Cases Of Ovarian Hyperstimulation Syndrome Research Articles

Spontaneous Ovarian Hyperstimulation Syndrome in a Normal Singleton Pregnancy

It is known that most cases of ovarian hyperstimulation syndrome (OHSS) are associated with the therapies for ovulation induction. However, OHSS may rarely be associated with a spontaneous ovulatory cycle, usually in the case of multiple gestations, hypothyroidism or polycystic ovary syndrome. A case of OHSS in a woman who became pregnant naturally and who had no underlying disease is presented here. The patient was managed expectantly with no complications. Although spontaneous ovarian hyperstimulation is a rare entity, it is important to differentiate it from other causes of ovarian enlargement. Occasionally, life-threatening situations may occur, but it is usually a self-limiting process.

Use of gonadotropin-releasing hormone antagonists to overcome the drawbacks of intrauterine insemination on weekends

To assess the usefulness of the GnRH antagonist cetrorelix to prevent LH surge and to avoid intrauterine insemination at weekends when a gynecologist on duty is not available and the ultrasound scan on Friday showed > 1 and < 3 follicles > or = 17 mm in diameter. Open-label, randomized, prospective study. Reproductive medicine unit in an acute care teaching hospital in Barcelona, Spain. Infertile patients undergoing controlled ovarian hyperstimulation (COH) and IUI. Treatment with recombinant FSH was started on day 3. In women assigned to the control group (n = 32), recombinant FSH was continued up to the day of hCG administration. In patients assigned to the GnRH antagonist group (n = 35), half of the dose of recombinant FSH was given for 2 more days in addition to cetrorelix (0.25 mg SC) until the day of hCG administration. Recombinant FSH doses, E(2) level on the day of hCG administration, number and diameter of follicles, endometrial thickness, and number of pregnancies. Only a case of premature ovulation occurred in the cetrorelix group. There were no significant differences between the study groups in the total mean number of follicles, follicles > 10 mm and < 17 mm, and follicles > or = 17 mm. The mean concentration of E2 on the day of hCG administration and the endometrial thickness were significantly higher in the cetrorelix group. Eleven pregnancies were achieved, 7 (20%) in the cetrorelix group (4 singleton, 3 twins) and 4 (12.5%) in controls (4 singleton). No case of ovarian hyperstimulation syndrome (OHSS) occurred. The use of cetrorelix to avoid IUI at weekends when the ultrasound scan on Friday shows > 1 and < 3 follicles > or = 17 mm is a useful alternative for medical centers in which a gynecologist on call is not available.

Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles

To determine the incidence of ovarian hyperstimulation syndrome (OHSS) in a large series of GnRH antagonist-stimulated cycles and to assess the predictive value of E2 and the number of follicles on the day of hCG administration. Prospective cohort study of women undergoing IVF treatment with a GnRH antagonist protocol over a 2-year period. Tertiary university hospital. One thousand eight hundred one patients who underwent 2,524 cycles. Multifollicular ovarian stimulation with recombinant FSH and GnRH antagonist for IVF-ICSI treatment. Incidence of OHSS in GnRH antagonist cycles, predictive value of E2, and number of follicles on the day of hCG for OHSS occurrence. Fifty-three patients were hospitalized because of OHSS (2.1%; 95% confidence interval [CI]:1.6-2.8). Early OHSS presented in 31 patients (1.2%; 95% CI: 0.9-1.8), whereas the late type was a complication in 22 patients (0.9%; 95% CI: 0.5-1.3). Late OHSS cases compared with the early OHSS cases always occurred in a pregnancy cycle (100% vs. 40%); had higher probability of being severe (72.7% vs. 42%), and more often were related to a multiple pregnancy (40% vs. 0). Receiver operating characteristic curve analysis for several E2 concentrations and number of follicles with a diameter of > or =11 mm revealed that the predictive value of the optimal threshold of > or =13 follicles (85.5% sensitivity; 69% specificity) was statistically significantly superior to the optimal threshold of 2,560 ng/L for E2 concentrations (53% sensitivity, 77% specificity) in identifying patients at risk for OHSS. Considering that severe OHSS represents the most clinically significant pattern, the combination of a threshold of > or =18 follicles and/or E2 of > or =5,000 ng/L yields a 83% sensitivity rate with a specificity as high as 84% for the severe OHSS cases. Clinically significant OHSS still remains a limitation of multifollicular ovarian stimulation for IVF even with the use of GnRH antagonist protocols. The number of follicles can discriminate the patients who are at risk for developing OHSS, whereas E2 concentrations are less reliable for the purpose of prediction. There is more than ever an urgent need for alternative final oocyte maturation-triggering medication.

