Polycystic ovary syndrome and oocyte developmental competence

Folliculogenesis is a complex process, in which multiple endocrine and intraovarian paracrine interactions create a changing intrafollicular microenvironment for appropriate oocyte development. Within this microenvironment, bidirectional cumulus cell-oocyte signaling governs the gradual acquisition of developmental competence by the oocyte, defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. These regulatory mechanisms of follicle growth, controlled in part by the oocyte itself, are susceptible to derangement in polycystic ovary syndrome (PCOS), a heterogeneous syndrome characterized by ovarian hyperandrogenism, insulin resistance, and paracrine dysregulation of follicle development. Consequently, only a subset of PCOS patients experience reduced pregnancy outcome after ovarian stimulation for in vitro fertilization. Recent data implicate functional associations between endocrine/paracrine abnormalities, metabolic dysfunction, and altered oocyte gene expression with impaired oocyte developmental competence in women with PCOS. Therefore, an understanding of how developmentally relevant endocrine/paracrine factors interact to promote optimal oocyte developmental is crucial to identify those PCOS patients who might benefit from long-term correction of follicle growth to improve fertility, optimize follicular responsiveness to gonadotropin therapy, and enhance pregnancy outcome by in vitro fertilization.     

Adverse effects of luteinizing hormone on fertility: fact or fantasy

High tonic serum concentrations of luteinizing hormone (LH) in the follicular phase, frequently witnessed in polycystic ovary syndrome, have been associated with decreased reproductive function. Impaired rates of fertilization, conception and miscarriage are obtained when LH levels are high before oocytes are collected, during ovulation induction or in women with regular cycles. Conversely, treatment that decreases LH concentrations, such as gonadotrophin-releasing hormone analogue or laparoscopic ovarian puncture, eases induction of ovulation and pregnancy and improves miscarriage rates. Tonic hypersecretion of LH appears to induce premature oocyte maturation, causing the problems with fertilization and miscarriage.     

The role of luteinizing hormone in folliculogenesis and ovulation induction

OBJECTIVE: To review the physiologic, pathophysiologic, and clinical roles of LH in follicle and oocyte development and maturation and to assess the effects of LH content in exogenous gonadotropin preparations used for ovulation induction. DESIGN: Critical review of the scientific literature devoted to folliculogenesis. Evaluation of comparison studies that used different gonadotropin preparations for ovulation induction. CONCLUSION(S): Folliculogenesis and oocyte maturation are complex processes that require the action of both LH and FSH. Luteinizing hormone is essential to provide the androgen substrate for estrogen synthesis, which in turn contributes to oocyte maturation and may play a relevant role in optimizing fertilization and embryo quality. Although the excessive LH secretion that is present in some disorders is detrimental to reproductive function, this is not applicable to ovulation induction with hMG because this menotropin does not increase daily plasma LH levels. The results of ovulation induction with hMG or FSH-only regimens did not differ in studies conducted in patients with polycystic ovary syndrome and in most studies conducted in ovulatory women undergoing assisted reproductive techniques; conversely, hMG was clearly superior to purified FSH for the treatment of hypogonadotropic hypogonadism. Miscarriage rates were not affected by the use of hMG. Thus, low but detectable LH concentrations positively influence the outcome of ovulation induction in patients with ovulatory disorders and women undergoing assisted reproductive techniques.     

Akupunktur bei assistierter Reproduktion und PCOS

In controlled trials, acupuncture alleviated pain during oocyte aspiration for in vitro fertilization/embryo transfer (IVF/ET) treatment and regulated uterine and ovarian blood flow. Recent clinical and experimental data on the effect of acupuncture in polycystic ovary syndrome (PCOS) clearly demonstrate that acupuncture affects PCOS via modulation of endocrine, neuroendocrine and endogenous regulatory systems and exerts long-lasting beneficial effects on ovulation and on metabolic and endocrine systems. Some trials even suggest that acupuncture at embryo transfer has a positive impact on pregnancy rates. Results of recent trials are discussed, as are the difficulties and confounders associated with the interpretation of controlled trials and an attempt to standardize reporting of acupuncture interventions (STRICTA). Acupuncture is a safe intervention in the hands of competent practitioners and is low in cost, but well-designed studies are lacking. Clinicians and scientists are encouraged to conduct large, prospective, randomized trials to demonstrate more precisely the physiological impact of acupuncture on the reproductive system and its possible impact on pregnancy rates.     

