Anovulatory Patients Research Articles

Relationship of baseline ovarian volume to ovarian response in World Health Organization II anovulatory patients who underwent ovulation induction with gonadotropins

Objective: To assess whether ovarian volume of World Health Organization II anovulatory patients in the early follicular phase predicts the response to ovulation induction with gonadotropins. Design: Retrospective data analysis of two prospective, randomized, multicenter studies. Setting: Clinical development unit of biotechnology company Patient(s): Four hundred sixty-five World Health Organization II anovulatory patients undergoing ovulation induction. Main Outcome Measure(s): Ovarian response to stimulation, ovulation (mid-luteal serum progesterone > 30 nmol/L), cancellation rate, pregnancy rate, and incidence of the ovarian hyperstimulation syndrome (OHSS) according to baseline ovarian volume (day 2–5) before stimulation. Result(s): Mean ovarian volume was 11.55 ± 6.0 cm 3 (range, 0.8–49.3 cm 3). Small ovarian volume was associated with lower rates of cycle cancellation owing to risk for OHSS (3 vs. 29 patients [2.8% vs. 9%]). Patients with small ovarian volume (<7.25 cm 3) required fewer ampules of FSH (1373 IU vs. 1629 IU) and shorter duration of stimulation (16 vs. 18.1 days) and had higher ovulation rate than did patients with mid-range and larger ovarian volume (84.3% vs. 69.1% and 68.8%, respectively). The clinical pregnancy rate per cycle of hCG administration was similar in the three groups (25.8%, 28.1%, and 27.5%). Conclusions: World Health Organization II anovulatory women with medium-sized or large ovaries who are undergoing low-dose gonadotropin stimulation for ovulation induction may have higher risk for OHSS than do women with small ovaries. Women with small ovaries who meet criteria for administration of hCG respond better to ovulation induction and have a similar likelihood of conceiving compared with women with larger ovaries.

Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome

Objective: To assess pregnancy outcome in anovulatory infertility patients diagnosed with polycystic ovary syndrome (PCOS) who were treated with metformin. Design: Case series. Setting: Outpatient. Patient(s): Anovulatory patients (n = 48) with a diagnosis of PCOS based on clinical, diagnostic, and laboratory evaluations were enrolled in the study over a 15-month period. Intervention(s): Metformin was started at 500 mg b.i.d. for 6 weeks and then increased to 500 mg t.i.d. if no ovulation occurred. Clomiphene citrate (CC; 50 mg) was added if no ovulatory response occurred after 6 weeks. Main Outcome Measure(s): Resumption of menses, presumptive ovulation, and pregnancy. Result(s): Nineteen of 48 (40%) patients resumed spontaneous menses following treatment and showed presumptive evidence of ovulation with metformin alone; 15/48 (31%) required CC (50 mg) in conjunction with metformin therapy, and 10 of these 15 (67%) had evidence of ovulation; 20/48 (42%) conceived with a median time to conception of 3 months, and 7 of these 20 (35%) had spontaneous abortions (SAB); 19/48 (40%) had gastrointestinal-related side effects, and 5 of 48 patients (10%) had to decrease the dosage of metformin. Only 1 patient discontinued therapy. Conclusion(s): Metformin alone in patients with PCOS results in a substantial number of pregnancies, with 69% (20/29) of those who ovulated conceiving in less than 6 months.