Substituting HCG with GnRH agonist to trigger final follicular maturation – a retrospective comparison of three different ovarian stimulation protocols

The study retrospectively evaluated the influence of triggering final oocyte maturation with gonadotrophin-releasing hormone (GnRH) agonist on the outcome of IVF cycles. Four hundred and sixty consecutive women admitted to the IVF unit during a 4-year period were enrolled in the study. Ovarian stimulation characteristics and clinical pregnancy rate were compared between three groups: patients at risk of developing ovarian hyperstimulation syndrome (OHSS), undergoing either the long GnRH-agonist protocol (agonist group) or the flexible multidose GnRH-antagonist protocol who received GnRH-agonist for final oocyte maturation (antagonist–agonist group); and patients not at risk of developing severe OHSS undergoing the flexible multidose GnRH-antagonist protocol who received human chorionic gonadotrophin (HCG) for final oocyte maturation (antagonist-HCG group). Implantation and clinical pregnancy rates were lowest in the antagonist–agonist group despite the fact that no difference were was observed in fertilization rates between the groups. Moreover, the high-responder antagonist–agonist group required shorter stimulation and had higher numbers of oocytes retrieved as compared with the high-responder agonist-group. No case of severe OHSS was observed in the antagonist–agonist group. The use of flexible multidose GnRH-antagonist protocol with GnRH-agonist for final oocyte maturation, in high-responder patients, eliminates the risk of OHSS but results in decreased implantation and pregnancy rates.

Complications of IVF and ovulation induction

The frequency and importance of complications of IVF and other ovulation induction (OI) are poorly known. We examined the occurrence of serious complications and miscarriages leading to hospitalization or operation after IVF (including microinjections and frozen embryo transfers) and OI treatment (with or without insemination). Women who received IVF (n = 9175) or OI treatment (n = 10 254) 1996-1998 in Finland were followed by a register linkage study until 2000. After the first IVF treatment cycle, 14 per 1000 women had a serious case of OHSS (ovarian hyperstimulation syndrome), with 23 per 1000 throughout the study period (mean of 3.3 treatments). The corresponding values after OI were very low. The rates of registered ectopic pregnancies and miscarriages after IVF were nine and 42 respectively per 1000 women, with corresponding rates after OI of eight and 42. Infections and bleeding were not common after IVF and even rarer after OI. Overall, 15% of IVF and 8% of OI women had at least one hospital episode during the study period. Though there was a low risk of complications after each IVF treatment cycle, repeated attempts resulted in serious complications for many women, and these occurred much more often than after ovulation induction alone.

Invitro fertilization outcome in severe ovarian hyperstimulation syndrome: An age-matched contemporaneous control study.

Aim: Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening, iatrogenic complication of assisted reproduction and has been associated with poor invitro fertilization outcome. The aim of the present study was to evaluate the pregnancy rate and outcome following severe OHSS, at a single center over a three-year period. Methods: The incidence of severe OHSS at the IVF Center, National University of Singapore, in Singapore, was 4% (48 cases over 1200 cycles) during the period of 1997-2000. The present retrospective study compared 48 cases of severe OHSS to 144 age-matched, contemporaneous controls without OHSS. Results: The total gonadotropin required for severe OHSS group was found to be lower than for that of controls (2664.06±768.29IU vs 3349.58±2003.73IU), although duration of stimulation was similar. The OHSS group was associated with a fivefold increase (OR 5.293, 95% CI: 2.116-13.238) in pregnancy rate compared to controls (87.5% vs 56.9%; P<0.05). Late OHSS was more common (38/48 cases) and had a pregnancy rate of 97% per embryo transfer. There was no significant difference in the multiple pregnancy (54% vs 48%; P>0.05) and miscarriage rates (14% vs 7.3%; P>0.05) between the groups. Conclusion: Severe OHSS at our center were mostly late onset. The pregnancy rate was significantly higher, but multiple pregnancy and miscarriage rates were not significantly increased when compared to the age-matched contemporaneous controls. (Reprod Med Biol 2005; 4: 207-211).

