Ovulation induction in anovulatory women

Ovulation induction therapy is administered to stimulate follicular growth and induce ovulation in anovulatory infertile women. In anovulatory women with polycystic ovary syndrome, the treatment of choice is clomiphene citrate, whereas in clomiphene nonresponders, gonadotrophins are given as secondary therapy. Currently, insulin-sensitizing agents are used in the treatment of polycystic ovary syndrome to restore menstrual cyclicity. In selected patients, laparoscopic drilling has also been suggested. In anovulatory patients affected with hypogonadotropic hypogonadism, treatment is based on gonadotrophin replacement therapy or pulsatile gonadotrophin-releasing hormone infusion. In ovulation induction therapy the clinician's attention should be directed at restoring normal ovary function. When pharmacotherapy is required, monofollicular growth should be induced to reduce the risk of multiple pregnancy.     

Laparoscopic electrosurgical furrowing technique for the treatment of polycystic ovaries

A retrospective analysis of reproductive outcomes was conducted in 30 anovulatory women treated with a new laparoscopic electrosurgical furrowing technique. All patients had polycystic ovary syndrome refractory to ovulation induction with clomiphene citrate and gonadotropin therapy. Bilateral ovarian furrowing was success-fully accomplished in all 30 patients without technical difficulty or surgical complications. Average furrowing time was 5 minutes per ovary and all patients were discharged by 12 hours postoperatively. Regular ovulatory function resumed in 25 women (83.3%); the 5 refractory patients were administered clomiphene citrate. Spontaneous conception occurred in 21 ovulatory patients (70.0%) and clomiphene-assisted conception occurred in 3 of the 5 refractory women, for an overall pregnancy rate of 80% (24/30). Twenty-three pregnancies resulted in viable term deliveries; one (4.2%) ended in a first-trimester abortion. These results suggest that the laparoscopic electrosurgical furrowing technique for the treatment of anovulatory infertility in women with polycystic ovary syndrome refractory to clomiphene citrate and gonadotropin therapy is effective, safe, and easily performed. Further evaluation is warranted to confirm the appropriateness of this procedure.     

The efficacy of every-other-day administration of gonadotropin-releasing hormone in women with hypothalamic amenorrhea: gonadotropin-releasing hormone treatment can induce clomiphene responsiveness

The efficacy of every-other-day gonadotropin-releasing hormone administration was investigated in clomiphene-human chorionic gonadotropin (hCG) resistant, anovulatory women with hypogonadotropism or normogonadotropism. One hundred micrograms of gonadotropin-releasing hormone was injected intramuscularly three times a week for four weeks (one course). Ten of 11 hypogonadotropic patients responded to clomiphene or clomiphene-hCG after one to three courses of gonadotropin-releasing hormone treatment. Once the patients were converted to clomiphene responsiveness, ovulatory response continued without additional treatment, and all four patients who desired pregnancy conceived. Among eight normogonadotropic women, four with amenorrhea of one year or less became clomiphene-hCG responders after one or two courses of gonadotropin-releasing hormone treatment. They were subsequently treated with gonadotropin-releasing hormone after every one or two ovulatory cycles. One of the four women who desired to be pregnant conceived. We conclude that intramuscular gonadotropin-releasing hormone treatment is effective in inducing responsiveness to clomiphene, especially in hypogonadotropic anovulatory women. In normogonadotropic women, gonadotropin-releasing hormone treatment may be useful in those who have been amenorrheic for less than a year.     

Bromocriptine treatment of hyperprolactinemic infertility with ovulatory disturbances

We studied 77 women with hyperprolactinemic infertility and possible ovulatory disturbances. Galactorrhea was present in 27. Ovulation was normal in 15, 21 were anovulatory and 41 had luteal phase deficiency. All patients received bromocriptine for three months, resulting in normal serum prolactin levels. After that time, if no pregnancy occurred, clomiphene (with or without human chorionic gonadotropin) or human menopausal gonadotropin and human chorionic gonadotropin were added to the treatment. The overall pregnancy rate was 65%. The incidence of hyperprolactinemia in infertile patients is higher than expected, and patients with luteal phase deficiency can benefit from treatment with bromocriptine and ovulatory agents.     