Development of gonadotrophins for clinical use

The 20th century witnessed the steady development of knowledge about reproductive physiology and endocrinology in animals and humans. These advances led to the identification of higher centres governing the ovary and its follicles. Effects of X-rays on the head and other agents, or excision of the pituitary gland, led to anomalies in oestrous and menstrual cycles in animals and women, respectively. Studies on pituitary and placental extracts revealed the presence of hormones regulating the ovarian follicles and the corpus luteum for the implanting embryo. These were identified as follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotrophin (HCG). Increasing understanding of the mechanisms of action of these hormones led to treatments of animals and amenorrhoeic women with FSH- and LH-containing preparations in order to induce the growth of follicles and ovulation.Human FSH-rich preparations were obtained by extracting urinary gonadotrophins from the urine of post-menopausal women, and thousands of amenorrhoeic and/or anovulatory patients were treated with human menopausal gonadotrophin (HMG) and HCG to induce multifolliculation and ovulation. The introduction of IVF greatly increased the numbers of women treated in this fashion, now including cyclic women. By the mid-1980s, following the appearance of Creutzfeld–Jakob disease in women treated with gonadotrophins extracted from human pituitaries, and other safety considerations, attempts were being made to purify urinary gonadotrophin preparations, using antibodies. Increasing interest in recombinant preparations, which were pure, highly specific and highly active preparations, characterized the last years of the 20th century and the new millennium. These preparations included recombinant FSH (rFSH), recombinant LH (rLH) and recombinant HCG (rHCG). Yet, in one sense, the recombinant preparations could change the procedures of ovarian stimulation, because they focused attention on the membranal receptor in the follicle, and how best to stimulate it. Small molecules are currently being investigated, with some proving to be very active and specific, and even capable of bypassing many parts of the receptor conformation. Here lies the immediate future of this field, utilizing small, defined molecules at low cost to stimulate follicle growth, ovulation and luteinization, and perhaps one day to remove the need for gonadotrophins in clinical work.

Glucose tolerance during pregnancy in patients with polycystic ovaries pregnant after HMG therapy.

Objective: Insulin resistance has been suggested as a component of the pathophysiology of the polycystic ovary syndrome (PCOS). Previous studies have compared glucose tolerance in PCO pregnant patients to normal subjects who became pregnant spontaneously. The effect of the ovulation induction therapy cannot therefore be excluded. The aim of this work was to evaluate glucose tolerance during pregnancy in PCOS patients who become pregnant after therapy with human menopausal gonadotrophins (HMG) compared to non-PCO anovulatory patients who became pregnant on the same therapy.

Gestational diabetes in patients with polycystic ovaries pregnant after HMG therapy.

Objective: Impaired glucose tolerance has been suggested as a component of the pathophysiology of the polycystic ovary syndrome (PCOS). Previous studies have compared glucose tolerance in PCO pregnant patients to normal subjects who became pregnant spontaneously. The effect of the ovulation induction therapy cannot therefore be excluded. The aim of this work was to evaluate glucose tolerance during pregnancy in PCOS patients who become pregnant after therapy with human menopausal gonadotrophins (HMG) compared to non-PCO anovulatory patients who became pregnant on the same therapy.

Prospective randomized trial comparing the effects of letrazole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI).

Objective: CC is commonly used to increase the number of pre-ovulatory follicles in ovulatory patients prior to IUI. However, pregnancy rates following induction with CC and IUI are lower than expected for the number of follicles produced. This is probably the result of the negative effect of CC on endometrial development. Recently, a report of a small cohort of anovulatory patients suggested that LE, a non-steroidal aromatase inhibitor, could result in a successful ovulation induction with a normally developed endometrium and high pregnancy rates when administered to patients who developed a thin endometrium when treated with CC. In this study we investigated whether treatment with LE offers an advantage over treatment with CC in patients with unexplained infertility undergoing IUI treatment. Design: Prospective randomized double blind trial. Materials/Methods: Patients with at least 12 months of unexplained infertility and the absence of ovarian cysts on ultrasound scan performed between day 1 and 3 of the menstrual cycle, were offered to participate in the study. The patients were randomized to receive either 100 mg of CC or 2.5 mg of LE for five days starting from cycle day 3. Ultrasound scans and blood tests were performed on cycle day 7, and as required thereafter, until the dominant follicle reached 18 mm in mean diameter. Ovulation was then triggered with 10,000 IU hCG and IUIs were performed 24 and 48 hours later. In subsequent cycles patients remained in their original study group. A maximum of three cycles were offered to each patient. Results: In the period between November 2000 and March 2001 a total of 49 patients were recruited into the study. Of these 25 received LE and 24 received CC. There was no difference between the two groups in age (30.7 years vs. 32.8 years p = .11), duration of infertility (26 vs. 24 months p = .82), semen characteristics or any other relevant parameters. On day 7 of the menstrual cycle the group receiving CC had significantly higher serum E2 (898 vs. 326 pmol/mL p < .0001) and FSH levels (7.0 vs. 6.2 IU/mL p = .03). Both groups had a similar number of measurable follicles (5.5 in CC vs. 6.0 in LE group p = .8) and endometrial thickness (5.4 mm in CC vs 5.5 mm in LE group p = .9). Patients in both groups required a similar period of time to satisfy the criteria for hCG administration (10 days in CC vs. 11 days in LE group p = .3). On the day of hCG administration the patients in the CC group had higher E2 levels (2322.5 vs. 605 pmol/mL p < .0001), more follicles 14 mm in the mean diameter (2 vs 1 p = .005), a thinner endometrium (6.9 vs 8.6 mm p = .03) and an increased uterine artery Pulsatility Index (3.6 vs. 3.1 p = .0005). A non-significant increase in pregnancy rate was observed in patients receiving the LE treatment (16.7% vs. 5.6% per patient p = .55). Conclusions: Patients with unexplained infertility, when treated with LE rather than CC develop less pre-ovulatory follicles but achieve a superior uterine environment. Due to its less detrimental effects on uterus LE could replace CC, at least in some patients, with unexplained infertility undergoing ovulation induction and IUI. Supported By: ‘Serono’ Canada.

Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome.

We evaluated the fertility promoting effect of metformin in infertile patients with polycystic ovary syndrome. Twenty-nine infertile patients with polycystic ovary syndrome (PCOS) are included in our prospectively designed study and 15 normal menstruating women served as controls for reproductive hormones and ovarian volumes. All PCOS patients received a total of 78 cycles of clomiphene citrate (CC) in the beginning, then patients who could not get pregnant were switched to metformin plus clomiphene citrate. PCOS patients served as their own controls for the ovulation and pregnancy rates. At the end of the CC cycles 4.2% of patients got pregnant and 65.2% of the remaining group got pregnant with metformin plus CC cycles (p=0.0001). We have not observed any serious side effects of metformin. The high pregnancy rate of our study population is consistent with the hypothesis that insulin resistance plays an important role in the pathogenesis of anovulation in patients with PCOS.

Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome

The present study probes putative disruption of hypothalamic control of multihormone outflow in polycystic ovarian syndrome by quantitating the joint synchrony of leptin and LH release in adolescents with this syndrome and eumenorrheic controls. To this end, hyperandrogenemic oligo- or anovulatory patients with polycystic ovarian syndrome (n = 11) and healthy girls (n = 9) underwent overnight blood sampling every 20 min for 12 h to monitor simultaneous secretion of leptin (immuno-radiometric assay), LH (immunofluorometry), and androstenedione and T (RIA). Synchronicity of paired leptin-LH, leptin-androstenedione, and leptin-T profiles was appraised by two independent bivariate statistics; viz., lag-specific cross-correlation analysis and pattern-sensitive cross-approximate entropy. The study groups were comparable in chronological and postmenarchal age, body mass index, fasting plasma insulin/glucose ratios, and serum E2 concentrations. Overnight mean (± sem) serum leptin concentrations were not distinguishable in the two study groups at 30 ± 4.8 (polycystic ovarian syndrome) and 32 ± 7.4 μg/liter (control). Serum LH concentrations were elevated at 9.5 ± 1.4 in girls with polycystic ovarian syndrome vs. 2.8 ± 0.36 IU/liter in healthy subjects (P = 0.0015), androstenedione at 2.8 ± 0.30 (polycystic ovarian syndrome) vs. 1.2 ± 0.11 ng/ml (control) (P = 0.0002), and T at 1.56 ± 0.29 (polycystic ovarian syndrome) vs. 0.42 ± 0.06 ng/ml (P < 0.0001). Cross-correlation analysis shows that healthy adolescents maintained a positive relationship between leptin and LH release, wherein the latter lagged by 20 min (P < 0.01). No such association emerged in girls with polycystic ovarian syndrome. In eumenorrheic volunteers, leptin and androstenedione concentrations also covaried in a lag-specific manner (0.0001 < P < 0.01), but this linkage was disrupted in patients with polycystic ovarian syndrome. Anovulatory adolescents further failed to sustain normal time-lagged coupling between leptin and T (P < 0.01). Approximate entropy calculations revealed erosion of orderly patterns of leptin release in polycystic ovarian syndrome (P = 0.012 vs. control). Cross-entropy analysis of two-hormone pattern regularity disclosed marked disruption of leptin and LH (P = 0.0099), androstenedione and leptin (P = 0.0075) and T-leptin (P = 0.019) synchrony in girls with polycystic ovarian syndrome. In summary, hyperandrogenemic nonobese adolescents with oligo- or anovulatory polycystic ovarian syndrome manifest: 1) abrogation of the regularity of monohormonal leptin secretory patterns, despite normal mean serum leptin concentrations; 2) loss of the bihormonal synchrony between leptin and LH release; and 3) attenuation of coordinate leptin and androstenedione as well as leptin and T output. In ensemble, polycystic ovarian syndrome pathophysiology in lean adolescents is marked by vivid impairment of the synchronous outflow of leptin, LH and androgens. Whether analogous disruption of leptin-gonadal axis integration is ameliorated by therapy and/or persists into adulthood is not known.