A case of ovarian hyperstimulation syndrome associated with the methylenetetrahydrofolate reductase mutation gene

To report a case of ovarian hyperstimulation syndrome with methylenetetrahydrofolate reductase (MTHFR) gene 677T homozygosis mutation and A1298C gene heterozygosis mutation. Case report. A pregnant woman in an academic hospital. A woman with ovarian hyperstimulation syndrome. Nadroparin was administered for 2 weeks at a dosage of 200 IU/kg twice per day and then once per day; also administered once per day were folates, 5 mg; B6 vitamin, 15 mg; and B12 vitamin, 1 mg. Clinical follow-up. Delivery was regular within the set time limits, and the fetus was born alive and in good health. We believe that MTHFR mutation research could be executed in women before ovarian stimulation treatment, but other observations are necessary to support this recommendation.

Comparison of GnRH agonists and antagonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome

During IVF or ICSI cycles, ovarian hyperstimulation syndrome (OHSS) is a major problem. The aim of this prospective, multicentre, comparative study (using historical controls) was to assess the efficacy of a GnRH antagonist protocol in preventing OHSS in selected patients who had experienced OHSS or had been at risk of OHSS in their previous IVF/ICSI attempt. Patients underwent a new cycle where the same gonadotrophin protocol was used [same dose of recombinant FSH (rFSH)] but a different protocol was used for pituitary desensitization: cetrorelix 0.25 mg multiple-dose antagonist instead of GnRH agonist long protocol. Cetrorelix 0.25 mg was administered daily, starting when the leading follicle reached a diameter of 14 mm. In other words, rFSH was administered in the new cycle according to the dosage and the step-up or step-down modalities used during the previous cycle, independently of ultrasound findings and serum estradiol (E(2)) levels. Eighty-seven patients entered the study. Out of the 87 cycles involving GnRH agonists, 49 (56.3%) were cancelled and out of the 87 involving GnRH antagonists 28 (32.2%) were cancelled [McNemar's test; 95% confidence interval (CI) -35.8% to -11.2%; P < 0.001]. After GnRH agonist cycles, we recorded 24 cases of OHSS (18 moderate and six severe; 27.6%), whereas after the GnRH antagonist cycles there were 10 cases of OHSS (nine moderate and one severe; 11.5%) (95% CI-26.4% to -5.7%; P = 0.006). There was a statistically significant reduction in the total number of follicles with a diameter >10 mm (Wilcoxon's test; Z = 6.1; P < 0.001) and of E(2) levels on the day of HCG administration (2538 versus 4322.4 pg/ml; P < 0.001) in the GnRH antagonist cycles versus GnRH agonist cycles. Twenty-nine patients had an embryo transfer in the first cycle (76.3% of oocyte retrievals) and 57 in the cycle using GnRH antagonist (96.6%). This 20.3% difference was also significant (Z-test; 95% CI 6.8-36.0%; P = 0.003). After the antagonist cycles, 18 pregnancies (20.7 per initiated cycle; 31.6% per embryo transfer) were obtained. Although this study presents some limitations owing to the use of historical controls, our data show a favourable effect of GnRH antagonists in reducing the incidence of OHSS and the number of assisted fertilization cycles cancelled because of the risk of OHSS in high responder patients. As a consequence, GnRH antagonist plus gonadotrophin administration could also increase the percentage of oocyte retrievals and embryo transfers in this high risk group of patients.

Unexpected Pregnancy and Ovarian Hyperstimulation Syndrome Following Ivf Cycle with all Embryos Frozen: A Case Report

We report a patient with late onset of severe ovarian hyperstimulation syndrome (OHSS) combined with pregnancy subsequent to in vitro fertilization (IVF) cycles without embryo transfer, which is extremely rare. This case of severe OHSS was in a 27-year-old woman who underwent controlled ovarian hyperstimulation (COH), oocyte collection, and IVF. All embryos were cryopreserved to prevent possible OHSS due to an extremely high level of estradiol (6,357 pg/mL). No embryo was transferred in this cycle. However, she was admitted 7 days after oocyte retrieval because of massive ascites and enlarged ovaries. Pregnancy was diagnosed by serum β-human chorionic gonadotropin (51 mIU/mL) 4 days later. Fetal heartbeat was demonstrated by ultrasound examination during follow-up. Prompt recognition of pregnancy and proper medical intervention should be given to patients with late-onset OHSS, even if no embryo was transferred in the fresh cycle. We suggest that more preventive procedures for OHSS may be necessary for patients undergoing COH and receiving no embryo transfer, such as oocyte donors and patients with polycystic ovary syndrome.

Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile

Ovarian hyperstimulation syndrome (OHSS) in IVF/ICSI cycles may occur either as an early (early onset) or a late pattern (late onset). This observational study was designed to identify whether the onset pattern of OHSS is associated with the occurrence of pregnancy and the early pregnancy outcome. Among 4376 consecutive IVF/ICSI cycles, 113 patients were hospitalized for OHSS after IVF/ICSI treatment and were included in the study. The setting was the Dutch-speaking Brussels Free University Hospital, between June 2000 and September 2002. Early OHSS occurred in 53 patients, and late OHSS complicated 60 patients. A total of 96.7% of the late OHSS cases occurred in a pregnancy cycle and were more likely to be severe than the early cases (P < 0.05). Although in the early group there initially was a 41.5% positive HCG rate per cycle, the clinical pregnancy rate fell to 28.3% as a result of a significantly (P < 0.05) increased preclinical pregnancy loss rate compared with the non-OHSS patients (31.8 versus 88.3%, respectively). The ongoing pregnancy rate per cycle was 14.4% in the early and 26.4% in the late group. Multiple pregnancy rates were high in both groups (40 and 45.5%, respectively), but only in the late group did the incidence reach significance compared with the non-OHSS population (45.5 versus 29.1%, P = 0.02). Estradiol levels and number of follicles on the day of HCG were significantly higher in the early OHSS group. However, there was no difference in estradiol values on the day of hospital admittance between the two groups. In addition, the number of follicles on the day of HCG administration appears to be a better prognostic indicator for the occurrence of severe OHSS than the estradiol values (87% of the severe cases had > or = 14 or follicles of a diameter > or = 11 mm, whereas only 50% of them had an estradiol value > or = 3000 ng/l). The early OHSS pattern is associated with exogenously administered HCG and a higher risk of preclinical miscarriage, whereas late OHSS may be closely associated with the conception cycles, especially multiple pregnancies, and is more likely to be severe. Further clarification of these two different clinical entities could have implications for research protocols as well as for preventive and management strategies for OHSS.

N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate–resistant patients with polycystic ovary syndrome

To evaluate the effect of N-acetyl-cysteine (NAC), a mucolytic drug with insulin sensitizing properties, as an adjuvant therapy in subjects with polycystic ovary syndrome (PCOS) resistant to clomiphene citrate (CC). Placebo-controlled, double-blind randomized trial. University-based hospital and private infertility practice. One hundred fifty women diagnosed with CC-resistant PCOS, aged 18-39 years undergoing therapy for infertility were included. The patients were assigned randomly to receive either NAC 1.2 g/d (group I) or placebo (group II) with CC 100 mg/d for 5 days starting at day 3 of the cycle. Ovulation rate and pregnancy rate (PR). Combination of CC and NAC significantly increased both ovulation rate and PR in women with CC-resistant PCOS (49.3% vs. 1.3% and 21.3% vs. 0%, respectively). No cases of ovarian hyperstimulation syndrome (OHSS) were reported in the NAC group; two cases of miscarriage (12.5%) were reported. The NAC as an adjuvant to CC was more effective than placebo for CC-resistant patients with PCOS. It is safe and well tolerated.

Letrozole in IVF/ICSI cycles to optimize the number of mature follicles and to maintain estradiol levels within the “safe” range

Background Controlled ovarian stimulation may lead to a large cohort of follicles and high estradiol levels, both of which increase the risk of ovarian hyperstimulation syndrome (OHSS). There may be a reduction in pregnancy rates in this milieu. Addition of letrozole in our pilot study showed a trend towards reducing the number of small and intermediate sized follicles. Estradiol levels were also lower than those expected for the follicle number. The aim of this study is to look for any statistically or clinically significant difference on adding letrozole to the controlled ovarian stimulation protocol. Methods Forty two consecutive intracytoplasmic sperm injection (ICSI) cycles where letrozole was used were compared with 40 in patients with polycystic ovarian syndrome (PCOS) in whom letrozole was not given. Results A fall in the estradiol levels for the expected number of follicles was seen. There were no cases of moderate or severe OHSS in the letrozole group. There was a reduction in the cleavage rates in the letrozole group. There were no differences in the clinical pregnancy rates or miscarriage rates.

