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This study was performed to improve our knowledge and understanding of the needs of women affected by female genital mutilation. We looked at the types of complications of these practices which present to a large metropolitan women's hospital in order to determine how we can appropriately treat and support affected women. This was an observational study of women from countries with a high prevalence of female genital mutilation who presented to the Royal Women's Hospital between October, 1995 and January, 1997. Fifty-one patients with a past history of female genital mutilation who were attending the hospital for antenatal or gynaecological care consented to participate in the study. We found that 77.6% of women identified as having had female genital mutilation had undergone infibulation. More than 85% of the women in our study reported a complication of the procedure. The major complications were dyspareunia, apareunia and urinary tract infections; 29.4% of these women required surgery to facilitate intercourse. In our study group there was no difference in Caesarean section rates between the women who had previously delivered in Australia compared with those who had delivered in Africa. Women who have had a female genital mutilation procedure have specific needs for their care which present challenges to both their general practitioners and obstetrician/gynaecologists. These women have significant complications related to their procedure including social and psychosexual problems which require sympathetic management.

The three-dimensional cocrystal structures of ovine prostaglandin G/H synthase-1 (PGHS-1) with S-flurbiprofen and murine PGHS-2 with S-flurbiprofen and indomethacin reveal that the carboxylate acid groups of these nonsteroidal anti-inflammatory drugs (NSAIDs) form a salt bridge with the guanidinium group of Arg120 in PGHS-1 and Arg106 in PGHS-2. Mutagenesis studies confirmed that the Arg120 residue of PGHS-1 is critical for binding of substrate and inhibitors through ionic interactions of its guanidinium group with the carboxylate moieties of arachidonic acid and certain NSAIDs. We report here that the analogous R106E substitution in human PGHS-2 results in a catalytically active enzyme with a 30-fold higher Km value for arachidonic acid. Comparison of the inhibition of hPGHS-2(R106E) with wild-type hPGHS-2 by 11 structurally diverse selective and nonselective PGHS inhibitors revealed a 0-1000-fold decrease in inhibitory potency on the mutant enzyme. The loss of inhibitory potency of NSAIDs on hPGHS-2(R106E) could not be correlated with the presence or absence of a carboxylate functional group in the inhibitor, as was demonstrated previously for the PGHS-1(R120E) mutant, or with the selective or nonselective nature of the PGHS inhibitor. The decreases in the inhibitory potencies on hPGHS-2(R106E) by the carboxylate-containing NSAIDs flurbiprofen, indomethacin, meclofenamic acid, and diclofenac on hPGHS-2(R106E) were 965-, 48-, 5.5-, and 4.5-fold, respectively. The nonuniversal requirement for interaction of the carboxylate group of certain NSAIDs with the Arg106 residue in hPGHS-2 is supported by the observation that the methyl ester derivative of indomethacin was a more potent inhibitor than indomethacin on both hPGHS-2 and hPGHS-2(R106E). The greatest loss of potency for inhibition of hPGHS-2(R106E) was observed with the hPGHS-2-selective sulfonamide-containing inhibitors NS-398 and flosulide. The PGHS-2-selective inhibitor DuP697 and a desbromo-sulfonamide analogue of DuP697 displayed equivalent potency on hPGHS-2(R106E) and hPGHS-2. The change in inhibitory potency of NS-398 on hPGHS-2(R106E) was due to a difference in the kinetics of inhibition, with NS-398 displaying time-dependent inhibition of hPGHS-2 but time-independent inhibition of PGHS-2(R106E). The time-dependent inhibition of hPGHS-2 by DuP697 was not affected by the presence of the R106E mutation. We conclude that the Arg106 residue of hPGHS-2 is involved in binding arachidonic acid and certain NSAIDs, but interactions with Arg106 are not a universal requirement for inhibition by either carboxylate-containing NSAIDs or PGHS-2-selective inhibitors.

A retrospective analysis was carried out to assess the outcome of ovarian stimulation on in vitro fertilization when human chorionic gonadotropin (hCG) was administered after 5, 6, or 7 days of continuously rising plasma estradiol (E2). There was no significant difference in the number and size of large follicles in each group although the number of small follicles (less than 15 mm in diameter) decreased significantly after 7 days of E2 rise. After hCG injection in the 7-day group, the E2 level fell below the previous day's value in 40% of patients, whereas a similar fall was observed in only 16% of patients in the 5- and 6-day groups. In those cycles where a luteinizing hormone surge occurred, most surges were detected during the seventh day of E2 rise. The pregnancy rate was 31% when hCG was given after 6 days of rising E2, 21% after 5 days, and 14% after 7 days. In patients achieving pregnancy in the 6-day group, 53% of embryos were derived from leading follicles. In the 7-day group, only 15% of embryos associated with pregnancies were derived from leading follicles. These results strongly suggest that in stimulated cycles, hCG should be administered after 6 days of continuously rising E2. It is therefore postulated that 6 days of rising E2 represents a mean optimal period for follicular growth and oocyte maturation in stimulated cycles.

The gestation sac size in pregnancies resulting from in-vitro fertilization (IVF) and embryo transfer have been compared with those in spontaneous pregnancies. Small-for-dates gestational sac sizes were found in 36% of the IVF pregnancies. This proportion held for both singleton and multiple pregnancies. With increasing gestation beyond 8 weeks the gestation sac volume increasingly approached normal. In contrast to spontaneous conceptions, IVF pregnancies had a low rate of pregnancy loss once fetal heart movements were demonstrated, when the gestation sac size was small-for-dates. Small sac size in an IVF pregnancy may lead to the misdiagnosis of a failed pregnancy.

The cyclic enkephalin analogue H-Tyr-cyclo[-D-N delta-Orn-Gly-Phe-Leu-] (1-c) and the rigid narcotic alkaloid 7 alpha-[(1R)-1-hydroxy-1-methyl-3-phenylpropyl]-6,14- endo-ethenotetrahydrooripavine (PEO) were studied by using computer graphics methods to investigate potential geometrical congruencies of their respective pharmacophoric elements. Particular emphasis was placed on the relative spatial disposition of the tyramine moiety and the additional aromatic ring that occurs in both molecules. A three-dimensional vector map was generated defining the locus of the C21 aromatic ring for all those conformers of PEO having up to 10 kcal above the minimum energy conformer. A systematic conformational search on the cyclic peptide afforded four allowable sets of conformers whose side chain of the phenylalanine residue coincided with the vector map of PEO. Local energy minima for the peptide within the revised mutual vector space were found and subjected to bimolecular energy refinement with correspondingly local energy minima for the opiate alkaloid. Several low-energy conformers of the cyclic peptide were identified that permitted a good fit with the alkaloid provided that the tyramine moiety of the respective molecules does not coincide. In the designated conformations the basic nitrogen of the former occupies a distinct geometrical locus, and the side chain of the leucine residue has no structural correlate in the alkaloid.