Different routes of progesterone administration and polycystic ovary syndrome: A review of the literature

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in woman of reproductive age. Although extensive studies have been performed in past decades to investigate the pathobiological mechanisms underlying the unset of this disease, its etiology remains unknown. Progesterone is a hormone of paramount importance in ovulation, implantation and luteal phase support. Low levels of progesterone have been found in the early luteal phase in PCOS patients. Granulosa cells from polycystic ovaries show an altered progesterone production. Moreover, the lack of cyclical exposure to progesterone may have a role in the development of the gonadotropin and androgen abnormalities found in PCOS patients. Ovulation failure and progesterone deficiency may facilitate the hypothalamic–pituitary abnormalities causing the associated disordered luteinizing hormone secretion in PCOS. Progesterone may be administered to PCOS patients in the following cases: to induce withdrawal bleeding, to suppress secretion of luteinizing hormone, in ovulation induction in clomiphene citrate-resistant patients and in luteal phase support in assisted reproduction. We discuss the pharmacologic characteristics of the different routes of progesterone administration with reference to these diverse indications, the therapeutic objectives and patient compliance.     

Different routes of progesterone administration and polycystic ovary syndrome: a review of the literature.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in woman of reproductive age. Although extensive studies have been performed in past decades to investigate the pathobiological mechanisms underlying the unset of this disease, its etiology remains unknown. Progesterone is a hormone of paramount importance in ovulation, implantation and luteal phase support. Low levels of progesterone have been found in the early luteal phase in PCOS patients. Granulosa cells from polycystic ovaries show an altered progesterone production. Moreover, the lack of cyclical exposure to progesterone may have a role in the development of the gonadotropin and androgen abnormalities found in PCOS patients. Ovulation failure and progesterone deficiency may facilitate the hypothalamic-pituitary abnormalities causing the associated disordered luteinizing hormone secretion in PCOS. Progesterone may be administered to PCOS patients in the following cases: to induce withdrawal bleeding, to suppress secretion of luteinizing hormone, in ovulation induction in clomiphene citrate-resistant patients and in luteal phase support in assisted reproduction. We discuss the pharmacologic characteristics of the different routes of progesterone administration with reference to these diverse indications, the therapeutic objectives and patient compliance.     

In vitro maturation and fertilization of oocytes from unstimulated normal ovaries, polycystic ovaries, and women with polycystic ovary syndrome.

OBJECTIVE: To investigate differences in immature oocyte maturation, fertilization, and pregnancy rates among women with unstimulated normal ovaries, polycystic ovaries (PCOs), or PCOS. DESIGN: Prospective observational study. SETTING: University fertility clinic. PATIENT(S): One hundred forty-four women undergoing 180 in vitro oocyte maturation treatment cycles. INTERVENTION(S): Transvaginal immature oocyte recovery from unstimulated ovaries 36 hours after hCG priming. In vitro oocyte maturation and fertilization. Fresh embryo transfer. MAIN OUTCOME MEASURE(S): Immature oocytes collected, metaphase II oocytes, and embryos produced. Implantation and pregnancy rates. RESULT(S): The overall oocyte maturation and fertilization rates attained were 80.3% (1,222 of 1,522) and 76.5% (935 of 1,222), respectively. Significantly fewer immature oocytes were retrieved from normal ovaries (5.1 +/- 3.7) compared with the PCO (10.0 +/- 5.1) or PCOS (11.3 +/- 9.0) groups. Fertilization and cleavage rates were comparable among the three groups. The implantation, pregnancy, and live birth rates per transfer for normal ovaries were 1.5%, 4.0%, and 2.0%, respectively; for PCOs 8.9%, 23.1%, 17.3%, respectively; and for women with PCOS 9.6%, 29.9%, and 14.9%, respectively. CONCLUSION(S): Immature oocytes retrieved from normal ovaries, PCOs, or women with PCOS, when using hCG priming before oocyte retrieval, have a similarly high maturation, fertilization, and cleavage potential. In vitro maturation is a useful treatment option, particularly for women with PCOs.     

