimulationOvarian hyperstimulation syndromeIn vitro maturationHyperandrogenismCabergoline
Polycystic ovary syndrome (PCOS) has been implicated as a main endocrine disorder that can cause oligo- or anovulation. PCOS has been studied for a long period and was first described by Stein and Leventhal in 1935 [1].
A consensus between the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) (Table 8.1) defined the diagnosis criteria for PCOS as oligo- and/or anovulation, hyperandrogenism (clinical and/or biochemical), and the appearance of polycystic ovaries on ultrasound. Most PCOS cases can be diagnosed using these criteria; however, there are some variant phenotypes, and the diagnosis is often difficult. Although PCOS has been well studied, an optimal treatment to achieve pregnancy remains unclear. In this chapter, the current status of PCOS and management methods of the disorder are discussed. Furthermore, how to control ovarian hyperstimulation syndrome (OHSS), the most troublesome side effect of PCOS during ovarian stimulation, is discussed.
Table 8.1
The ESHRE/ASRM consensus criteria for PCOS
|
2 out of 3 |
|
1. Oligo- or anovulation |
|
2. Clinical and/or biochemical signs of hyperandrogenism |
|
3. Polycystic ovaries |
|
And exclusion of other etiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome) |
Revised diagnostic criteria, 2003
Physiology of PCOS
The hyperandrogenic status may affect folliculogenesis and oogenesis in PCOS patients. The sources of androgen during the fetal period are the fetal ovary itself and the hyperandrogenic adrenal cortex [2]. Fetal androgen excess in females may cause a heterogeneous PCOS phenotype later in life, because PCOS has been ascribed to genetic origins. Gharani et al. [3] reported a pentanucleotide repeat polymorphism in the CYP11a promoter region related to hyperandrogenism in PCOS patients. Insulin resistance frequently occurs in PCOS patients. Androgen exposure in the uterus and later in puberty has been implicated in impaired insulin action and may cause insulin resistance. The development of insulin resistance has been linked to fat distribution and thus, can be improved by weight loss.
Anti-Mullerian Hormone (AMH)
Anti-Mullerian hormone is a member of the transforming growth factor-β (TGF-β) superfamily and is recognized as an excellent parameter for predicting the ovarian reserve. To determine whether AMH could be used as a predictor of ovarian response in PCOS patients. Lie et al. [4] measured AMH and inhibin B concentrations during ovulation induction treatment with recombinant follicle-stimulating hormone (r-FSH) stimulation. However, they concluded that neither of these parameters were suitable to predict the outcome of ovulation induction.
Serum AMH levels are usually elevated in PCOS patients, and it is widely believed that AMH elevation is in response to robust follicle growth. However, AMH overproduction by granulosa cells may also be another cause [5]. Furthermore, AMH production was suppressed by FSH addition to the culture media. Lie et al. [5] indicated that enhanced promoter activity can cause excessive AMH production in PCOS granulosa cells and that, FSH may inhibit excessive AMH secretion by suppressing the luciferase activity of the AMH promoter. Collectively, these findings indicated that AMH elevation was not caused by the increased number of antral follicles but rather by the abnormal secretion of granulosa cells in PCOS patients [5].
Antral Follicle Count (AFC)
Antral follicle count is used to measure small (4–5 mm) follicles with transvaginal sonography and has been recognized as a predictor of ovarian reserve. Recent developments in ultrasonography have enabled the use of ovarian volume as a predictor. However, this methodology is complicated and thus, is not suitable for a routine testing [6].
The effectiveness of AFC is dependent on the measurement technique thus, results may vary during different menstruation phases. Holte et al. [7] indicated that an AFC up to 30 is an indicator of pregnancy and live birth rates in PCOS patients. Interestingly, this report indicated that AFC predicts not the quantity, but rather the quality of oocytes. It is different from AMH that reflects the number of growing follicles.
