Non-response to ovarian stimulation in normogonadotrophic, normogonadal women: a clinical sign of impending onset of ovarian failure pre- empting the rise in basal follicle stimulating hormone levels

The most important aspect of diminished ovarian reserve is the associated decline in reproductive potential. Assessment of ovarian reserve is mainly based on measurement of early follicular phase follicle stimulating hormone (FSH) concentration. The objective of this study was to report the identification of a group of 12 infertile women initially diagnosed as having unexplained or anovulatory infertility, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins. All developed ovarian failure within a relatively short time span. Non-response to ovarian stimulation was defined by failure to achieve development of follicles >12 mm and failure to raise oestradiol concentration >350 pmol/l in two successive cycles of human menopausal gonadotrophin (HMG) doses of up to five ampoules per day for 5-8 days. Within a mean of 9 months following the failed attempts of ovarian stimulation the mean day 3 FSH concentrations rose from 5.4 +/- 2.7 IU/l to 53.5 +/- 19.7 IU/l. In these patients, day 3 FSH concentration failed to indicate the low ovarian reserve manifested only by lack of clinical response to treatment with gonadotrophins which was the first sign of impending ovarian failure. We conclude that women with normal early follicular phase serum FSH concentrations who do not respond to ovarian stimulation by HMG are at risk of developing ovarian failure within several months.      

Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements

Low-dose follicle stimulating hormone (FSH) regimens for induction of ovulation for women with polycystic ovaries have succeeded in reducing the rate of ovarian hyperstimulation syndrome (OHSS) almost to nil and the rate of multiple pregnancies to a minimum of 6%. This has been achieved by reaching, but not exceeding, the threshold level of FSH, starting with a daily dose of 75 IU for 14 days, using small incremental dose rises where necessary, and inducing uniovulation in 70% of cycles. Conception rates are as good, if not better, than those achieved with conventional therapy. The miscarriage rate is still relatively high (20-25%) and obese women fare worse. Serum oestradiol concentrations and the number of large and intermediate follicles on the day of human chorionic gonadotrophin administration are much lower, in parallel with lower serum FSH concentrations. Inhibin values increase with the rise in serum FSH concentrations but those of luteinizing hormone decrease steadily throughout the follicular phase. New data using recombinant hFSH (rhFSH), rather than urinary gonadotrophin as the ovarian stimulant, demonstrate that treatment time is shortened. However, the ideal regimen has still to be formulated.     

Controlled ovarian hyperstimulation: are we monitoring the appropriate sex-steroid hormones?

We prospectively evaluated the behavior of serum 17-hydroxyprogesterone (17-OHP), sex-steroid hormones, and C-reactive protein (CRP) levels in 27 patients during controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). While routine measurement of COH via serum 17-OHP may replace estradiol (E(2)) and progesterone levels, additional studies are needed to elucidate the ceiling level of serum 17-OHP beyond which intervention is required to prevent severe ovarian hyperstimulation syndrome.     

LH as a diagnostic criterion for polycystic ovary syndrome in patients with WHO II oligo/amenorrhoea

Elevated LH is common in polycystic ovary syndrome (PCOS), but is not part of the diagnostic criteria. LH concentrations are usually assessed in the early 'follicular' phase when it is suppressed, and therefore the prevalence is underestimated. In this study, LH is measured during the 'specific oligomenorrhoeic phase', when LH is least suppressed, and its importance as a diagnostic tool for PCOS is evaluated. Patients presenting with oligo- or amenorrhoea between 2002 and 2006 were selected, with the exclusion of women with WHO III oligoamenorrhoea, hyperprolactinaemia or with wrongly timed endocrine measurements. A total of 252 patients were included (198 oligo/amenorrhoeic PCOS patients and 54 oligo/amenorrhoeic controls). Mean LH concentrations were higher in PCOS patients than in controls (11.0 versus 4.1 IU/l, P < 0.001). The receiver operating characteristics (ROC) curve showed an optimal cut-off for LH of > or =6.5 IU/l, resulting in a sensitivity of 84%, specificity of 78% and a likelihood ratio of 3.8, and elevated LH concentrations predicted PCOS accurately in 93%. In conclusion, elevated LH concentrations are found in a large majority of PCOS patients when measured at the appropriate time, and could be used as an additional diagnostic test to differentiate between oligo/amenorrhoeic PCOS patients and other causes of oligo- or anovulation.     

