Ovulation induction in women with polycystic ovary syndrome

To date, clomiphene citrate (CC) remains the first therapeutical step for inducing ovulation in anovulatory PCOS patients. Metformin alone or combined with CC is a valid second step approach, whereas the laparoscopic ovarian diathermy can be useful only in selected cases.     

Ovulation induction in women with polycystic ovary syndrome: an update

Infertility is frequently caused by anovulation. The affected women present with irregular menstrual cycles and the most common diagnosis is polycystic ovary syndrome. Ovulation induction is commonly used to treat these women. Clomiphene citrate (a selective estrogen receptor modulator or SERM) remains the most used medication for treating this condition. Alternatives that have been used include other SERMs such as tamoxifen, aromatase inhibitors, insulin sensitizing agents, and ovarian drilling. Evidence for and against the effectiveness of these agents has fluctuated over the last decade. Controversies surrounding the use of ovulation induction such as development of functional cysts, high-order multiple births, and development of ovarian cancer have been further studied and some controversies have almost been laid to rest in the last decade.     

Ovulation induction in polycystic ovary syndrome

Management of polycystic ovary syndrome (PCOS) usually spans a woman's reproductive years. While treatment of androgenic symptoms is often a primary concern, periodically, the regimen has to be modified because of a desire for pregnancy. As these women are usually anovulatory, ovulation induction is generally required. The premise on which ovulation induction in PCOS is based is two-fold: increasing ovarian exposure to follicle stimulating hormone (FSH) and/or correcting hormonal derangements. Potential differences in pathogenesis, evidenced clinically by phenotypic diversity, suggest that treatment should be individualized. This paper is an overview of treatments available and also provides a critical appraisal of management options. These options include the use of clomiphene citrate, insulin sensitizers, and the combination. Protocols for ovulation induction with FSH injections are outlined and the relative risks of multiple gestation and severe ovarian hyperstimulation syndrome of these various protocols discussed. The use of aromatase inhibitors and the occasional use of glucocorticoids are briefly reviewed. Finally, the role of laparoscopic ovarian diathermy in the management of anovulatory infertility in PCOS is outlined.     

Ovulation induction for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having high serum concentrations of LH. Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomiphene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and so ovulation induction has to be monitored carefully with serial ultrasound scans. The recognition of an association between hyperinsulinaemia and PCOS has resulted in the use of insulin sensitizing agents, such as metformin, which appear to ameliorate the biochemical profile and improve reproductive function.     

Ovulation induction for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having high serum concentrations of LH. Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomiphene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and so ovulation induction has to be monitored carefully with serial ultrasound scans. The recognition of an association between hyperinsulinaemia and PCOS has resulted in the use of insulin sensitizing agents, such as metformin, which appear to ameliorate the biochemical profile and improve reproductive function.     

Ovulation induction in sterile females with the polycystic ovary syndrome

The outcomes of ovulation induction in 34 infertile women with polycystic gonads were presented. The ovulation was inducted by the ovarian wedge resection or conservative treatment with either clomiphen alone or in association with human chorionic gonadotropin (HCG). The procedure of choice of specific method of management was dependent on the results of laparoscopy, while an ovarian biopsy was performed and histopathological evaluation of segments. In patients with insignificantly enlarged ovarian tunica albuginea conservative treatment with hormones was carried out, in patients with either marked enlarged tunica albuginea or thecal cells in stroma ovarian wedge resection was performed. The presented method of management caused the ovulatory cycles in 85.2% of cases and pregnancies in 61.7% of cases.     

Ovulation induction with human menopausal gonadotropins

This review has summarized the evolution of hMG stimulation of ovulation in amenorrheic individuals, its monitoring, and its complications. Based on the principles learned from these individuals, use of hMG has now extended to women with cervical mucus deficiencies or luteal phase defects, as well as in vitro fertilization. Recommendations regarding the use of hMG at the current time when assessment by both serum E2 and ultrasound are available have been made. Briefly, it is suggested that an "E2 window" of at least 1000 pg/ml be achieved over the course of a 9- to 12-day follicular phase. Furthermore, assessment of these monitoring modalities should be made in combination in order that findings from one modality alone not be allowed to initiate premature hCG administration.     