Disruption of the synchronous secretion of leptin, LH, and ovarian androgens in nonobese adolescents with the polycystic ovarian syndrome.

The present study probes putative disruption of hypothalamic control of multihormone outflow in polycystic ovarian syndrome by quantitating the joint synchrony of leptin and LH release in adolescents with this syndrome and eumenorrheic controls. To this end, hyperandrogenemic oligo- or anovulatory patients with polycystic ovarian syndrome (n = 11) and healthy girls (n = 9) underwent overnight blood sampling every 20 min for 12 h to monitor simultaneous secretion of leptin (immuno-radiometric assay), LH (immunofluorometry), and androstenedione and T (RIA). Synchronicity of paired leptin-LH, leptin-androstenedione, and leptin-T profiles was appraised by two independent bivariate statistics; viz., lag-specific cross-correlation analysis and pattern-sensitive cross-approximate entropy. The study groups were comparable in chronological and postmenarchal age, body mass index, fasting plasma insulin/glucose ratios, and serum E2 concentrations. Overnight mean (+/- SEM) serum leptin concentrations were not distinguishable in the two study groups at 30 +/- 4.8 (polycystic ovarian syndrome) and 32 +/- 7.4 microg/liter (control). Serum LH concentrations were elevated at 9.5 +/- 1.4 in girls with polycystic ovarian syndrome vs. 2.8 +/- 0.36 IU/liter in healthy subjects (P = 0.0015), androstenedione at 2.8 +/- 0.30 (polycystic ovarian syndrome) vs. 1.2 +/- 0.11 ng/ml (control) (P = 0.0002), and T at 1.56 +/- 0.29 (polycystic ovarian syndrome) vs. 0.42 +/- 0.06 ng/ml (P < 0.0001). Cross-correlation analysis shows that healthy adolescents maintained a positive relationship between leptin and LH release, wherein the latter lagged by 20 min (P < 0.01). No such association emerged in girls with polycystic ovarian syndrome. In eumenorrheic volunteers, leptin and androstenedione concentrations also covaried in a lag-specific manner (0.0001 < P < 0.01), but this linkage was disrupted in patients with polycystic ovarian syndrome. Anovulatory adolescents further failed to sustain normal time-lagged coupling between leptin and T (P < 0.01). Approximate entropy calculations revealed erosion of orderly patterns of leptin release in polycystic ovarian syndrome (P = 0.012 vs. control). Cross-entropy analysis of two-hormone pattern regularity disclosed marked disruption of leptin and LH (P = 0.0099), androstenedione and leptin (P = 0.0075) and T-leptin (P = 0.019) synchrony in girls with polycystic ovarian syndrome. In summary, hyperandrogenemic nonobese adolescents with oligo- or anovulatory polycystic ovarian syndrome manifest: 1) abrogation of the regularity of monohormonal leptin secretory patterns, despite normal mean serum leptin concentrations; 2) loss of the bihormonal synchrony between leptin and LH release; and 3) attenuation of coordinate leptin and androstenedione as well as leptin and T output. In ensemble, polycystic ovarian syndrome pathophysiology in lean adolescents is marked by vivid impairment of the synchronous outflow of leptin, LH and androgens. Whether analogous disruption of leptin-gonadal axis integration is ameliorated by therapy and/or persists into adulthood is not known.