Polycystic ovary syndrome and ovulation induction

Polycystic ovary syndrome (PCOS) is likely the most common cause of anovulatory infertility. Although many options are available for ovulation induction in these patients, there is currently no evidence-based algorithm to guide the initial and subsequent choices of ovulation induction methods. In obese women with PCOS, mild to moderate weight loss results in improvement of ovulatory dysfunction, and should be advocated at the onset of the evaluation. Clomiphene citrate is currently the 1st line medical therapy for ovulation induction. Glucocorticoids do not result in consistent ovulation and have significant side effects. Exogenous pulsatile GnRH treatment has low ovulation and pregnancy rates with a high risk of miscarriage. The most commonly used medical agents for ovulation induction in clomiphene-resistant women with PCOS are parenteral gonadotropins. Various gonadotropin preparations and different protocols are available; however the risk of multiple pregnancy and ovarian hyperstimulation is high with gonadotropin therapy. The frequent association between PCOS and insulin resistance has prompted recent studies on the effect of insulin-sensitizing agents on spontaneous and as an adjuvant to conventional ovulation induction therapies. Overall, the improvement in ovulation with insulin sensitizing drugs is modest, and unresolved issues such as variability in ovarian response remain to be addressed in future studies. Nevertheless, these agents may be beneficial in a subset of PCOS patients. Surgical ovulation induction methods such as ovarian diathermy have been reported to be moderately effective. However, due to the inherent associated risks and unknown effect on long-term reproductive potential, this modality should be reserved for patients who are clomiphene-resistant and unable or unwilling to proceed to gonadotropin therapy.     

Pregnancy considerations in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) are subfecund, and while anovulatory infertility is most likely the primary cause, other factors may contribute. Recent data suggest that women with PCOS are at increased risk for preterm labor, preeclampsia, and gestational diabetes, though the evidence for increased miscarriage rates is less certain. There is no evidence-based schema for achieving pregnancy in women with PCOS, though lifestyle modification, clomiphene citrate, and metformin are the current front line therapies. There are few data to support treatment during pregnancy with metformin in women with PCOS to prevent pregnancy loss or pregnancy complications.     

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.     

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.     

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.     

卵泡期经阴道小卵泡穿刺抽吸术治疗多囊卵巢综合征排卵障碍

目的 探讨对克罗米芬治疗无反应的多囊卵巢综合征患者在卵泡期经阴道小卵泡穿刺抽吸术后,使用促性腺激素诱发排卵时卵泡的发育及其结局。方法 选择17例对克罗米芬治疗无反应,或对促性腺激素治疗发生卵巢过度刺激或无反应,但输卵管通畅、男方精液正常的多囊卵巢综合征不孕患者,在月经(人工周期)第5天给予促性腺激素治疗,给药5d后,在B超指引下经阴道行小卵泡穿刺抽吸术,双侧卵巢仅留1—2个较大卵泡,术后继续给予促性腺激素,观察卵泡发育、排卵和妊娠情况及血中性激素水平变化。结果 17例中除2例(11．8％)对该治疗方法无反应外,15例出现优势卵泡发育和排卵,其中单卵泡发育9例(52．9％),双卵泡发育4例(23.5％),3卵泡发育2例(11．8％),发育的优势卵泡全部排卵。总共有7例妊娠,全部为单胎妊娠,单周期治疗妊娠率41．2％(7／17)。结论 卵泡期经阴道小卵泡穿刺抽吸术能使对克罗米芬治疗无反应的多囊卵巢综合征不孕患者,使用促性腺激素治疗获得良好的单卵泡发育和单胎妊娠率。     

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.     