Ovarian Stimulation for PCOS (Table 8.2)
Table 8.2
Methods of ovarian stimulation and their feature
|
Method of ovarian stimulation |
Feature |
|
Clomiphene citrate |
Easy to administer. Thin endometrium. Low implantation |
|
Letrozole |
It has an identical effect to Clomiphene citrate in ovarian stimulation but does not make endometrium thin |
|
Selective estrogen receptor modulator (SERM) |
Good for failed CC cases. Not well studied |
|
Low-dose FSH |
Decrease OHSS. Higher duration of stimulation. Costs a lot |
|
Gonadotropins + GnRH agonist |
Possible OHSS. Good clinical outcome |
|
Gonadotropins + GnRH antagonist |
GnRH is available as a trigger instead of human chorionic gonadotropin (hCG), which may exacerbate OHSS |
The main symptoms of infertility in PCOS patients are anovulation and oligo-ovulation. For ovulatory PCOS patients, the prediction of the day of ovulation is difficult. Therefore, ovulation induction is routinely performed in these patients. Clomiphene citrate (CC) is commonly the first choice of induction; however, it may pose a risk of reduced endometrial receptivity and ovarian hyperstimulation syndrome (OHSS). To avoid this risk, Cyclofenil or aromatization inhibitors, such as Letrozole, can be used as alternative drugs. In medication-resistant cases, gonadotropin administration is sometimes effective, but it may increase the risk of OHSS, that is reportedly, the greatest risk factor in PCOS.
Clomiphene Citrate (CC)
Clomiphene citrate is commonly used for ovarian stimulation in PCOS patients and effectively yields mature follicles. It works by the feedback mechanisms in the hypothalamic and pituitary ovarian axis by occupying estrogen receptors. CC is a first-line stimulator, and the most effective dosage is 100–150 mg/day for 5 days from the third or fifth day of the menstrual cycle. Imani et al. [8] reported that over 75 % of ovulations occur within these dosages, and CC induces ovulation in almost 75–80 % of selected women with PCOS-related infertility [9]. However, CC administration is not recommend for more than 12 months, as the National Institute for Clinical Excellence (NICE) guidelines [10] contraindicate the extended use of CC because of the increased risk of ovarian cancer and decreased possibility of conception.
CC versus Low-Dose FSH
Clomiphene citrate is frequently administered to PCOS patients for ovulation induction because it is inexpensive, easy to give, and simple to administer for patients. However, the pregnancy outcome was better in a group who received FSH stimulation [11]. Thus, CC seems to be disadvantageous in terms of decreased cervical mucus production and has a deleterious effect on endometrial receptivity. Moreover, Homburg [12] reported that CC administration increased the rate of miscarriage and concluded that these detrimental effects occur via physiological features that work by its antiestrogenic actions and by the negative feedback mechanism on FSH secretion. In this study, CC was administered at a starting dosage of 50 mg/day and increased up to 150 mg/day, and 50 IU of recombinant FSH was added with 25 IU increments weekly. The results showed better clinical and cumulative pregnancy rates in the FSH administration group. However, multiple pregnancy rates increased slightly [12].
Letrozole
Letrozole is an oral non-steroidal aromatase inhibitor and is used as an ovulation induction agent for PCOS patients. It has been used as an alternative to CC. Letrozole produces fewer follicles and reduces the incidence of multiple pregnancies and ovarian hyperstimulation compared with CC. Several different dosages of Letrozole have been used clinically. Rahmani et al. [13] showed that the yield of follicles is dose-dependent from 2.5 mg to 7.5 mg. In addition, they showed that large amounts of the agent increased not only follicle production but also the risk of OHSS. There are meta-analyses comparing efficacy of the induction potential between CC and Letrozole. He and Jiang [14] performed a meta analysis to compare the efficacy of the induction potential between CC and Letrozole and showed that the efficacy of Letrozole was not superior to that of CC but rather, identical as a report of Cochrane data base suggested.
Selective Estrogen Receptor Modulators (SERMs)
In addition to CC, SERMs, such as Tamoxifen, that can reduce the estrogen receptivity have been recently used for ovulation induction. The mechanism of Tamoxifen in improving folliculogenesis may involve direct action on the ovary without intervention of the hypothalamic-pituitary-adrenal axis. Dhaliwal et al. [15] showed that 38.8 % of PCOS patients in a group that failed to achieve pregnancy by CC administration conceived following Tamoxifen administration and achieved a pregnancy rate of 28.5 %. The pregnancy rate was higher in a group administered 80 mg/day than in a group administered 40 mg/day. It was elucidated that Tamoxifen administration did not increase the incidence of ovarian cancer [16]. Raloxifene (marketed as Evista by Eli Lilly and Company, Indianapolis, IN, USA) is an oral SERM that induces ovulation in a manner similar to CC [17].