Specific factors predict the response to pulsatile gonadotropin-releasing hormone therapy in polycystic ovarian syndrome.

Ovulation induction is particularly challenging in patients with polycystic ovarian syndrome (PCOS) and may be complicated by multifollicular development. Pulsatile GnRH stimulates monofollicular development in women with anovulatory infertility; however, ovulation rates are considerably lower in the subgroup of patients with PCOS. The aim of this retrospective study was to determine specific hormonal, metabolic, and ovarian morphological characteristics that predict an ovulatory response to pulsatile GnRH therapy in patients with PCOS. Subjects with PCOS were defined by chronic amenorrhea or oligomenorrhea and clinical and/or biochemical hyperandrogenism in the absence of an adrenal or pituitary disorder. At baseline, gonadotropin dynamics were assessed by 10-min blood sampling, insulin resistance by fasting insulin levels, ovarian morphology by transvaginal ultrasound, and androgen production by total testosterone levels. Intravenous pulsatile GnRH was then administered. During GnRH stimulation, daily blood samples were analyzed for gonadotropins, estradiol (E(2)), progesterone, inhibin B, and androgen levels, and serial ultrasounds were performed. Forty-one women with PCOS underwent a total of 144 ovulation induction cycles with pulsatile GnRH. Fifty-six percent of patients ovulated with 40% of ovulatory patients achieving pregnancy. Among the baseline characteristics, ovulatory cycles were associated with lower body mass index (P < 0.05), lower fasting insulin (P = 0.02), lower 17-hydroxyprogesterone and testosterone responses to hCG (P < 0.03) and higher FSH (P < 0.05). In the first week of pulsatile GnRH treatment, E(2) and the size of the largest follicle were higher (P < 0.03), whereas androstenedione was lower (P < 0.01) in ovulatory compared with anovulatory patients. Estradiol levels of 230 pg/mL (844 pmol/L) or more and androstenedione levels of 2.5 ng/mL (8.7 nmol/L) or less on day 4 and follicle diameter of 11 mm or more by day 7 of pulsatile GnRH treatment had positive predictive values for ovulation of 86.4%, 88.4%, and 99.6%, respectively. Ovulatory patients who conceived had lower free testosterone levels at baseline (P < 0.04). In conclusion, pulsatile GnRH is an effective and safe method of ovulation induction in a subset of patients with PCOS. Patient characteristics associated with successful ovulation in response to pulsatile GnRH include lower body mass index and fasting insulin levels, lower androgen response to hCG, and higher baseline FSH. In ovulatory patients, high free testosterone is negatively associated with pregnancy. A trial of pulsatile GnRH therapy may be useful in all PCOS patients, as E(2) and androstenedione levels on day 4 or follicle diameter on day 7 of therapy are highly predictive of the ovulatory response in this group of patients.

Recombinant versus Urinary Follicle-Stimulating Hormone in the Low-Dose Regimen in Anovulatory Patients with Polycystic Ovary Syndrome: A Safer and More Effective Treatment

Background: We studied polycystic ovarian syndrome (PCOS) in fifty 25- to 37-year-old women who failed to conceive with clomiphene citrate treatment. Methods: Twenty patients were submitted to treatment with low-dose (75 IU) urinary FSH (uFSH) in order to achieve ovulation and 30 patients were treated with recombinant FSH (rFSH) according to the same protocol. Results: Ovulation was achieved in 75 and 97% of the cycles after uFSH and rFSH, respectively (p < 0.02). The length of treatment needed to achieve ovulation, the number of ampules given and dose per kilogram were significantly lower in the rFSH group. Mild ovarian hyperstimulation syndrome (OHSS) was observed in 9 uFSH cycles, whereas only 1 of the women treated with rFSH developed an OHSS (1/38 vs. 9/36; p < 0.01). Conclusion: rFSH is more efficient than uFSH in inducing ovulation in PCOS patients. The high prevalence of ovulatory cycles using a lower dose guaranteed greater safety of treatment and significantly reduced the incidence of OHSS.

