Ovulation induction management of PCOS

Ovulation induction is the principal infertility treatment for women with polycystic ovarian syndrome (PCOS). Among PCOS patients who are overweight or obese, weight loss is the most physiologic method of inducing ovulation. For women in whom weight loss is not possible, or for lean women with PCOS, clomiphene citrate is an effective first-line method of ovulation induction. In clomiphene-resistant women, alternative treatments include adjunctive metformin or dexamethasone, aromatase inhibitors, or ovarian drilling. If there is no pregnancy despite several cycles of successful ovulation induction, gonadotropin treatment should be considered, in which case in vitro fertilization is recommended as the safest and most effective strategy.     

Polycystic Ovary Syndrome: Fertility Management

Polycystic ovary syndrome (PCOS) is characterized by a series of symptoms, including oligomenorrhea or amenorrhea anovulation or infertility; it is associated with insulin resistance and compensatory hyperinsulinemia. Several treatment options are available for women with anovulatory infertility related to PCOS. Clomiphene citrate (CC) is the first-choice for induction of ovulation in PCOS patients. Laparoscopic ovarian drilling (LOD) or gonadotropin ovarian stimulation can be offered after failure of CC to achieve pregnancy. Hyperinsulinemia related to PCOS can be corrected by weight loss or insulin-sensitizing agents, such as metformin, which alone or in combination with other agents are capable of restoring ovulation. Only very limited clinical data are available on the use of letrozole at present, so letrozole cannot be recommended for routine use in ovulation induction. When all treatments fail, in vitro fertilization and embryo transfer (IVF/ET) can be tried and can have excellent results. Many treatment options available today ensure that the majority of women who are subfertile due to PCOS can be treated successfully.     

Primum Non Nocere

Surgical ovarian wedge resection was the first established treatment for women with anovulatory polycystic ovary syndrome (PCOS) but was largely abandoned both due to the risk of postsurgical adhesions and the introduction of medical ovulation induction. Laparoscopic ovarian drilling (LOD) is an alternative method to induce ovulation in PCOS patients with clomiphene citrate resistance instead of gonadotropins. Surgical therapy with LOD may avoid or reduce the need for gonadotropins or may facilitate their use. However, the procedure, though effective, can be traumatic on the ovaries, which may cause postoperative adhesions and/or diminished ovarian reserve. In over-enthusiastic hands, this day-care procedure might lead to iatrogenic premature ovarian failure in young women. Some trials have compared LOD with gonadotropins, but, because of variations in study design and small sample size, the results are inconsistent and definitive conclusions about the relative efficacy of LOD and gonadotropins cannot be extracted from the individual studies. Today, evidence-based reviews conclude that there is no evidence of a significant difference in rates of clinical pregnancy, live birth or miscarriage in women with clomiphene-resistant PCOS undergoing LOD compared to other medical treatments. The reduction in multiple pregnancy rates in women undergoing LOD is the only pro-LOD argument. However, there are ongoing serious concerns about the long-term effects of LOD on ovarian function.     

Surgical or medical treatment of polycystic ovary syndrome: a cost-benefit analysis.

With the availability of laparoscopic ovarian cautery, there has been a resurgence in interest in the surgical treatment of clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Comparison of ovulation and pregnancy rates has found no difference in success rates between ovarian cautery and gonadotropin ovulation induction for such women. We have therefore compared the cost of laparoscopic ovarian cautery with that of a typical cycle of gonadotropin ovulation induction, and also found that there is little difference. Because of the potential advantages of ovarian cautery, we recommend this surgery as the next line of treatment if clomiphene citrate fails to induce ovulation in PCOS patients, before gonadotropins are introduced.     