A standardized protocol with minimal monitoring for controlled ovarian stimulation of egg donors results in improved pregnancy rates

Controlled ovarian stimulation (COS) of egg donors involves a number of differences in ovum stimulation protocols designed to optimize the number and quality of viable oocytes for their respective recipients while minimizing the risks of ovarian hyperstimulation syndrome (OHSS) for the donor. For many years, Boston IVF's egg donor program used a standard donor protocol (SDP) for their egg donors. At the end of 2002 we designed a new ovum donation protocol (NDP) involving less monitoring and standardized dosing regimen. We compared the results of this new protocol with the standardized protocol. Retrospective, non-randomized, comparative analysis. Anonymous egg donors undergoing COS from January 2001 to December 2003 using either the NDP (N = 172) or the SDP (N = 162) were compared. All donors were treated with the long gonadotropin releasing hormone (GnRH) agonist protocol. For the SDP, treatment started on cycle day 3 with follitropin alfa (r-hFSH) 225 IU. Ultrasound (US) evaluations and estradiol (E2) levels were measured on cycle day 5 and continued every 1–3 days until administration of human chorionic gondadotropin (hCG). The NDP started on cycle day 3 with 300 IU r-hFSH for 2 days. E2 was measured on stimulation days 3 and 5. On day 3, if the E2 >150 pg/mL, r-hFSH was decreased by 75 IU; if E2 <75 pg/mL, r-hFSH was increased by 75 IU. On day 5, if the E2 >500 pg/mL, the r-hFSH was decreased by 75 IU; if E2 <150 pg/mL, r-hFSH was increased by 75 IU. Following day 5, the patient was monitored with US only. For both groups, hCG was administered when 2 leading follicles were >18 mm. Statistical analyses were performed using Chi square, Fisher exact of Student's two-tailed t-tests, as required, with p < 0.05 indicating statistical significance. One patient (0.6%) in the NDP group and two patients (1.2%) in the SDP group were hospitalized for one day for OHSS management. One patient (0.6%) in the NDP group and none in the SDP group underwent a transvaginal paracentesis procedure for OHSS. The NDP for COS of anonymous egg donors results in a significant decrease in the number of E2 and US evaluations and significantly higher pregnancy rates and number of frozen embryos. In addition, there was no appreciable increase in the number of cases of severe OHSS. We conclude that an aggressive standardized protocol with minimal monitoring results in less inconvenience for the donors and significantly improves pregnancy rates without increasing the number of adverse events.

Prevalence of thrombophilia in women with severe ovarian hyperstimulation syndrome and cost-effectiveness of screening.

To determine the prevalence of markers of thrombophilia in patients with severe ovarian hyperstimulation syndrome (OHSS) and to evaluate the cost-effectiveness of screening for factor V Leiden and prothrombin G20210A mutations in women entering an IVF program. Case-control study and cost-effectiveness analysis. University teaching hospital. Women undergoing controlled ovarian hyperstimulation for IVF complicated by severe OHSS (group 1, n = 20), women undergoing controlled ovarian hyperstimulation for IVF without development of severe OHSS (group 2, n = 40), and healthy control subjects (group 3, n = 100). Investigation of markers of thrombophilia. Estimate of number of IVF patients needed to detect a case of severe OHSS and thrombosis associated with thrombophilia genetic mutation was calculated from the available data. Blood samples were analyzed for inherited (resistance to activated protein C due to the factor V Leiden mutation; prothrombin G20210A mutation; deficiencies in antithrombin, protein C, and protein S) and acquired (presence of circulating lupus anticoagulants and/or anticardiolipin antibodies; deficiencies of antithrombin and protein S; acquired protein C resistance) markers of thrombophilia. The cost of preventing one thrombotic event in a patient developing severe OHSS after IVF and having factor V Leiden or prothrombin G20210A mutations was calculated. None of the OHSS patients or controls had antithrombin, protein C, or free protein S deficiencies. All of them tested negative for antiphospholipid antibodies. No patient in group 1 had the factor V Leiden or prothrombin G20210A mutations. The prothrombin G20210A mutation was detected in 1 out of 40 patients (2.5%) in group 2. Both factor V Leiden and prothrombin G20210A mutations were detected in two of the control subjects (2%) (group 3). The estimated cost of preventing one thrombotic event arising as a consequence of screening for factor V Leiden and prothrombin G20210A mutation is a minimum of 418,970 dollars and 2,430,000 dollars, respectively. The prevalence of thrombophilia is not increased in women with severe OHSS. Screening for V Leiden and prothrombin G20210A mutation in an IVF general population is not cost-effective.