Le rôle de l’hormone lutéinisante dans la physiologie du follicule et du corps jaune

Luteinizing hormone (LH) is an hypophyseal glycoprotein involved in both follicular maturation and corpus luteum function. During the follicular phase, effects of LH must be considered according to the stages of follicular development: in the early follicular phase, LH acts through specific receptors, constitutively present on thecal cells, for stimulating androgen production. Androgens seem to be positively involved in the folliculogenesis in primates. Indeed, a positive correlation has been recently established between androgen receptor expression and follicular cell proliferation. Furthermore, androgens are active through a conversion to estrogens in granulosa cells. Estrogens are needed for achieving pregnancy. Thus, a question remains: what in the minimal amount of endogenous LH required for an optimal production of oestradiol? Several models have been investigated in clinical situations with hypogonadotrophic hypogonadism: WHO type I anovulation or GnRH analog-induced hypogonadisms. A large majority of these studies conclude that the minimal amount of LH needed during the follicular phase is probably low (<1.5 IU/L of plasma LH level). Recent availability of GnRH antagonist will give a new opportunity for evaluating this minimal LH threshold. During the late follicular phase, LH plays a biphasic role, with a positive effect on steroidogenesis but a negative effect on cell proliferation. As suggested by S. Hillier, this negative effect on cell proliferation may be relevant to control the rate of follicular growth. One study, performed in WHO type I anovulatory patients, seems to confirm this assumption but further evaluation is needed to give support to this concept. Finally, LH is also involved in corpus luteum function. Due to the short half-life of LH as compared to hCG, the role of LH must be evaluted according to the adjunct therapies. For example, following a long-term GnRH agonist administration that constantly induces a profound hypophyseal desensitization, LH administration must be repeated to adequately sustain the corpus luteum function. This conclusion must be reconsidered with the recent introduction of GnRH antagonists. Indeed, according to their short-term effects on LH secretion, it may be presumed that a single injection of LH may be effective to maintain an adequate corpus luteum function.

The Use in Daily Clinical Practice of Recombinant FSH (Follitropin-α; Gonal-F 75 IU) in Ovulation Induction (OI) Prior to Intrauterine Insemination (IUI): Follow-Up Study in 1000 Cycles

Objectives: Analyze the cycle characteristics, monitoring resources used (ultrasound scans; US) and effectiveness of treatment consisting in ovulation induction (OI) with human recombinant FSH (rFHS) in daily clinical practice, according to dosage and regimes specified in the European summary of product characteristics (SmPC) for rFSHs. Design: Follow up study of OI cycles, prior to IUI, performed between January 1998 and November 1999 in 44 clinics, in which rFSH 75 IU (follitropin α; Gonal-F®) was used as the starting dose of choice. A specific case report form was used. Materials and Methods: 1.021 OI cycles. The study population was segmented into ovulatory and anovulatory (WHOII) patients for analysis. Results are given as proportions and means (SD). Student “t” test and multivariable analysis were performed, as appropriate. Results: Patients’ age was as follows: <25 years (0.4%); 25–29 (27.4%); 30–34 (46.1%); 35–39 (21.3%); 40–44 (3.4%); 45–49 (1.4%) and the causal factors were: anovulation, 37.4%; male factor, 35.7%; unilateral tubal factor, 19.1%; cervical factor, 13.1%; unexplained infertility, 11.1%; mild endometriosis, 5.2%; uterine factor, 5%; immunological factor, 3.1%; luteal phase deficiency, 1%. Primary infertility accounted for 81.4% of the cases and secondary infertility for 18.6%. Male and female factors co-existed in 31% of cases. Anovulation was present in 382 cycles. The remaining 639 did not show ovulatory disorders. The following table refers to the main resources (drug, days and monitoring visits) used in these groups. Total dose and stimulation length for anovulatory and ovulatory women were significantly higher in the anovulatory patients. From a clinical standpoint, there were no differences either in the mean number of follicles >16 mm in diameter on the day of hCG administration (1.11 vs. 1.30) or in the endometrium thickness (9.50 vs. 9.48). Cancellation rates were 10.7% and 5.6% in anovulatory and ovulatory patients respectively. Pregnancy rates per cycle (US) were 15.2% (anovulatory) and 11.4% (ovulatory) (overall 12.8%), of them 6.8% and 4% were multiple. Miscarriage rates were 10.3% (anovulatory) and 13.6% (ovulatory) and ovarian hyperestimulation syndrome, none severe, appeared in 1.8% and 1.3% of the treated cycles, respectively. Conclusions: Anovulatory patients required a higher amount of drug and showed significantly longer stimulation than ovulatory patients. However, in >80% of the cycles only 3 or fewer US scans were required in both populations for monitoring purposes. Good pregnancy rates, with a low risk of multiple pregnancies and OHSS, are obtained by administering rFSH at a starting dose of 75 IU, and adopting well known protocols, predominantly the low dose protocol, with increases of 37.5 IU in daily clinical practice.