Optimizing ovulation induction in women with polycystic ovary syndrome

Recent developments in our understanding of the pathophysiology of polycystic ovary syndrome led to the introduction of new therapeutic approaches. It is apparent that a significant proportion of women with polycystic ovary syndrome have insulin resistance and compensatory hyperinsulinemia. Growing evidence indicates that elevated serum insulin induces hyperandrogenism, which in turn leads to anovulation and infertility. Hyperinsulinemia also contributes to the increased risk for cardiovascular disorders and type 2 diabetes mellitus. These concepts provide rationale for therapies focused on treatments of insulin resistance. In particular, weight loss and exercise have been shown to increase insulin sensitivity and improve ovulatory function. Metformin, an insulin-sensitizing agent, is particularly effective in women with polycystic ovary syndrome who have significant insulin resistance. Metformin use leads to a decrease in serum insulin and androgen levels as well as an improvement in ovulatory function. Moreover, it appears to ameliorate cardiovascular risk factors. Other approaches to ovulation induction in women with polycystic ovary syndrome include traditional therapies using clomiphene citrate or gonadotropins. In clomiphene-resistant subjects, one can consider laparoscopic ovarian drilling and other forms of partial ovarian resection or destruction.     

The use of gonadotropins for the induction of ovulation in women with polycystic ovarian disease

Ten infertile patients with polycystic ovarian disease were treated with 18 cycles of "pure" human pituitary follicle-stimulating hormone (HP-FSH) and 10 cycles of human menopausal gonadotropin (HMG) consisting of FSH and luteinizing hormone (LH) in a 1:1 ratio. Human chorionic gonadotropin was used to trigger ovulation when optimal follicular development was achieved as judged by urinary estrogen determinations. Of the 18 cycles utilizing HP-FSH, 14 were presumptively ovulatory, 2 were conceptual, and in 5 cycles ovarian enlargement was noted. Of the 10 HMG cycles, none was ovulatory, no conceptions resulted, and 6 instances of hyperstimulation were noted. Pretreatment serum LH levels were significantly higher than normal follicular phase values. These observations suggest that endogenous LH levels in patients with polycystic ovaries are quite adequate for follicular development so that the administration of exogenous LH is unwarranted. Furthermore, the data suggest that HP-FSH or low-LH-containing HMG may prove to be an additional safe and effective nonsurgical treatment modality for patients who are anovulatory because of polycystic ovaries.     

The use of human gonadotropins for the induction of ovulation in women with polycystic ovarian disease

During the years 1974 to 1977, a total of 77 treatment cycles of human menopausal gonadotropin (hMG)-human chorionic gonadotropin (hCG) were administered to 41 infertile patients with polycystic ovarian disease who failed to conceive on clomiphene. Twenty-seven patients (65.9%) conceived, two of them twice, making twenty-nine pregnancies. The abortion rate was 24.1% and the multiple pregnancy rate was 36.3%. Of the 77 treatment cycles, 7.8% were complicated by mild hyperstimulation and 3.9% by severe hyperstimulation. In six treatment cycles (7.8%), ovulation occurred spontaneously prior to the hCG injection. hMG-hCG is an additional safe and effective, nonsurgical treatment for women with polycystic ovarian disease who have failed to respond to clomiphene therapy. The reaction to exogenous gonadotropins is unpredictable and probably depends on the stage of follicular development prior to the stimulation. Therefore, daily estrogen determinations from the 1st day of treatment are mandatory in order to avoid hyperstimulation and/or multiple births.     

Ovulation induction in polycystic ovary syndrome with urinary follicle-stimulating hormone or human menopausal gonadotropin

In patients with polycystic ovarian disease (PCOD) ovulation was induced with a combination of human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) or with urinary follicle-stimulating hormone (uFSH; Metrodin, Serono Laboratories, Inc., Randolph, MA) alone. hMG/hCG and uFSH resulted in comparable rates of ovulation and conception in patients with PCOD. The incidence of hyperstimulation and the potential for multiple births appeared lower with uFSH. The fact that endogenous ovulation did not occur in hMG patients who had hCG withheld or in 3 of the 11 uFSH patients who had preovulatory levels of estradiol and follicles greater than 15 mm may imply that these similarly derived gonadotropins in some instances block endogenous ovulation.     

Ovulation induction with pulsatile luteinizing hormone-releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: endocrine results

The pituitary and gonadal response to pulsatile luteinizing hormone-releasing hormone (LH-RH) administration during the first and consecutive second treatment unit (TU) was studied in nine women with clomiphene citrate-resistant polycystic ovary-like disease (PCOD). The control group consisted of eight eumenorrheic women. Luteinizing hormone levels, LH amplitudes, and total urinary excretion/24 hours did not differ between ovulatory and anovulatory TUs, but were significantly higher compared with the control group. Follicle-stimulating hormone (FSH) in PCOD did not differ from normal cycles. Androgen values in the anovulatory TUs were significantly higher compared with the ovulatory TUs (P = 0.001). We conclude that LH-RH therapy may result in ovulation; however, it does not redress the intrinsic abnormality in PCOD and FSH, and androgen levels do not seem to be critical in ovulation induction.     