Ovarian hyperstimulation syndrome is predicted by HCG serum concentration following the ovulatory dose of HCG

Background and Significance: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovarian stimulation therapy. The severe form is rare, with a reported incidence of 0.5 to 5%. Human chorionic gonadotropin (hCG) is routinely used to induce oocyte maturation and may be a risk factor for development of OHSS. Objective: The purpose of this retrospective study was to evaluate the relationship between serum hCG concentration the day after ovulatory dose of hCG and the subsequent occurrence of OHSS. Materials and Methods: Following ovarian stimulation, hCG was administered via intramuscular injection. Doses varied from 2,500 to 20,000 IU, based on each patient’s weight, age, estradiol concentration, and follicle count. Serum hCG concentrations were measured 12 to 16 hours after injection. Mild OHSS was defined as a constellation of symptoms, including intractable nausea, abdominal distension, vomiting, or diarrhea requiring office visit evaluations. Severe OHSS was defined as a progression of illness accompanied by one or more of the following: tense ascites requiring aspiration, laboratory abnormalities, progressive oliguria, and respiratory difficulty. Logistic regression was used to evaluate the effect of follicle count and hCG serum concentration following the ovulatory dose on the probability of occurrence of OHSS. Results: The study group included 877 IVF cycles that received ovulatory hCG dose between January, 1998 and August, 2003 at a private infertility clinic. Serum concentrations of hCG the day after ovulatory dose ranged from 37 to 731 IU/L, with a mean of 172 IU/L. The study group included 27 cases of OHSS, of which 12 were severe. Follicle count (p<0.0001) and hCG serum concentration (p=0.02) were significant predictors of OHSS (including both mild and severe cases). Similarly, follicle count (p<0.0001) and hCG serum concentration (p=0.05) were significant predictors of severe OHSS. In both models, lack of fit was not significant. Tabled 1[hCG] IU/LEstimated prob(OHSS)Estimated prob(severe OHSS)Follicle countFollicle count15253545152535451000.2%1.6%11.5%50.5%0.1%0.7%4.3%22.6%2000.4%2.7%17.9%63.1%0.2%1.2%7.2%33.7%3000.6%4.5%26.8%74.2%0.3%2.0%11.8%46.9%4001.0%7.3%38.1%82.8%0.5%3.4%18.9%60.6% Open table in a new tab Conclusions: The hCG serum concentration has a dramatic effect on the probability of OHSS and severe OHSS. Patients with low follicle count have relatively low risk of OHSS regardless of hCG level. Clinicians should use restrained hCG dosage, particularly when 25 or more follicles are present.

Effects of low-dose metformin in Japanese women with clomiphene-resistant polycystic ovary syndrome.

Background and Aims: The aim of the present prospective observational study was to evaluate the effects of low-dose, short-term metformin, in combination with clomiphene (CC), in CC-resistant infertile Japanese women with polycystic ovary syndrome (PCOS). Methods: Metformin therapy was administered orally (one 250mg tablet, twice daily) to 15 CC-resistant infertile patients with PCOS, beginning on the third day of progestin-induced withdrawal bleeding, and was continued for 14days in the first cycle. In the event of anovulation, 100mg/day of CC was given during subsequent cycles on days 5-9, in addition to the aforementioned dose of metformin. Hormonal and metabolic parameters were measured on the second or third days of the first cycle and also the fourth cycle, following an overnight fast. Results: None of the 15 women successfully ovulated during the first cycle with metformin treatment alone. After two subsequent cycles with the combination of CC and metformin, ovulation was confirmed in 17 of 29 cycles (61%) and in 13 of 15 patients (87%). Two women became pregnant within 2months of therapy (13%). There were no cases of ovarian hyperstimulation syndrome. Following three cycles of metformin therapy, a slight reduction in serum levels of luteinizing hormone (LH), free testosterone, androstenedione, dehydroepiandrosterone sulfate, hemoglobin A1c and total cholesterol was seen, while serum LH/follicle-stimulating hormone ratio and serum level of low-density lipoprotein cholesterol were significantly decreased. Although there were no significant differences between the responder (n=11) and non-responder (n=2) groups at baseline, the levels of plasma fasting insulin was significantly higher and fasting glucose/insulin ratio was significantly lower in the non-responder group compared with the responder group after three cycles. Conclusion: Low-dose, short-term metformin, combined with CC, can improve ovulation rates in CC-resistant infertile Japanese women with PCOS. (Reprod Med Biol 2004; 3: 19-26).