Effects of Tamoxifen (Tx) on Endometrial Thickness and Pregnancy Rates in Women Undergoing Superovulation with Clomiphene Citrate (CC) and Intrauterine Insemination (IUI)

Objective: CC is commonly used to either provoke ovulation in anovulatory patients, or to increase the number of pre-ovulatory follicles in ovulatory patients prior to IUI. However, pregnancy rates following induction with CC and IUI are lower than expected for the number of follicles produced. This may be a result of the anti-estrogenic effect of CC on the endometrium. Tx has been previously been shown to act as an estrogen agonist on endometrial cells causing, after prolonged use, endometrial hyperplasia. In this study we investigated the potential positive effect of Tx on the endometrium, and pregnancy rates in patients treated with CC prior to IUI.

The Prevalence of Polycystic Ovaries in Women With Infertility

Polycystic ovaries (PCO) are highly prevalent in women presenting with hirsutism or recurrent miscarriage but the functional significance of PCO in ovulatory women presenting with infertility remains unclear. We examined the prevalence of PCO, on ultrasonography, among women presenting with infertility. Among 289 couples classified in four main diagnostic categories, PCO were found in 81 (83%) of 98 anovulatory patients, 40 (53%) of 76 patients whose partners had sperm dysfunction, 26 (50%) of 52 patients with tubal disease and in 28 (44%) of 63 patients with unexplained infertility. By comparison, in a control group of 67 parous volunteers, 19 (28%) were found to have PCO. PCO patients with unexplained infertility had higher midfollicular luteinizing hormone and testosterone compared with the group with normal ovaries. The prevalence of PCO was significantly higher in each of the infertility groups than in controls, and a similar tendency (not significant) was observed among women with unexplained infertility. Ovulatory PCO women with infertility had higher testosterone concentrations in comparison with PCO controls. In summary, the prevalence of PCO among ovulatory women with infertility is higher than that in the normal population, suggesting that PCO may, perhaps by virtue of an effect of hyperandrogenaemia, contribute to the causes of subfertility in women with regular menses.

Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia

Although ovarian cysts commonly occur in patients with congenital lipoid adrenal hyperplasia (CLAH), the mechanism of development remains to be determined. To clarify the pathogenesis of the ovarian cysts, endocrinological examinations were performed in patients with CLAH. The subjects were three Japanese CLAH patients. Basal body temperature, serum and urinary gonadotropin levels, serum and/or urinary ovarian hormones and mutations of the steroidogenic acute regulatory protein (StAR) gene were examined. The basal body temperature was not biphasic in any patient. Basal LH levels were high in all CLAH patients and markedly responded to LH-releasing hormone in two patients. Urinary gonadotropin analysis revealed repetitive LH surges in the menstrual cycles of the CLAH patients. No increase in the urinary pregnanediol suggested anovulation in all patients, and bilateral ovarian cysts were found in two of the subjects. Examination of the StAR gene revealed a frameshift mutation 840delA at codon 238, a nonsense mutation Q258X at codon 258, a homozygotic mutation at Q258X, and a compound heterozygotic mutation with 251insG and Q258X. We concluded that the development of ovarian cysts may be derived from continued anovulation in CLAH patients. Elevated LH levels may be explained by increased sensitivity of the anterior pituitary to circulating estrogen.

The prevalence of polycystic ovaries in women with infertility.