Gonadotropins Combined with Gonadotropin-releasing Hormone (GnRH) Agonists and Antagonists
Many years have passed since the application of gonadotropins for ovulation induction in PCO patients. However, there is no consensus on an optimal protocol for ovulation induction that can also avoid side effects (mainly OHSS) and enable production of good quality oocytes/embryos. Gonadotropins are used in combination with GnRH agonists or antagonists. Commonly, an ovulation stimulation method for PCOS patients, using a GnRH antagonist is preferable to that using a GnRH agonist. The reason is because if OHSS is expected to occur, the human chorionic gonadotropin (hCG) injection used for triggering ovulation that may induce OHSS can be switched to GnRH agonist administration. Instead of hCG injection, we use 900 μg of a nasal spray of GnRH agonist twice daily.
Abuzeid et al. [18] reported a method to start the GnRH antagonist in the early stage of menstrual cycle for PCO patients. With the use of GnRH antagonists, implantation rates, pregnancy rates, and delivery rates were improved. Thereafter, they tried to start GnRH antagonist from day 1 and day 5, and the early starting group showed better implantation rates. This report suggested these improvements occurred via the suppression of luteinizing hormone (LH) level, which may have deleterious effects on follicular growth and oocyte quality.
Addition of hCG
Human chorionic gonadotropin administration for the final maturation of oocyte is essential; however, hCG may be a strong risk factor for OHSS. On the other hand, trials were conducted to enhance ovarian stimulation with the addition of low-dose hCG during stimulation protocols in PCOS patients [19, 20]. Ashrafi et al. [19] indicated that low-dose hCG combined with recombinant FSH reduced the use of FSH and yielded more mature oocytes. Furthermore, no severe cases of OHSS were reported in the study.
In Vitro Maturation (IVM)
The IVM procedure has been performed in many centers worldwide and mainly applied to PCO patients. The first study of IVM of mammalian oocytes was performed back in 1935 by Pincus and Enzmann [21]. Thereafter, Edwards et al. [22, 23] suggested its clinical application in humans, by obtaining immature oocytes from patients following ovarian stimulation. Veeck et al. [24] achieved the first successful birth from immature oocytes produced during an in vitro fertilization (IVF) program. Thereafter, Cha et al. [25] first reported the use of immature oocytes from unstimulated ovaries of patients in an oocyte donation program. In IVM, the size of aspirated follicle is 5–7 mm, but it is not easy to puncture follicles intravaginally. As the difficulty of the ovum pick-up (OPU) technique is one reason why this procedure cannot be mainstream in assisted reproductive technology, we developed a new needle for OPU in IVM and found that it was effective in easily acquiring many small follicles, even for beginners. The needle was composed of two segments; an inner fine needle to puncture the small follicles and an outer sheath to grasp the ovary because is liable to embed deep into the abdominal cavity during the puncture procedure.
The medium for culturing immature oocytes commonly contains FSH and hCG, based in a balanced salt solution. Nowadays, several media, specially designed for IVM, are commercially available. The issues to be discussed commonly are FSH and hCG priming. hCG priming has been performed in many centers since Chian et al. [26] proposed its significance, but the effectiveness of FSH priming in IVM is not yet recognized. Our group has applied IVM for PCOS patients since 1999. Up to 2010, we have performed the procedure in 1143 cycles and found that although pregnancy and implantation rates were acceptable, IVM was yet not superior to conventional IVF (Table 8.3).
Table 8.3
Clinical outcome of IVM procedure
|
Fresh cycle |
Frozen cycle |
Thawed cycle |
Total |
|
|
No. of period |
670 |
473 |
1143 |
|
|
No. of oocyte |
5770 |
3532 |
9302 |
|
|
Ave. no. of oocyte |
8.6 |
7.5 |
||
|
% Maturation |
50.7 |
52.6 |
51.7 |
|
|
% Fertilization |
81.2 |
84.3 |
82.4 |
|
|
% Possible transfer |
31.3 |
30.6 |
||
|
% ET |
60.9 |
66.1 |
62.8 |
|
|
No. of pregnancy |
111 |
65 |
176 |
|
|
% Pregnancy/ET |
27.2 |
24.3 |
26.1 |
|
|
% Implantation |
13.2 |
11.3 |
12.5 |
1999–2010 IVF Namba Clinic and IVF Osaka Clinic
In vitro maturation is the ultimate and only method for preventing OHSS in PCO treatment. Gremeau et al. [27] reported that IVM is a preferable alternative to IVF with ovarian stimulation, and effectively eliminates OHSS, but the live birth rate was significantly lower than with the conventional ovarian stimulation method.
