2. The enigmatic PCOS
Polycystic ovary syndrome (PCOS) is a major cause of female infertility. Despite substantial effort, the etiology and pathogenesis of PCOS and polycystic ovaries (PCO) in women remain unknown. A case-control study was performed in order to determine whether overexpression of CYP17 or CYP11A messenger (m)RNA in theca cells from polycystic ovaries is related to polymorphic regions in the gene promoters that may increase transcription. Fifty-one women with PCOS and 280 regularly cycling controls underwent genotyping. Thecal cells were obtained from 23 women with PCOS and 51 controls. Ovarian tissue was obtained from women with PCOS undergoing wedge resection for treatment of their infertility and from controls undergoing ovariectomy for indications unrelated to the study. Expression of mRNA in theca cells was measured by using competitive reverse transcriptase polymerase chain reaction. Genotype analysis for polymorphisms in the CYP11A and CYP17 promoters was performed by using polymerase chain reaction. Although expression of CYP11A and CYP17 mRNA was higher in women with PCOS, no significant dose effects of CYP11A or CYP17 alleles were observed with respect to serum testosterone; follicular fluid androstenedione, estradiol, and androstenedione-to-estradiol ratio; or CYP11A or CYP17 mRNA expression. Overexpression of CYP17 and CYP11A mRNA in theca cells from polycystic ovaries is explained by polymorphic differences in the gene promoters.
Recent studies in laboratory animals have documented a link between dysfunction of two oocyte growth factors, growth differentiation factor-9 (GDF-9) and bone morphogenetic factor-15 (BMP-15), and aberrant folliculogenesis. Because aberrant follicle development is a hallmark of PCOS, it was wondered whether the expression patterns of these growth factors might be disrupted in PCOS and PCO oocytes. To address this issue, the pattern and level of expression of GDF-9 and BMP-15 mRNA in ovaries from normal cycling (n = 12), PCOS (n = 5), and PCO (n = 7) patients was studied. In situ hybridization studies showed that the expression of GDF-9 and BMP-15 is restricted to the oocytes in all ovaries examined. Interestingly, a decreased level of GDF-9 signal was observed in developing PCOS and PCO oocytes, compared with normal. This difference was evident throughout folliculogenesis, beginning at recruitment initiation and continuing through the small Graafian follicle stage. By contrast, there were no qualitative or quantitative changes in the expression of BMP-15 mRNA in PCOS oocytes during folliculogenesis. There were also no significant differences between normal and PCOS and PCOs in the levels of the mRNA encoding the housekeeping gene, cyclophilin. Together, these results indicate that the expression of GDF-9 mRNA is delayed and reduced in PCOS and PCO oocytes during their growth and differentiation phase. Because oocyte-derived GDF-9 is crucial for normal folliculogenesis and female fertility, it was suggest that a dysregulation of oocyte GDF-9 expression may contribute to aberrant folliculogenesis in PCOS and PCO women.
Daneshmand S, Weitsman SR, Navab A, Jakimiuk AJ, Magoffin DA. (2002)
Overexpression of theca-cell messenger RNA in polycystic ovary syndrome does not correlate with polymorphisms in the cholesterol side-chain cleavage and 17alpha-hydroxylase/C(17-20) lyase promoters. Fertil Steril. 77:274-280
Teixeira Filho FL, Baracat EC, Lee TH, Suh CS, Matsui M, Chang RJ, Shimasaki S, Erickson GF. (2002) Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 87:1337-1344.
3. Risk of cancer following IVF
A historical cohort analysis was performed to assess whether ovarian hyperstimulation and IVF increase the risk for cancer. Five thousand twenty-six women who underwent IVF between 1981 and 1992 were studied. Cancer incidence rates were determined through linkage to the National Cancer Registry and were compared with expected rates with respect to age, sex, and place of birth. Twenty-seven cases of cancer were observed, and 35.6 were expected (standardized incidence ratio, 0.76 [95% CI, 0.50-1.10]). Eleven cases of breast cancer were observed, whereas 15.86 were expected (standardized incidence ratio, 0.69 [95% CI, 0.46-1.66]). One case of ovarian cancer and 1 case of cervical cancer were observed, compared with 1.74 and 1.73 cases expected, respectively. The type of infertility, number of IVF cycles, and treatment outcome did not significantly affect risk for cancer. Thus, in a cohort of women treated with IVF, no excess risk for cancer was noted.
Dor J, Lerner-Geva L, Rabinovici J, Chetrit A, Levran D, Lunenfeld B, Mashiach S, Modan B.
(2002) Cancer incidence in a cohort of infertile women who underwent in vitro fertilization. Fertil Steril. 77:324-327.
4. Early pregnancy loss in IVF as a positive predictor of subsequent IVF success
A retrospective cohort study was performed to determine the significance of biochemical pregnancy losses and clinical spontaneous abortion (SAB) on outcomes of future IVF cycles. Patients with an early pregnancy loss had a greater ongoing clinical pregnancy rate in the immediate next cycle when compared with those women who had a negative pregnancy test (37.3% vs. 27.3%). Patients with a history of a biochemical pregnancy or a clinical spontaneous abortion had an ongoing clinical pregnancy rate in the next cycle of 38.4% and 42.3%, respectively, compared with 27.3% in women who had a history of a negative pregnancy test. The cumulative pregnancy rate after the first IVF attempt was 54.1% in patients with a previous biochemical pregnancy loss, 61.4% in those with a previous clinical SAB, and 46.5% in women with a previous negative pregnancy test. Thus, women who experience an early pregnancy loss after IVF have a greater likelihood of success in subsequent IVF cycles when compared with patients who fail to conceive.
Bates GW Jr, Ginsburg ES (2002) Early pregnancy loss in in vitro fertilization (IVF) is a positive predictor of subsequent IVF success. Fertil Steril. 77:337-341.