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The establishment of human pregnancies by the use of fertilization in vitro and placing cleaving embryos into the uterus is described. Preovulatory oocytes were aspirated at laparoscopy from the ovaries of patients soon after the beginning of the mid-cycle surge of luteinizing hormone (LH) during the natural cycle. The LH surge was identified by assaying 3-hourly samples of urine, and measurements of oestrogens in 24-hour samples were used to assess follicular growth. The surge of LH was identified in 68 patients and it showed a diurnal rhythm. Preovulatory oocytes were aspirated from most of the patients. Fertilization and cleavage occurred in 34 instances, and 32 embryos were put into the mother via the cervical canal. Four patients became pregnant. There were indications that a diurnal rhythm played a role in establishing cleaving embryos, each of the four pregnancies occurring when the embryos were placed in late evening. Each of the pregnancies resulted from oocytes which were aspirated from their follicles 24 hours or longer after the L h surge began. Details are given of three abortive pregnancies in patients given gonadotrophins to stimulate the maturation of oocytes used for fertilization in vitro. 737

The program for in vitro fertilization at Bourn Hall began in October 1980. Various types of infertility have been treated during this time using the natural menstrual cycle or stimulation of follicular growth with antiestrogens and gonadotrophins. Follicular growth and maturation are assayed by urinary estrogens and LH, monitored regularly during the later follicular stage. Many patients had an endogenous LH surge; others needed an injection of HCG to induce ovulation. All oocytes were recovered by laparoscopy. Wide variations occurred in the time interval between the start of the LH surge and oocyte recovery and between oocyte recovery and insemination. Embryos taken between the one- and the eight-cell stage were replaced into their mother, no standard procedure being adopted for all patients. The results of all treatments including patient's responses during the follicular and luteal phases, oocyte recovery, fertilization, cleavage, replacement, implantation, abortion, and birth and the effect of factors such as replacing two or more embryos, maternal age, and previous obstetric history are described in detail. The incidence of implantation after embryo replacement improved from 16.5% initially to 30% currently. More than 118 babies have been born, and many pregnancies are continuing.

There have been several causes of infertility attributed to gamete quality, congenital anatomical abnormalities and surgical complications. Published research into the reasons for failure of implantation of embryos has been confined to histochemical and histological studies of the endometrium. This paper presents preliminary data from an ongoing study to test the hypothesis that poor uterine perfusion is a cause of failure of implantation of embryos. It would follow that poor uterine perfusion is a cause of infertility. One-hundred-and-fifty-three patients who had been unsuccessful in conceiving despite three previous in-vitro fertilization attempts have been studied. Doppler ultrasound studies of the ascending branch of the uterine artery, during spontaneous ovarian cycles, revealed a poor mid-secretory uterine response in 48% of patients studied. Patients with poor mid-secretory uterine response were treated with orally administered hormone therapy to improve the mid-secretory uterine response prior to subsequent embryo replacement. The results of subsequent in-vitro fertilization therapy in patients with good uterine response and in women with improved uterine response after hormone therapy are presented. The numbers of patients in each group are insufficient for statistical analyses, but the trends observed support the hypothesis that poor uterine blood flow is a cause of infertility. Further evaluation is warranted.

Doppler studies of the uterine artery using an off-set Doppler transducer with a mechanical sector imaging transducer indicate clear changes in uterine perfusion during the ovarian cycle. In this study, 16 volunteers had Doppler studies performed at least twice weekly during spontaneous ovarian cycles. Endocrine assays were performed on each occasion to measure plasma oestradiol, progesterone and luteinizing hormone levels. Conventional criteria to assess uterine impedance using systolic/end diastolic ratio and Resistance Index were modified to obtain meaningful results and a new flow velocity wave form classification is presented. The results indicate increasing uterine perfusion with rising levels of plasma oestradiol and progesterone and a direct correlation with falling oestrogen levels in the follicular phase. We conclude that off-set mechanical sector duplex systems can be used effectively to monitor uterine responses to the hormone environment.

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