Sequential clomiphene citrate-menotropin therapy for induction or enhancement of ovulation

Either to induce ovulation in anovulatory infertility patients or to enhance ovulation in patients with mild endometriosis or luteal phase inadequacy, we utilized a sequential regimen of low-dose clomiphene citrate (CC) followed by human menopausal gonadotropin (hMG) injections on alternate days; duration and dosage of menotropin therapy was individualized by using serum estradiol levels for monitoring until the time of administration of human chorionic gonadotropins. Previous therapeutic efforts without menotropins had been unsuccessful in all patients. One third of 70 treated patients conceived during 156 treatment cycles. The pregnancy rate was 44% in anovulatory patients (n = 34), and 26% in patients with ovulation dysfunction (n = 23). Pregnancy rates declined with patient's age. Four of the 23 patients that conceived had a spontaneous abortion (17%). The multiple gestation rate was 10.5%. A relative inhibition of cervical mucus development was noted and shown to be caused by CC. Hyperstimulation occurred in three patients. The discussed CC-hMG regimen approaches the effectiveness of standard hMG therapy; but compared with standard hMG therapy, it has significant economic advantages and seems to have a markedly lower rate of multiple gestation. However, like standard hMG therapy, CC-hMG therapy requires careful monitoring specifically, because hyperstimulation may occur.     

The treatment of infertility in polycystic ovary syndrome: a brief update

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. First-line medical ovulation induction therapy to improve fertility outcomes is clomiphene citrate, whilst gonadotrophins, laparoscopic ovarian surgery or possibly metformin are second line in clomiphene citrate-resistant PCOS women. There is currently insufficient evidence to recommend aromatase inhibitors over that of clomiphene citrate in infertile anovulatory PCOS women in general or specifically in therapy naive or clomiphene citrate-resistant PCOS women. IVF/ICSI treatment is recommended either as a third-line treatment or in the presence of other infertility factors.     

Ovulation induction with gonadotropins in women with polycystic ovary disease

Seventy-two infertile women with polycystic ovary disease (PCOD) and clomiphene citrate treatment failure underwent 220 human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) treatment cycles for ovulation induction over a period of 19 months. Forty-two patients ovulated but failed to conceive on clomiphene, and the remaining 30 failed to ovulate on clomiphene. Monitoring of treatment consisted of serum 17 beta-estradiol (E2) levels and ultrasonic assessment of follicular growth. Treatment was withheld whenever the E2 levels exceeded 1,500 pg/mL and/or when more than two follicles greater than or equal to 17 mm in diameter each were encountered on ultrasonography. Twenty-nine patients conceived (40.2%), and 23 delivered viable infants. Twenty-three of the 29 pregnancies were achieved in the 42 patients who ovulated on clomiphene, while only 6 pregnancies resulted in the 32 anovulatory patients on clomiphene. Six patients (20.6%) aborted in the first trimester. Multiple pregnancies consisted of only two sets of twins (6.9%). There were only two cases of mild hyperstimulation (2.7%) and no severe hyperstimulation. Because of the low occurrence of multiple pregnancies and hyperstimulation and the reasonable success rate, all PCOD patients should be started on this protocol.     

An Hypothesis for High Multiple Pregnancies after Clomiphene

A triplet and a quadruplet pregnancy following induction of ovulation with clomiphene are described; in each patient secondary amenorrhoea followed oral contraceptive use and several anovulatory or inadequate menstrual cycles had occurred on initial clomiphene therapy. Conception occurred in the first cycle after increasing drug dosage or the addition of human chorionic gonadotrophin (HCG) to the treatment regimen. We suggest, in explanation of these pregnancies, that repeated suboptimal stimulation of the ovaries as a result of clomiphene therapy develops several follicles to a critical stage; a subsequent greater ovulatory stimulus allows for synchronous development of several large follicles and multiple ovulation.     