Polycystic ovaries (PCO) are highly prevalent in women presenting with hirsutism or recurrent miscarriage but the functional significance of PCO in ovulatory women presenting with infertility remains unclear. We examined the prevalence of PCO, on ultrasonography, among women presenting with infertility. Among 289 couples classified in four main diagnostic categories, PCO were found in 81 (83%) of 98 anovulatory patients, 40 (53%) of 76 patients whose partners had sperm dysfunction, 26 (50%) of 52 patients with tubal disease and in 28 (44%) of 63 patients with unexplained infertility. By comparison, in a control group of 67 parous volunteers, 19 (28%) were found to have PCO. PCO patients with unexplained infertility had higher midfollicular luteinizing hormone and testosterone compared with the group with normal ovaries. The prevalence of PCO was significantly higher in each of the infertility groups than in controls, and a similar tendency (not significant) was observed among women with unexplained infertility. Ovulatory PCO women with infertility had higher testosterone concentrations in comparison with PCO controls. In summary, the prevalence of PCO among ovulatory women with infertility is higher than that in the normal population, suggesting that PCO may, perhaps by virtue of an effect of hyperandrogenaemia, contribute to the causes of subfertility in women with regular menses.

Pregnancies resulting from in vitro matured oocytes retrieved from patients with polycystic ovary syndrome after priming with human chorionic gonadotropin

Objective: To describe pregnancies that resulted from in vitro matured oocytes derived from two unstimulated, anovulatory patients with polycystic ovary syndrome after priming with hCG before oocyte retrieval. Design: Case series. Setting: McGill Reproductive Center, Royal Victoria Hospital, McGill University. Patient(s): Two women with polycystic ovary syndrome. Intervention(s): Progesterone induction of a withdrawal bleeding episode. The administration of subcutaneous hCG 36 hours before oocyte retrieval in a natural menstrual cycle. In vitro maturation of immature oocytes, fertilization, and ET. Luteal support with oral estrogen and progesterone. Main Outcome Measure(s): Pregnancy outcome. Result(s): Two clinical pregnancies were confirmed after oocyte maturation in vitro, fertilization with intracytoplasmic sperm injection, and ET. Conclusion(s): The administration of hCG 36 hours before harvesting of immature oocytes may improve the maturational and developmental competence of the oocytes and the pregnancy rates of unstimulated patients with polycystic ovary syndrome.

Insulin action during variable hyperglycemic–hyperinsulinemic infusions in hyperandrogenic anovulatory patients and healthy women

Objective: To determine whether 3-month GnRH analogue (GnRH-a) administration to hyperandrogenic anovulatory patients and healthy women affects glucose utilization or endogenous glucose production (EGP) in the postabsorptive state and during variable hyperglycemic–hyperinsulinemic infusions. Design: Prospective, nonrandomized study. Setting: Academic research environment. Patient(s): Twelve hyperandrogenic anovulatory patients and 11 healthy women matched by body mass index and waist to hip circumference ratio. Intervention(s): Variable hyperglycemic–hyperinsulinemic infusions replicated physiological increases in circulating glucose and insulin levels before and after 3-month GnRH-a administration. Main outcome measure(s): Glucose utilization and EGP. Result(s): In the postabsorptive state, plasma glucose and insulin levels, glucose utilization, and EGP were similar in hyperandrogenic patients and healthy women. During variable hyperglycemic–hyperinsulinemic infusions, glucose use increased and EGP decreased to similar degrees in both groups of women. Three-month GnRH-a administration to hyperandrogenic patients and healthy women did not affect plasma glucose and insulin levels, glucose utilization and EGP in the postabsorptive state, or glucose utilization and EGP during variable hyperglycemic–hyperinsulinemic infusions. Conclusion(s): Glucose use and EGP in the postabsorptive state and during variable hyperglycemic–hyperinsulinemic infusions are similar in hyperandrogenic anovulatory patients and healthy women of similar body fat distribution and are unaffected by 3-month GnRH-a administration.

P-247. Pregnancies induced by weight reduction in anovulatory obese polycystic ovary syndrome patients

P-247. Pregnancies induced by weight reduction in anovulatory obese polycystic ovary syndrome patients