Ovulation induction with pulsatile luteinizing releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: clinical results

Eighty-four treatment units were given to 11 women with clomiphene citrate-resistant polycystic ovarian disease (PCOD). PCOD was defined as oligomenorrhea elevated luteinizing hormone (LH), normal follicle-stimulating hormone (FSH), and preference-elevated androgens. Luteinizing-releasing hormone (LRH) was administered intravenously via a portable infusion pump. Doses varied between 5 and 40 micrograms/pulse given at 60-, 90-, or 120-minute intervals. In 11 women, 85 treatment units (TUs) were completed, of which 74 were ovulatory, showing no specific advantage of any particular pulse dose or pulse interval. Five pregnancies occurred in three women. Two women did not ovulate during 52 and 284 consecutive days of therapy, respectively. Oligomenorrheic patients with PCOD can be made more regular by means of LRH, not necessarily leading to a regular menstrual cycle. In general, LRH is sufficient for luteal support. No signs of hyperstimulation were observed, although two patients incidently developed unilocular cysts with a maximum diameter of 8 cm. Ovulation induction with LRH in PCOD is possible, although the disease itself does not change during therapy. This may be further evidence that altered hypothalamic LRH secretion is more the result, rather than the cause, of the phenomenon of PCOD.     

罗格列酮用于多囊卵巢综合征促排卵治疗的效果观察

目的　探讨罗格列酮 (rosiglitazone)对存在胰岛素抵抗的多囊卵巢综合征 (polycysticovarysyndrome ,PCOS)患者促排卵治疗的效果。 方法　选择存在胰岛素抵抗的PCOS患者 96例 ,将其随机分为A、B、C组。A组 (2 8例 )口服氯米芬、B组 (3 2例 )口服罗格列酮、C组 (3 6例 )口服罗格列酮联合氯米芬 ,3组用药时间均为 3个月经周期。比较 3组用药前后的胰岛素抵抗指数的变化和排卵情况。结果　B组和C组患者治疗后 ,应用稳态模型评估的胰岛素抵抗指数 (homeostasismodelassessmentinsulinresistance ,HOMAIR)分别由 1 2± 0 6、1 1± 0 5下降为 0 6± 0 2、0 6± 0 4,两组治疗前后比较 ,差异也有显著性 (P <0 0 5)。C组治疗后排卵率为 80 % ,明显高于A组的 59%和B组的 3 5% ,差异有显著性 (P <0 0 5)。结论　罗格列酮能有效地改善胰岛素抵抗 ,提高促排卵治疗的成功率     

Ovulation induction in women with polycystic ovary syndrome: randomized trial of clomiphene citrate versus low-dose recombinant FSH as first line therapy

This single centre randomized controlled trial was undertaken to compare the efficacy and safety of clomiphene citrate and low-dose recombinant FSH as first line pharmacological therapy for anovulatory infertility associated with polycystic ovary syndrome (PCOS). Seventy-six infertile patients with PCOS were randomized to receive clomiphene citrate (50-150 mg/day for 5 days) (clomiphene citrate group, n = 38) or recombinant human FSH (FSH group, n = 38) in a chronic, low-dose, step-up protocol (daily starting dose 75 IU) for up to three consecutive cycles. Ovarian response was monitored by transvaginal ultrasonography and human chorionic gonadotrophin (HCG) was given to trigger ovulation in all cycles with appropriate follicular development. The primary outcome measure was cumulative pregnancy after undergoing up to three treatment cycles. Secondary outcomes were cycle cancellation rate, ovulation rate per cycle, cumulative ovulation rate, pregnancy rate per cycle, incidence of OHSS, cumulative live birth rate, and multiple birth rate. One hundred and four clomiphene citrate cycles and 91 FSH cycles were evaluable. The relative risk and its 95% confidence interval were 1.17 (0.97-1.46) for HCG cycles with ovulation, 1.78 (0.92-3.54) for the pregnancy rate per woman, and 1.83 (0.79-4.40) for live births per woman in favour of FSH. The cumulative pregnancy rate after three treatment cycles was 43% with FSH and 24% with clomiphene citrate (P = 0.06). By logistic regression analysis, the factors predicting ovulation included female age, serum androstenedione and use of FSH. Predictors of pregnancy were duration of infertility and use of FSH. This randomized controlled trial suggests that low-dose recombinant FSH may be an effective alternative to clomiphene citrate in first-line treatment for anovulatory PCOS patients. Thus, further studies, possibly multi-centre, in order to avoid problems with patient recruitment, are warranted to confirm these results.