Polycystic ovarian syndrome: diagnosis and management of related infertility

Polycystic ovarian syndrome (PCOS) is a common gynaecological endocrinopathy seen in women of reproductive age, characterized by a combination of hyperandrogenism (either clinical or biochemical), chronic oligo/anovulation, and polycystic morphology of ovaries. It is a disease with metabolic, reproductive, and psychological impacts. It is the most common cause of anovulatory infertility. Lifestyle modifications including dietary modifications and exercise are the first line therapy, effectively improving the metabolic and endocrine milieu, and ovulation which ultimately improves pregnancy rate. Ovulation induction with aromatase inhibitor (letrozole) or anti-estrogen (Clomiphene citrate) is the first option as regards medical treatment. The aim of ovulation induction is mono-follicular growth to avoid multiple pregnancies. Gonadotropins and laparoscopic ovarian drilling form the second line of treatment. In vitro Fertilization (IVF) is positioned as third-line management option for PCOS in absence of associated factors demanding IVF, but is associated with significant risk of ovarian hyperstimulation syndrome (OHSS). GnRH antagonist protocol with GnRH agonist trigger for final oocyte maturation and freeze-all policy helps to eliminate OHSS risk up to a large extent. Pregnancy with any form of therapy is at an increased risk of developing gestational diabetes, pregnancy-induced hypertension, and pre-eclampsia, which needs to be counselled to patients while treating PCOS related infertility.     

Use of luteinizing hormone releasing hormone agonists in polycystic ovary syndrome

Luteinizing hormone releasing hormone (LHRH) agonists have been used in conjunction with gonadotrophins, and occasionally with pulsatile LHRH, for ovulation induction in women with clomiphene-citrate-resistant polycystic ovary syndrome (PCOS) and also for superovulation for in vitro fertilization (IVF) and gamete intrafallopian transfer in women with PCOS. In IVF, LHRH agonists given by the 'long protocol' before gonadotrophins are commenced have consistently shown higher pregnancy rates and higher live birth rates. Although the optimal time to commence LHRH agonist is not clearly determined, commencement in the early follicular phase possibly with pre-treatment with the combined oral contraceptive pill would avoid the risk of inadvertent administration during early pregnancy. The role of LHRH agonists in ovulation induction is less clear cut, although there may be some advantages in patients with refractory PCOS. The role of LHRH agonists in ovarian hyperstimulation syndrome and recurrent miscarriage is also discussed.     

Polycystic ovary syndrome: diagnosis and management of related infertility

Polycystic ovary syndrome (PCOS) is one of the most common complex and heterogeneous endocrine disorder in women with uncertain aetiology. The syndrome is associated with a wide range of symptoms and the diagnosis is based on the Rotterdam criteria. This review describes the currently available evidence regarding the therapeutic challenges raised in these women. Before any intervention is initiated, pre-conceptional counselling should be provided emphasizing the importance of life style changes, especially weight reduction and exercise in overweight women. The recommended first-line treatment for ovulation induction remains clomifene citrate. Second-line interventions include exogenous gonadotropins and laparoscopic ovarian drilling. The recommended third-line treatment is in vitro fertilization. More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Metformin use in PCOS should be restricted to women with glucose intolerance.     

Abnormal chromosome behavior in human oocytes which remained unfertilized during human in vitro fertilization

Chromosomal abnormalities and abnormal embryonic development have previously been observed after human in vitro fertilization (IVF). Chromosomal abnormalities may arise not only after fertilization but even earlier during meiotic maturation of human oocytes in culture. Since chromosomal analysis is simple in oocytes during meiotic maturation, the chromosomal status was analyzed in oocytes which remained unfertilized in a human in vitro fertilization program. In 50 fertilization attempts the chromosomes of 62 unfertilized oocytes could be analyzed; 45 of them were in the process of meiotic maturation. In three oocytes two small polar bodies were observed 16–18 hr after insemination in the absence of fertilization. In one oocyte abnormal chromosome behavior was found during the first meiotic division, and in four oocytes during metaphase of the second meiotic division. These data suggest that chromosomal analysis of unfertilized oocytes in human IVF may improve the understanding of human oocyte maturation and fertilization.     