OHSS Management
It is well known and experienced that OHSS is often induced by ovarian stimulation for PCO patients; therefore, prevention of OHSS is the main consideration when performing this procedure. Once OHSS occurs, appropriate measures must be undertaken to save the patient’s life.
Ovarian hyperstimulation syndrome is characterized by several symptoms, such as ovarian swelling and accumulation of abdominal, pleural, and pericardiac fluids. Hyperstimulation of the ovaries induces histamine secretion that may enhance vascular endothelial growth factor (VEGF) production by the granulosa cells. VEGF increases the permeability of blood vessels that causes plasma leakage into third spaces. Those symptoms induce secondary severe clinical symptoms such as respiratory disorders and kidney and cardiac failures. If appropriate measures, as shown at Table 8.4, are not taken, patients may face life-threatening conditions such as multiple organ failure (Fig. 8.1).
Table 8.4
New strategies for prevention severe OHSS
|
1. Coasting: withholding gonadotropins and deferring the administration of hCG until E2 levels start dropping |
|
2. Continue to use GnRH agonist after OPU for a week at GnRH agonist protocol |
|
3. Cabergoline administration: Start at the day of hCG administration at the dose of 0.5 mg for 7–8 days |
Fig. 8.1
Pathogenesis of OHSS
The incidence of OHSS is reportedly 0.6–1.9 % in severe cases [28]. Severe OHSS cases require hospitalization, and patients suffer from critical conditions that are sometimes fatal. They have to endure pain caused by the pressure from enormously enlarged ovaries and ascites. Occasionally, patients may be incapable of assuming a supine position because of respiratory distress caused by the accumulation of pleural fluid.
The first choice for OHSS prevention is cryopreservation of all embryos, avoiding embryo transfer. This inhibits the effect of hCG from the placenta. Recently, pregnancy outcomes from cryopreserved and thawed embryos have been remarkably improved by the application of a vitrification procedure, and cryopreservation of all embryos is advantageous for PCOS patients.
The use of GnRH agonist as a trigger instead of hCG is an acceptable option to prevent OHSS. However, it is important to evaluate the impact of GnRH on oocytes and embryos. Acevedo et al. [29] reported no difference in maturation, fertilization, pregnancy, or implantation rates between triggering by hCG and a GnRH agonist.
Martinez et al. [30] reported a unique strategy for using a GnRH antagonist in a long protocol by a GnRH agonist. They withdrew the agonist during stimulation and replaced it with an antagonist. Consequently, they could use, the agonist for triggering ovulation and thus, prevented OHSS in three cases.
The use of recombinant hCG instead of urinary hCG is one of options to reduce OHSS. However, a review of the Cochrane database [31] found no significant difference in the incidence of OHSS between the two drugs.
Coasting is also an effective method for preventing OHSS during ovarian hyperstimulation. It is a method to withdraw exogenous gonadotropins and withhold hCG until the estrogen titer decreases to a safe level. Ohata et al. [32] described that coasting for 3–6 days remarkably decreased the ovary size, ascites volume, and recovery time. The effectiveness of this procedure has encouraged further clinical application of this method because it is simpler to perform than other methods used for preventing OHSS.
Recently, the administration of Cabergoline (a dopamine receptor-2 agonist) has been employed to prevent OHSS. Cabergoline is commonly used for hyperprolactinemia treatment and can be initiated either from the day of hCG administration or the day of oocyte retrieval [33].
The growth factors and hormones such as insulin- like growth factor (IGF), AMH, inhibin B, and hepatocyte growth factor in follicular fluid decreased when Cabergoline was administered for patients at high risk for OHSS [34]. This is physiological evidence of the effectiveness of Cabergoline in OHSS patients. Esinler et al. [35] compared the effectiveness of Cabergoline with coasting and found no occurrence of OHSS in patients receiving Cabergoline. Thus, they concluded that Cabergoline was more beneficial than coasting.
It is well known that hCG is an exacerbating factor. To avoid hCG usage, GnRH agonist is alternatively used as a trigger for ovulation. Physiologically, OHSS dynamism starts when the FSH-primed ovaries are exposed to hCG, which increases vascular permeability. Thereafter, the vascular VEGF and VEGF receptor 2 (VEGFR-2) express dominantly. The mechanism of effective OHSS prevention can be explained by the fact that dopamine agonists, such as Cabergoline, prevent VEGF overexpression [36].