Laparoscopic ovarian drilling in polycystic ovary syndrome

BACKGROUND AND OBJECTIVE: Patients with polycystic ovary syndrome (PCOS) treated with gonadotrophins often have a polyfollicular response and are exposed to the risks of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. The aim of the present study was to evaluate the efficacy of laparoscopic ovarian drilling (LOD) on the endocrinologic, clinical parameters and reproductive outcome of clomiphene-resistant anovulatory infertile patients with PCOS using monopolar diathermy. MATERIAL AND METHODS: Forty-five clomiphene-resistant anovulatory women with PCOS have participated in the study. Serum testosterone (T), follicle stimulating hormone (FSH) and luteinizing hormone (LH), fasting insulin and glucose levels, body mass indexes, modified Ferriman Gallwey (FG) hirsutism scores of the subjects are recorded before and after the procedure. Endocrinologic and clinical profile and reproductive outcome of the patients were analysed. RESULTS: Ovarian drilling was successfully employed without any surgical complications and mean +/- S.D. duration of follow-up time was 29.73 +/- 10.64 months. In the follow-up period 93.3% of the subjects were recorded to have regular cycles and 64.4% pregnancy rate was achieved, spontaneously. The serum levels of T, free T, LH, LH:FSH ratio, insulin and FG scores were significantly reduced after LOD, although glucose levels and glucose/insulin ratio remained unchanged. CONCLUSION: In choosing ovulation induction method in clomiphene resistant PCOS patients, LOD may avoid or reduce the risk of OHSS and multiple pregnancy than gonadotrophins with the same success rate of conception. The high pregnancy rate, and economic aspect of the procedure offer an attractive management for patients with PCOS.     

Laparoscopic ovarian drilling in clomiphene citrate-resistant women with polycystic ovary syndrome.

STUDY OBJECTIVE: To analyze the efficacy of laparoscopic ovarian drilling using monopolar diathermy in women with anovulatory infertility with clomiphene-resistant polycystic ovary syndrome (PCOS), and to determine factors influencing pregnancy rate and pregnancy outcomes. DESIGN: Prospective study (Canadian Task Force classification II-2). SETTING: Infertility clinic in a tertiary referral teaching hospital. PATIENTS: Seventy women with clomiphene-resistant PCOS. INTERVENTION: Laparoscopic ovarian drilling, with follow-up for 4.5 years. MEASUREMENTS AND MAIN RESULTS: Follow-up data, which were available for 66 patients, showed a spontaneous ovulation rate of 81.8%, cumulative ovulation rate of 93.9%, and pregnancy rate of 54.5%. Successful pregnancies were commonly complicated by gestational diabetes mellitus and pregnancy-induced hypertension. Pregnancy rates (23.5%) were low in women with tuboperitoneal disease and those whose partners had subfertile male factors. Statistical evaluation using a proportion test (Z test) and multivariable logistical regression analysis showed that elevated luteinizing hormone levels (>10 IU/L), short duration of infertility (<3 yrs), and absence of preexisting tubal disease were associated with better outcomes. CONCLUSION: Laparoscopic ovarian drilling is an effective surgical procedure in women with clomiphene-resistant PCOS.     

The impact of insulin resistance on the outcome of laparoscopic ovarian electrocautery in infertile women with the polycystic ovary syndrome.

In this study we assessed how insulin resistance affects pregnancy rates in infertile women with the polycystic ovary syndrome (PCOS) treated with laparoscopic ovarian electrocautery. Sixty-four PCOS women were included in the study in a consecutive fashion. Following the CIGMA (continuous infusion of glucose with model assessment) test, 28 women were classified as insulin resistant and 36 women as non-insulin resistant. After the ovarian electrocautery patients were observed for 12-18 months. If pregnancy did not ensue, they were referred for one or more cycles of in vitro fertilization (IVF). Following ovarian electrocautery the non-insulin-resistant women more frequently achieved a regular menstrual cycle and ovulation than the insulin-resistant PCOS women. Consequently 18 (50%) of the non-insulin-resistant PCOS women achieved a pregnancy versus only five (18%) of women in the insulin-resistant PCOS group. Following treatment with both ovarian electrocautery and IVF, 27 (75%) of the non-insulin resistant PCOS women achieved a successful pregnancy, while 13 (46%) of the insulin-resistant PCOS group achieved this. In conclusion, insulin resistance may be an important marker of a poor outcome of treatment in PCOS infertility. Further studies are needed to evaluate the possible effect of treatment alternatives to alleviate the unfavorable influences of insulin resistance and hyperinsulinemia on ovulation induction in PCOS women.     