Retrospective comparison of two media for invitro maturation of oocytes

In-vitro maturation of oocytes (IVM) is a new IVF technology developed in order to avoid iatrogenic complications of standard IVF treatments. This technique is particularly useful in patients suffering from polycystic ovary syndrome (PCOS) who are concerned with the risk of ovarian hyperstimulation syndrome. This technique is nowadays routinely practised in many international centres. However, the efficiency of this technique needs to be improved for a better support of maturation conditions to maximize oocyte developmental competence. In order to improve IVM results, the efficiency of two IVM media was retrospectively compared. Ninety-three PCOS candidates undergoing their first IVM cycle were included in this study, and IVM was conducted with TCM-199 or IVM-Medicult medium. This is the first study comparing two maturation media. Both media resulted in the same results concerning total oocyte maturation, fertilization, early embryo development and pregnancy rates.     

The use of pure follicle-stimulating hormone for ovulation induction in normal ovulatory women in an in vitro fertilization program

Many ovulation induction protocols for follicular development have been reported. The present study examines pure follicle-stimulating hormone (pFSH) and human menopausal gonadotropin for ovulation induction in an in vitro fertilization and embryo transfer program. The study compares the number of ampules, the level of estradiol on the day of human chorionic gonadotropin administration and at laparoscopy, the number of oocytes retrieved, fertilization, cleavage, and pregnancy rates. The peak levels of estradiol on the day of human chorionic gonadotropin administration and the day of laparoscopy were similar, although fewer ampules of pFSH were required to reach similar criteria for oocyte maturation prior to retrieval. The fertilization rates were similar, but the cleavage and pregnancy rates favored the use of pFSH. The use of pFSH may be more physiologic in orchestrating follicular steroidogenesis in normal ovulatory women in an in vitro fertilization and embryo transplant program that subsequently could produce healthier oocytes and an improvement in the pregnancy rate.     

Oocyte quality in adult polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in women. Folliculogenesis in the PCOS ovary is often disrupted, leading to suboptimal oocyte competence for fertilization. This alteration in oocyte development is likely due to intrinsic molecular defects in the oocyte along with the state of androgen excess in PCOS patients. Many therapeutic options are available to infertile couples with PCOS, including controlled ovarian hyperstimulation and in vitro fertilization. However, because of immature oocytes, many patients are not able to conceive using standard infertility treatments. The advent of in vitro maturation may allow patients an alternative option by which to achieve conception. This review is intended to describe the mechanisms of aberrant folliculogenesis and their impact on fertility in the PCOS patient.     

Successful pregnancy following transfer of embryos from oocytes with abnormal zona pellucida and cytoplasm morphology

The failed or impaired fertilization in an IVF cycle may be a result of undetected abnormalities in sperm function, poor oocyte quality, or impaired spermatozoon-oocyte interaction. Whether oocyte dysmorphisms have an impact on intracytoplasmic sperm injection (ICSI) outcome, fertilization, and implantation is controversial. A 33-year-old nulligravida female with a 2-year history of primary infertility was referred to the Toronto Centre for Advanced Reproductive Technology for infertility management. The patient underwent several cycles of ovulation induction followed by timed intercourse or intrauterine insemination without a resulting pregnancy. Following the failed insemination cycles, she proceeded to IVF. Six morphologically abnormal oocytes (including three that were cucumber-shaped) were retrieved and all injected with a single spermatozoon. Four oocytes showed normal fertilization and developed to day-3 embryos with abnormal morphology and were transferred. Two weeks after the embryo transfer, the patient had a positive beta-human chorionic gonadotrophin (beta-HCG). The pregnancy was uneventful, and a healthy baby boy was delivered at 41 weeks of age by Caesarean section. Since fertilization, embryo development, and successful pregnancy was achieved in this case, it is recommend that oocytes with extreme morphological abnormalities should not be discarded as ICSI may overcome the barriers to fertilization and cleavage.     