Factors determining early pregnancy loss in singleton and multiple implantations

BACKGROUND: The incidence of first trimester pregnancy loss is much lower in IVF twin pregnancies than in IVF singleton pregnancies. The objective of this study was to determine which embryonic and maternal factors contribute to this finding. METHODS: Retrospective data analysis of the outcome of 1593 pregnancies after day 3 double-embryo transfer (DET) after IVF or ICSI treatment. RESULTS: Of 1148 single implantations at 6 weeks, 936 (81.5%) were ongoing pregnancies. Of 445 multiple implantations at 6 weeks, 354 (79.6%) were ongoing multiple pregnancies, 80 (17.9%) were ongoing singleton pregnancies and 11 (2.5%) ended in a spontaneous abortion. Total pregnancy loss was 18.5 and 2.5% (P < 0.001) in singleton and twin gestations, respectively. Loss per gestational sac was 18.5 and 11.46% (P < 0.001), respectively. Determinants contributing to the continuation of gestation beyond 6 weeks were young maternal age, possibility to cryopreserve embryos and short GnRH agonist flare-up stimulation protocol. Whereas factors promoting multiple implantation at 6 weeks of gestation were young maternal age, high cumulative embryo score (CES), male infertility, long stimulation protocol and thick endometrium. CONCLUSIONS: Although multiple implantation at 6 weeks is predominantly determined by (morphological) embryo quality, the continuation of pregnancy beyond 6 weeks becomes more dependent on the combination of genetic and developmental potential of the embryo(s) and an optimal uterine milieu.     

Endocrine studies of the ovulatory disturbances in Wilson's disease (hepatolenticular degeneration)

Women with Wilson's disease may have severe oligomenorrhea or amenorrhea whose cause is unknown. The endocrine profile of four such cases was investigated by measuring basal values and the response to dynamic tests of hypothalamic, pituitary, thyroid, and adrenal function, which all proved normal. Ovarian function was disturbed, as witnessed by low estradiol, high total testosterone (T) levels with normal free T, and mildly elevated androstenedione. An interference of ovarian follicular aromatase activity possibly due to copper intoxication could explain these findings as the cause of the ovulatory disturbances of Wilson's disease.     

Enhancement of chemically induced bladder carcinoma by cyclosporin A

The effects of cyclosporin A (CsA) on the induction of bladder carcinoma were investigated in Wistar rats using N-butyl-N (4 hydroxybutyl) nitrosamin (BBN) as a known initiator of carcinogenesis. Rats treated with 0.05% BBN+5 mg/kg per day CsA or 0.05% BBN+12.5 mg/kg per day CsA developed a dose-dependent (two to fourfold) enhancement of bladder tumor expansion and infiltration as compared to those treatment with 0.05% BBN alone. In control rats receiving CsA at doses of 5 mg/kg per day or 12.5 mg/kg per day, no bladder carcinoma occurred. All CsA-treated groups, with or without 0.05% BBN, displayed slight or moderate medullary atrophy of the thymus. The results indicate that immunosuppression with CsA enhances the induction of bladder tumors by BBN. Furthermore, the immunosurveillance theory that effective expression of the immune response may be important in the control of tumor development was confirmed in the carcinogenesis of epithelial cell tumors.     

Management of infertility and prevention of ovarian hyperstimulation in women with polycystic ovary syndrome

Anovulatory infertility is a prevalent presenting feature of polycystic ovary syndrome (PCOS). Restoration of ovulation might be achieved by ovarian stimulation or by reducing insulin and LH concentrations. Clomiphene citrate is the first-line ovulation-inducing agent, usually followed by direct stimulation with follicle stimulating hormone (FSH), if unsuccessful. The prevalent complications of ovarian hyperstimulation syndrome and multiple pregnancies can largely be avoided by administering FSH in a low dose and individualized regimen. Hyperinsulinaemia can be corrected by weight loss or insulin-sensitizing agents, such as metformin, which alone or in combination with other agents are capable of restoring ovulation. Advice about weight loss is critical in modern management of PCOS and infertility. Laparoscopic ovarian drilling produces similar results to FSH stimulation, and in vitro fertilization/embryo transfer (IVF/ET)-if all else fails-produces excellent results. The possible use of aromatase inhibitors, novel insulin sensitizers and in vitro maturation of oocytes is still being evaluated. The plethora of treatment options available today ensures that the great majority of women who are subfertile due to PCOS can be treated successfully.