Ovulation induction

In the woman with anovulation and polycystic ovarian syndrome, there are many options for ovulation induction. Treatment should be individualized, but clomiphene citrate is an excellent first-line agent. In the woman resistant to clomiphene citrate, combination therapy often results in pregnancy. Some women with PCOS only respond to gonadotropin therapy. These women are at a higher risk for multiple pregnancy and ovarian hyperstimulation syndrome. In the woman with anovulation and hypothalamic amenorrhea, the options for ovulation induction are limited. The luteal phase must be supported. The hypothalamus is unable to support the corpus luteum or early pregnancy.     

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. On the basis of the currently available evidence, a group of experts reached a consensus regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counseling should be provided emphasizing the importance of lifestyle, especially weight reduction and exercise in overweight women, smoking, and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotropins is associated with increased chances for multiple pregnancy, and, therefore, intense monitoring of ovarian response is required. Laparoscopic ovarian surgery alone is usually effective in less than 50% of women, and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC-gonadotropin paradigm) is reported to be highly effective with a cumulative singleton live-birth rate of 72%. Recommended third-line treatment is in vitro fertilization (IVF). More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-line, second-line, or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.     

PCOS: diagnosis and management of related infertility

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. It is characterised by a combination of hyperandrogenism (either clinical or biochemical), chronic oligo/anovulation, and polycystic ovaries. It is frequently associated with insulin resistance and obesity. PCOS receives considerable attention because of its high prevalence and possible reproductive, metabolic, and cardiovascular consequences. It is the most common cause of anovulatory infertility. Ovulation induction with an aromatase inhibitor or anti-oestrogen is the first-line medical treatment. The aim of ovulation induction is monofollicular growth to avoid multiple pregnancy. The second-line treatments include gonadotrophins and laparoscopic ovarian drilling. The role and benefit of metformin in ovulation induction is uncertain. Woman with PCOS undergoing IVF are at significant risk of ovarian hyperstimulation syndrome. Women with PCOS are also at an increased risk of developing gestational diabetes, pregnancy-induced hypertension, and pre-eclampsia.     

Laparoscopic treatment of polycystic ovaries with insulated needle cautery: a reappraisal

OBJECTIVE: To evaluate the reproductive outcome and adhesion formation after a standardized laparoscopic treatment of polycystic ovary syndrome (PCOS) in clomiphene-resistant infertile women. DESIGN: Retrospective study. SETTING: University teaching hospital. PATIENT(S): One hundred twelve clomiphene-resistant anovulatory women with PCOS. INTERVENTION(S): Laparoscopic ovarian drilling using an insulated needle cautery. MAIN OUTCOME MEASURE(S): Ovulatory rate, pregnancy rate, and adhesion formation. RESULT(S): After surgery, ovulation occurred spontaneously in 73.2% of patients. The cumulative probability of conception at 12, 18, and 24 months after surgery was 54%, 68%, and 72%, respectively. With use of Cox's proportional hazards model, the effects of age, body mass index, and duration of infertility were evaluated. These factors were not associated with the pregnancy rate. Of 15 women who underwent a second-look laparoscopy, 11 women were found to be free of adhesions. Four women had periadnexal adhesions that were filmy, minimal, and found on the ovarian surface only. CONCLUSION(S): Laparoscopic ovarian drilling is an effective alternative treatment in clomiphene-resistant anovulatory women with PCOS. The use of an insulated needle cautery is associated with a minimal amount of adhesion formation.     