Implications of polycystic ovary syndrome on oocyte development

Human follicle development requires the recruitment of primordial follicles into a cohort of growing follicles from which one follicle is selected to ovulate a mature oocyte. During this developmental process, complex endocrine and intraovarian paracrine signals create a changing intrafollicular hormonal milieu. With this microenvironment, appropriate cumulus cell-oocyte signaling governs oocyte developmental competence, defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. Many of these mechanisms are perturbed in polycystic ovary syndrome (PCOS), a heterogeneous syndrome characterized by ovarian hyperandrogenism, hyperinsulinemia from insulin resistance, and reduced fecundity. In addition to these endocrinopathies, PCOS also is characterized by paracrine dysregulation of follicle development by intraovarian proteins of the transforming growth factor-beta family. Consequently, PCOS patients undergoing ovarian stimulation for in vitro fertilization are at increased risks of impaired oocyte developmental competence, implantation failure, and pregnancy loss. Recent data demonstrate links between endocrine/paracrine factors and oocyte gene expression in PCOS and suggest that new clinical strategies to optimize developmental competence of PCOS oocytes should target correction of the entire follicle growth and oocyte development process.     

Leptin and ovarian folliculogenesis: implications for ovulation induction and ART outcomes

Leptin participates in regulation of ovarian folliculogenesis indirectly via control of luteinizing hormone and follicle-stimulating hormone secretion. More recent evidence suggests that leptin also has direct regulatory actions on the developing follicle. The presence of leptin receptors on follicular cells, including oocytes, and early preimplantation embryos suggests that leptin may play a direct physiologic role in follicular maturation, oocyte development, and early cleavage. Because circulating leptin levels are directly related to body adiposity, elevated leptin concentrations associated with obesity may partly explain the negative impact of obesity on fertility. The influence of leptin on follicular development and oocyte maturation has important implications for ovulation induction and assisted reproductive technologies. Moreover, polycystic ovarian syndrome may be associated with altered leptin phsyiology.     

多囊卵巢综合征患者卵丘形态与未成熟卵母细胞发育潜能关系

目的 研究多囊卵巢综合征患者无刺激周期取出的不同形态未成熟卵母细胞的发育潜能。方法 43例PCOS不孕患者进行了47个未成熟卵母细胞体外成熟培养（IVM）周期。所有患者均未经促卵泡素刺激,予以HCG36h后取卵。根据取出的卵-冠-丘复合物形态将其分为3组：卵丘紧密组、卵丘松散组、无卵丘组。比较3组的体外成熟率、受精率和优质胚胎率。结果 47个IVM周期共收集未成熟卵母细胞874枚,体外成熟率61.19%,受精率71.07%,着床率13.13%。卵丘松散组的体外成熟率明显高于卵丘紧密组（72.26%vs49.54%,P〈0.05）,受精率、优质胚胎率三组间无差异。结论 PCOS患者无刺激周期取出的未成熟卵母细胞中,卵丘松散、扩张的卵母细胞具有更好的体外成熟潜力。     

Human implantation: the last barrier in assisted reproduction technologies?

Implantation processes are highly complex involving the actions of numerous hormones, immunoglobulins, cytokines and other factors in the endometrium. They are also essential matters for the success of assisted reproduction. The nature of early embryonic development is of equal significance. It involves ovarian follicle growth, ovulation, fertilization and preimplantation growth. These processes are affected by imbalanced chromosomal constitutions or slow developmental periods. Post-implantation death is also a significant factor in cases of placental insufficiency or recurrent abortion. Clearly, many of these matters can significantly affect birth rates. This review is concerned primarily with the oocyte, the early embryo and its chromosomal anomalies, and the nature of factors involved in implantation. These are clearly among the most important features in determining successful embryonic and fetal growth. Successive sections cover the endocrine stimulation of follicle growth in mice and humans, growth of human embryos in vitro, their apposition and attachment to the uterus, factors involved in embryo attachment to uterine epithelium and later stages of implantation, and understanding the gene control of polarities and other aspects of preimplantation embryo differentiation. New aspects of knowledge include the use of human oocyte maturation in vitro as an approach to simpler forms of IVF, and new concepts in developmental genetics.