Effectiveness of stimulated menstrual cycles and Percoll sperm preparation in intrauterine insemination

To examine the usefulness of intrauterine insemination in women with various fertility factors, we retrospectively analyzed data from women treated during 1986 and 1987. Ninety-three patients underwent 1-11 cycles of single or double procedures, for a total of 423 inseminations in 263 treatment cycles. Twenty-six patients (28%) conceived, for a 10% total pregnancy rate per cycle, with 58% of the pregnancies resulting from double inseminations per cycle. An average of two treatment cycles was required to achieve pregnancy. Eight pregnancies (31%) occurred in spontaneous cycles, while 18 (69%) occurred in stimulated cycles. While clomiphene citrate therapy was useful in anovulatory patients, it was of no benefit in ovulatory patients being treated with intrauterine insemination. Human menopausal gonadotropin therapy was of benefit in both ovulatory and anovulatory patients when combined with intrauterine insemination. The live birth rate was higher (75%) in spontaneous cycles than in stimulated cycles (44%). Semen preparation was accomplished by sperm washing in 61% of the pregnancies and by Percoll preparation in 39%. The effectiveness of the discontinuous Percoll gradient for semen preparation for insemination was suggested by a pregnancy rate of 9% per cycle. While the mean sperm count in the pregnant group was 44 million, successful pregnancy was accomplished with a double insemination of 880,000 and 1.16 million rapidly progressive sperm in the first and second inseminate, respectively. The data confirm the important role of intrauterine insemination for the treatment of infertility.     

Clinical studies with d-Trp 6-luteinizing hormone-releasing hormone in anovulatory women.

Nine anovulatory patients with hypothalamic-pituitary dysfunction were treated with d-Trp6-luteinizing hormone-releasing hormone, an analog with far greater gonadotropin-releasing activity than luteinizing hormone-releasing hormone. Four of eight patients, who were formerly unsuccessfully treated with clomiphene, human chorionic gonadotropin, and human menopausal gonadotropin, ovulated after treatment with the peptide alone or with peptide preceded by clomiphene, and three became pregnant. The ninth patient, who had amenorrhea and anovulation due to excessive loss of weight caused by anorexia nervosa, also ovulated after treatment with the analog. These results demonstrate the effectiveness of this potent analog for induction of ovulation and pregnancy and point favorably toward clinical applications.     

Clomiphene citrate in the twenty-first century

Clomiphene citrate is the drug most commonly prescribed for ovulation induction. It is the first choice medication in normogonadotrophic oligo/amenorrhoeic infertility (WHO group 2), essentially associated with polycystic ovaries. Anovulatory women who are responsive to clomiphene citrate should be treated for at least six cycles and the treatment should probably be limited to a maximum of 12 cycles. It is necessary to monitor at least the first cycle with ultrasonography because of the risk of multiple pregnancy and the variable response of patients to different doses of clomiphene. In addition, the risk of ovarian hyperstimulation syndrome should not be underestimated. More triplets and higher order pregnancies result from ovulation induction than from in vitro fertilization, and multiple pregnancy has many risks for both mother and babies. The role of empirical clomiphene in the treatment of unexplained infertility is debatable and the present data are inconclusive. Obesity, hyperandrogenaemia and insulin resistance are important factors in clomiphene-resistant patients. Failure to ovulate in response to clomiphene has been approached by either medical or surgical treatment. An effective alternative medical treatment is gonadotrophin injections. Treatment with metformin and the new generation of insulin-sensitizing drugs is under evaluation. The most widely used surgical treatment today is laparoscopic ovarian drilling, which appears to be as effective as gonadotrophin therapy.     

Synergism of pulsatile LHRH therapy with oral clomiphene treatment

Eighteen anovulatory patients who were resistant to induction of ovulation with clomiphene and with subcutaneous pulsatile LHRH were treated with these two agents given simultaneously. Twelve of the 14 patients with polycystic ovary syndrome, 1 patient with weight-related amenorrhea and 1 of 3 patients with intrinsic pituitary disease responded to the combined treatment. Serial determinations of serum gonadotropin concentrations showed that these remained unchanged by clomiphene treatment, suggesting a direct action on the ovary. For induction of ovulation for in vivo fertilization, the combination of oral clomiphene with subcutaneous pulsatile LHRH is worth trying before proceeding to intravenous LHRH or hMG therapy.