Endocrine methods of ovulation induction

The rationale of ovulation induction is to achieve the development of a single follicle and ultimately a singleton healthy baby. Problems faced by women with anovulatory polycystic ovary syndrome are the sensitivity of the ovary to stimulation and health issues such as obesity. This chapter will discuss medical management including strategies to lose weight, address hyperinsulinaemia with insulin-sensitizing agents, such as metformin, and outline methods of ovulation induction from the usual first-line therapy of clomiphene citrate and the subsequent use of gonadotrophin therapy in clomiphene-resistant patients. Appropriately directed surgical ovulation induction with laparoscopic ovarian diathermy appears to be as efficacious as gonadotrophin therapy but will not be discussed in the context of this chapter.     

Evaluation of a new surgical approach for the treatment of clomiphene citrate-resistant infertility in polycystic ovary syndrome: laparoscopic ovarian multi-needle intervention

Laparoscopic ovarian drilling (LOD) is the accepted second-line treatment for clomiphene citrate-resistant anovulatory infertility in polycystic ovary syndrome (PCOS). Although multiple pregnancy rates are reduced with ovarian drilling procedures, postoperative adhesion formation is a potential complication in up to 85% of the women subjected to laparoscopic destructive ovarian procedures. Our objective was to determine the effectiveness of a new, specially designed laparoscopic device and technique that might enable treatment for patients with anovulatory PCOS with less trauma and fewer postoperative adhesions. Thirty-five infertile clomiphene citrate-resistant women with PCOS were included. Seventeen women underwent laparoscopic ovarian multi-needle intervention (LOMNI), and 18 women received step-up ovulation induction treatment with recombinant follicle-stimulating hormone followed by intrauterine insemination for three cycles. Patients were followed for a period of 6 months after either laparoscopic surgery or the initiation of ovulation induction therapy. Outcome measures were cycle regularity, pregnancy rate, safety, postoperative adhesion formation, and cost effectiveness. There were no significant differences between the two groups in terms of age, body-mass index, duration of infertility, and basal cycle-day 2 hormone levels. Significant improvement in cycle regularity (p <.01) was found after LOMNI. Cumulative pregnancy rates (35.3% in the LOMNI group vs 33.3% in the ovulation induction group) did not differ between the groups. No adverse events following surgery were noted. Moderate ovarian hyperstimulation syndrome and multiple pregnancies occurred in four and two patients, respectively, in the ovulation induction group. Eight nonpregnant women in the LOMNI group underwent repeat laparoscopy at the end of the follow-up period. No adhesion formation attributable to LOMNI was observed in any of those eight women. The cost of LOMNI was significantly (p <.001) lower than the ovulation induction treatment. In conclusion, LOMNI may be a safe, inexpensive, and effective procedure for the treatment of CC-resistant infertility in patients with PCOS. It seems to preserve the beneficial effects and probably omits unwanted effects (such as adhesion formation) of LOD.     

Update in polycystic ovary syndrome: new criteria of diagnosis and treatment in Japan

Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women of reproductive age. In 2006 the Japanese Society of Obstetrics and Gynecology (JSOG) proposed new, revised diagnostic criteria that in the future could also be valued internationally. Based on the new diagnostic criteria, the JSOG has also proposed the revised treatment criteria in 2008. In PCOS obese patients desiring children, weight loss and exercise is recommended. Nonobese patients, or those obese women who do not ovulate after lifestyle changes, are submitted to ovulation-induction therapy with clomiphene citrate (CC). Obese CC-resistant patients who have impaired glucose tolerance or insulin resistance are treated with a combination of metformin and CC. If these treatments options are unsuccessful, ovulation induction with exogenous gonadotropin therapy or laparoscopic ovarian drilling (LOD) is recommended. A low-dose step-up regimen is recommended with careful monitoring in order to reduce the risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Alternatively, with LOD high successful pregnancy rates of around 60 % are expected with a low risk of multiple pregnancies. If ovulation induction is unsuccessful, IVF-ET treatment is indicated. In high OHSS-risk patients, systematic embryo freezing and subsequent frozen embryo transfer cycles are recommended. In nonobese, anovulatory PCOS patients not desiring children, pharmacological treatments such as Holmström, Kaufmann regimens or low-dose oral anticonceptives are used to induce regular withdrawal bleeding. These treatments are especially important for preventing endometrial hyperplasia and endometrial cancer. These new diagnostic and treatment criteria hopefully will contribute to an improved care of PCOS patients in Japan.     