A Mutation in the Follicle-Stimulating Hormone Receptor as a Cause of Familial Spontaneous Ovarian Hyperstimulation Syndrome

Ovarian hyperstimulation syndrome (OHSS) occurs mainly after excessive stimulation of the ovaries by exogenous gonadotropins administrated in the context of in vitro fertilization procedures (iatrogenic OHSS). Recently, spontaneous and recurrent occurrence of the disease (spontaneous OHSS) was shown in two families to be caused by mutations affecting the follitropin receptor (FSHr). The two mutant FSHr (T449I, D567N) harbor aminoacid substitutions in the serpentine portion of the receptor and display abnormally high sensitivity to the pregnancy hormone hCG, thus providing a satisfactory explanation to the phenotype. In addition, mutant D567N showed also increased sensitivity to thyrotopin (TSH) and displayed increase in basal (ligand-independent) activity. In this report, we describe a new familial case of recurrent OHSS. The affected women were heterozygous for a different mutation involving codon 449, where an alanine was substituted for threonine. Similar to D567N, the T449A FSHr mutant shows an increase of its sensitivity to both hCG and TSH, together with an increase in basal activity. Together with the two previous studies, this report shows that inappropriate stimulation of the FSHr by hCG is a cause of spontaneous OHSS.

Ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome

Follicle Stimulating Hormone (FSH) secreting pituitary adenoma causing spontaneous ovarian hyperstimulation syndrome

Objectives: As a spontaneously occurring entity, ovarian hyperstimulation syndrome (OHSS) presents as an atypical and perplexing array of symptoms. It has been described in association with pregnancy in polycystic ovarian disease patients, severe primary hypothyroidism, and granulosa cell tumors. We present a case of spontaneous OHSS resulting from a FSH-secreting pituitary adenoma.

A prospective randomized clinical trial comparing 150 IU and 225 IU of recombinant follicle-stimulating hormone (Gonal-F*) in a fixed-dose regimen for controlled ovarian stimulation in in vitro fertilization treatment

ObjectiveTo compare fixed daily doses of the recombinant FSH (rFSH) Gonal-F (150 IU vs. 225 IU) for ovarian stimulation in IVF-ET. DesignSingle-center prospective, randomized study. SettingAssisted conception unit of a university hospital. Patient(s)One hundred twenty-four women aged 23–41 years participated in the study. Exclusion criteria were as follows: FSH of >10 IU/L, polycystic ovarian syndrome, one ovary or previous ovarian surgery, previous poor response to ovarian stimulation, or ovarian hyperstimulation syndrome (OHSS). Intervention(s)Randomized to commence 150 IU or 225 IU of Gonal-F per day without dose alterations during treatment. Main outcome measure(s)Number of oocytes retrieved and total rFSH dose. Result(s)More oocytes were retrieved in women aged ≤32 years in the 225-IU compared with the 150-IU group (11.8 ± 8.0 vs. 7.0 ± 5.8). In older women (≥33 years), the number of oocytes retrieved in the two groups were similar. No significant differences were found for fertilization rate, number of embryos formed and cryopreserved, and pregnancy rates between the two groups. The total rFSH dose used was higher in the 225-IU group (2,595.0 ± 510.0 vs. 1,897.5 ± 457.5 IU). The cancellation rate due to insufficient ovarian response was higher in the 150-IU group (15.0% vs. 3.3%). All cases of ovarian hyperstimulation syndrome (n = 4) occurred in the 225-IU group. Conclusion(s)Two hundred twenty-five IU is more effective than 150 IU in younger women but requires a higher total dose of Gonal-F. The use of 225 IU in older women did not result in a higher oocyte yield, suggesting that 225 IU of rFSH does not compensate for the age-related decline in the number of follicles available for stimulation.