Conclusions
It is difficult to effectively and safely stimulate the ovaries of PCOS patients while avoiding side effects, especially such as the development of OHSS. It is important to carefully access the ovarian reserve of patients and choose an appropriate stimulation protocol. For the assessment of ovarian function, the use of AMH, FSH, and AFC is advantageous. CC is the first-line stimulation drug for ovaries in PCOS patients. However, newer medications such as Letrozole and SERMs are potential advantageous candidates. In patients at high risk of OHSS development, IVM is an excellent option that can be employed. It is necessary to keep it in mind that OHSS is sometimes fatal. It is essential to avoid the onset of this disorder by any means.
References
1.
Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181–91.
2.
Arora S, Allahbadia GN. Early origins of polycystic ovary syndrome. In: Allahbadia GN, Agrawal R, editors. Polycystic ovary syndrome. Kent: Anshan Ltd; 2007. p. 3–12.
3.
Gharani N, Gharani N, Waterworth DM, et al. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet. 1997;6:397–402.CrossRefPubMed
4.
Lie FS, Schipper I, de Jong FH, Themmen AP, Visser JA, Laven JS. Serum anti-Müllerian hormone and inhibin B concentrations are not useful predictors of ovarian response during ovulation induction treatment with recombinant follicle-stimulating hormone in women with polycystic ovary syndrome. Fertil Steril. 2011;96:459–63.CrossRef
5.
Pellatt L, Hanna L, Brincat M, Galea R, Brain H, Whitehead S, Mason H. Granulosa cell production of anti-mullerian hormone is increased in polycystic ovaries. J Clin Endocrinol Metab. 2007;92:240–5.CrossRefPubMed
6.
Lass A, Skull J, McVeigh E, Margara R, Winston R. Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for in-vitro fertilization) can predict poor response. Hum Reprod. 1997;12:294–7.CrossRefPubMed
7.
Holte J, Brodin T, Berglund L, Hadziosmanovic N, Olovsso M, Bergh T. Antral follicle counts are strongly associated with live-birth rates after assisted reproduction, with superior treatment outcome in women with polycystic ovaries. Fertil Steril. 2011;96:594–9.CrossRefPubMed
8.
Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Fertil Steril. 2002;77:91–7.CrossRefPubMed
9.
Abu Hashim H, Bazeed M, Abd EI. Minimal stimulation or clomiphene citrate as first-line therapy in women with polycystic ovary syndrome: a randomized controlled trial. Gynecol Endocrinol. 2012;28:87–90.CrossRefPubMed
10.
National Collaborating Centre for Women’s and Children’s Health/National Institute for Clinical Excellence. Fertility: assessment and treatment for people with fertility problems, Clinical guideline, vol. II. London: RCOG Press; 2004.
11.
Homburg R, Hendriks ML, König TE, Anderson RA, Balen AH, Brincat M, Hompes P, Lambalk CB, 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.CrossRefPubMed
12.
Homburg R. Oral agents for ovulation induction-clomiphene citrate versus aromatasc inhibitors. Hum Fertil (Camb). 2008;11:17–22.CrossRef
13.
Rahmani E, Ahmadi S, Motamed N, Maneshi HO. Dosage optimization for letrozole treatment in clomiphene-resistant patients with polycystic ovary syndrome: a prospective interventional study. Obstet Gynecol Int. 2012;2012:758508.PubMedCentralCrossRefPubMed
14.
He D, Jiang F. Meta-analysis of letrozole versus clomiphene citrate in polycystic ovary syndrome. Reprod Biomed Online. 2012;23:91–6.CrossRef
15.
Dhaliwal LK, Suri V, Gupta KR, Sahdev S. Tamoxifen: an alternative to clomiphene in women with polycystic ovary syndrome. J Hum Reprod Sci. 2011;4:76–9.PubMedCentralCrossRefPubMed
16.
Cook LS, Weiss NS, Schwartz SM. Population-based study of tamoxifen therapy and subsequent ovarian, endometrial and breast cancers. J Natl Cancer Inst. 1995;87:1359–64.CrossRefPubMed
17.
de Paula Guedes Neto E, Savaris RF, von Eye Corleta H, de Moraes GS, de Amaral Cristovam R, Lessey BA. Prospective, randomized comparison between raloxifene and clomiphene citrate for ovulation induction in polycystic ovary syndrome. Fertil Steril. 2011;96:769–73.CrossRefPubMed
18.