Polycystic ovary syndrome treated with laparoscopic ovarian drilling with a harmonic scalpel. A prospective,randomized study

OBJECTIVE: To evaluate the endocrinologic profile and reproductive outcome after laparoscopic drilling using a harmonic scalpel for polycystic ovarian syndrome (PCOS) in clomiphene-resistant infertile women. STUDY DESIGN: We performed a prospective, randomized study of 34 infertile women with PCOS. Group A (17 women) underwent laparoscopic ovarian drilling using a harmonic scalpel laser. Group B (control group, 17 women) underwent laparoscopic ovarian drilling using a neodymium-yttrium-aluminum-garnet laser. Change in the hormonal profile after surgery, ovulation rate and pregnancy rate were compared between groups A and B. RESULTS: LH and testosterone serum levels and the LH-FSH ratio showed a statistically significant reduction after surgery, and the spontaneous ovulation rate was 94% in both groups. The cumulative pregnancy rates within two years of follow-up were 77% in group A and 60% in group B. CONCLUSION: Laparoscopic ovarian drilling using a harmonic scalpel is an effective treatment for PCOS in clomiphene-resistant, anovulatory women: it results in ovulation and conception without major complications.     

A prospective randomized trial comparing the clinical and endocrinological outcome with rosiglitazone versus laparoscopic ovarian drilling in patients with polycystic ovarian disease resistant to ovulation induction with clomiphene citrate

Objectives  

Rosiglitazone, an insulin sensitizing agent is used currently in women with clomiphene citrate (CC) resistant polycystic ovarian syndrome (PCOS). Our study proposed to compare the efficacy of rosiglitazone and CC with laparoscopic ovarian drilling (LOD) and CC in terms of biochemical effects, ovulation rate and pregnancy rate in patients of PCOS resistant to CC.     

An algorithm for treatment of infertile women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common condition with both a reproductive and metabolic phenotype. Women with PCOS often seek care because of infertility or menstrual cycle irregularities that result from chronic anovulation interspersed with occasional ovulatory cycles. Initially, it is important to delineate a differential diagnosis for oligo- or amenorrhea and to evaluate for disorders that may “masquerade” as PCOS. If fertility is a desired goal, then it is critical to optimize health conditions that impact fertility and gestation. Lifestyle modifications, including nutritional counseling and weight loss, should be a part of all treatment plans. Even minimal (5%) weight loss in obese women with PCOS improves both ovulation and pregnancy rates. The first line of treatment for ovulation induction remains the selective estrogen receptor modulator (SERM) clomiphene citrate. The role of insulin sensitizers, particularly metformin, remains unclear. A recent consensus panel recommended against its routine use in the absence of an elevated glucose or hemoglobin A1c. If a woman fails to achieve pregnancy after a trial of weight loss and six ovulatory cycles induced by clomiphene citrate, then ovulation induction with exogenous gonadotropin, with or without timed intrauterine insemination, or in vitro fertilitization, is a reasonable next step. Women with PCOS are particularly prone to excessive follicle development and are at increased risk for ovarian hyperstimulation syndrome (OHSS). Although limited data exist comparing approaches to ovulation induction or controlled ovarian stimulation in women with PCOS, the American Society for Reproductive Medicine recommends the use of “step-up” or “step-down” protocols in which a low dose of exogenous FSH or combined gonadotropins are employed in an attempt to constrain ovarian responsiveness. In vitro fertilization allows for the transfer of only one embryo or for cryopreservation of all embryos with subsequent transfer of a single embryo in a subsequent cycle without ovarian stimulation. Countless questions regarding pathogenesis and treatment of PCOS create opportunity for basic and clinical research and for refinement of existing therapeutic approaches.     

Review of nonsurgical and surgical treatment and the role of insulin-sensitizing agents in the management of infertile women with polycystic ovary syndrome

OBJECTIVES: To review the nonsurgical and surgical treatment and the role of insulin-sensitizing agents in the management of anovulatory infertile women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: The search term of subfertile women with anovulation and PCOS was used for identification of randomized controlled trials. Nonrandomized controlled studies were identified through computer MEDLINE and EMBASE searches for the years 1980-2002. RESULTS: For obese PCOS women weight loss of > 5% of pretreatment weight restores menstrual regularity in 89%, of whom 30% achieved spontaneous pregnancy. It was estimated that 75-80% of anovulatory PCOS women will respond to clomiphene citrate (CC) and 35-50% will achieve pregnancy. For CC-resistant PCOS women (20-25%), CC + metformin (1.5 g/day) for 3-6 months has a 70% chance of restoration of regular menses and ovulation, and a 23% chance of pregnancy. Laparoscopic ovarian drilling (LOD) can be offered to CC-resistant PCOS women. There was no statistically significant difference in the ovulation rate following LOD with electrocoagulation and laser [83% vs. 77.5%; odds ratio (OR) 1.4; 95% CI 0.9-2.1], while there was a significantly higher cumulative pregnancy rate at 12 months after surgery (65% vs. 54.5%; OR 1.5; 95% CI 1.1-2.1). CONCLUSION: Diet and exercise followed by CC should be used for nonsurgical ovulation induction. For CC-resistant PCOS women, metformin may be included in a stepwise approach before a surgical approach. LOD with electrocautery is superior to laser drilling and gonadotropin therapy.     

腹腔镜电凝打孔术治疗耐氯米芬多囊卵巢综合征不孕43例疗效分析

目的:探讨腹腔镜下卵巢表面电凝打孔术对耐氯米芬(CC)多囊卵巢综合征(PCOS)所致不孕症患者的疗效。方法:对耐氯米芬的PCOS不孕患者43例,行腹腔镜下卵巢表面电凝打孔术。术后随访3~12个月。观察手术前后血清黄体生成素(LH)、卵泡刺激素(FSH)、睾酮(T)、雌二醇(E2)、泌乳素(PRL)水平变化,卵巢体积及窦卵泡数的变化,术后月经和排卵情况、妊娠率及流产率。结果:术后LH、T、LH/FSH、PRL水平、卵巢体积、窦卵泡数均较术前明显降低(P<0.01),而FSH、E2术前、术后差异无显著性(P>0.05),月经情况明显改善,术后排卵率为93.0%(40/43),妊娠率为58.1%(25/43),流产率为16.0%(4/25)。结论:腹腔镜下卵巢表面电凝打孔术对于耐CC的PCOS不孕患者具有高排卵率和妊娠率以及低流产率的疗效。同时,具有创伤小、恢复快、并发症少的优点,是治疗耐CC的PCOS不孕患者的有效手段。     

Should insulin-sensitizing drugs be used in the treatment of polycystic ovary syndrome?

Insulin resistance is a central feature of polycystic ovary syndrome (PCOS). Hyperinsulinaemia contributes to anovulation, hyperandrogenism, infertility and early pregnancy loss in women with PCOS. Chronic hyperinsulinaemia also predisposes women with PCOS to increased risks of diabetes and cardiovascular events. Current data indicate that metformin, either as monotherapy or in combination with clomiphene in clomiphene-resistant patients, is an effective treatment for anovulation in PCOS. Initial evidence also suggests that insulin sensitizers may have a role in preventing early pregnancy loss. Of the available insulin-sensitizing agents, metformin has been the agent most frequently studied in PCOS, and has the least undesirable pregnancy safety profile. Ameliorating the metabolic syndrome associated with insulin resistance in PCOS with metformin may also prevent long-term cardiovascular and diabetes complications, pending further evidence. Based on these data, metformin should be a first-line therapy for women with PCOS.