Abuzeid MI, Mitwally M, Abuzeid YM, Bokhari HA, Ashraf M, Diamond MP. Early initiation of gonadotropin-releasing hormone antagonist in polycystic ovarian syndrome patients undergoing assisted reproduction: randomized controlled trial. J Assist Reprod Genet. 2012;29:1193–202.PubMedCentralCrossRefPubMed
19.
Ashrafi M, Kiani K, Ghasemi A, Rastegar F, Nabavi M. The effect of low dose human chorionic gonadotropin on follicular response and oocyte maturation in PCOS patients undergoing IVF cycles: a randomized clinical trial of efficacy and safety. Arch Gynecol Obstet. 2011;284:1431–8.CrossRefPubMed
20.
Nargund G, Hutchison L, Scaramuzzi R, Campbell S. Low-dose HCG is useful in preventing OHSS in high-risk women without adversely affecting the outcome of JVP cycles. Reprod Biomed Online. 2007;14:682–5.CrossRefPubMed
21.
Pincus G, Enzmann EV. The comparative behavior of mammalian eggs in vivo and in vitro: I. The activation of ovarian eggs. J Exp Med. 1935;62:655–75.CrossRef
22.
Edwards R. Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes. Nature. 1965;20:349–51.CrossRef
23.
Edwards R, Bavister B, Steptoe P. Early stages of fertilization in vitro of human oocytes matured in vitro. Nature. 1969;221:632–5.CrossRefPubMed
24.
Veeck LL, Wortham Jr JW, Witmyer J, et al. Maturation and fertilization of morphologically immature human oocytes in a program of in vitro fertilization. Fertil Steril. 1983;39:594–602.PubMed
25.
Cha KY, Koo JJ, Ko JJ, et al. Pregnancy after in vitro fertilization of human follicular oocytes collected from nonstimulated cycles, their culture in vitro and their transfer in a donor oocyte program. Fertil Steril. 1991;55:109–13.PubMed
26.
Chian RC, Buckett WM, Tulandi T, Tan SL. Prospective randomized study of human chorionic gonadotrophin priming before immature oocyte retrieval from unstimulated women with polycystic ovarian syndrome. Hum Reprod. 2000;15:165–70.CrossRefPubMed
27.
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 case-control study of 194 treatment cycles. Fertil Steril. 2012;98:355–60.CrossRefPubMed
28.
Smitz J, Camus M, Devroey P, Erard P, Wisanto A, Van Steirteghem AC. Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in vitro fertilization. Hum Reprod. 1990;5:933–7.PubMed
29.
Acevedo B, Gomez-Palomares JL, Ricciarelli E, Hernandez ER. Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates. Fertil Steril. 2006;86:1682–7.CrossRefPubMed
30.
Martinez F, Rodriguez DB, Buxaderas R, Tur R, Mancini F, et al. GnRH antagonist rescue of a long-protocol IVF cycle and GnRH agonist trigger to avoid ovarian hyperstimulation syndrome: three case reports. Fertil Steril. 2011;95:2432 e17–9.CrossRefPubMed
31.
Youssef MA, Al-Inany HG, Aboulghar M, Mansour R, Abou-Setta AM. Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF and ICSI cycles. Cochrane Database Syst Rev. 2011;(4):CD003719.
32.
Ohata Y, Harada T, Ito M, Yoshida S, Iwabe T, Terakawa N. Coasting may reduce the severity of the ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome. Gynecol Obstet Invest. 2000;50:186–8.CrossRefPubMed
33.
Seow KM, Lin YH, Bai CH, Chen HJ, Hsieh BC, Huang L, et al. Clinical outcome according to timing of cabergoline initiation for prevention of OHSS: a randomized controlled trial. Reprod Biomed Online. 2013;26:562–8.CrossRefPubMed
34.
Guventag Guven ES, Dilbaz S, Duraker R, Mentese A, Cinar O, Ozdegirmenci O. The effect of cabergoline on follicular microenvironment profile in patients with high risk of OHSS. Gynecol Endocrinol. 2013;29:749–53.CrossRef
35.
Esinler I, Bozdag G, Karakocsokmensuer L. Preventing ovarian hyperstimulation syndrome: cabergoline versus coasting. Arch Gynecol Obstet. 2013;288(5):1159–63.CrossRefPubMed
36.
Gomez R, Soares SR, Busso C, Garcia-Velasco JA, Simon C, et al. Physiology and pathology of ovarian hyperstimulation syndrome. Semin Reprod Med. 2010;28:448–57.CrossRefPubMed