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The interaction between the prostaglandin production of the human endometrium and myometrium has been further investigated using intact pieces of endometrium in homogenates of myometrium. There was an increase in the production of 6 oxo PGF, alpha when these tissues were incubated together, whereas there was no change in the production of PGE, PGF2 alpha or 13, 14 dihydro 15 - keto PGF2 alpha. This endometrial - myometrial interaction could have important implications in the pathogenesis of menorrhagia.

Three different regimens for termination of early pregnancy by medical means were compared to vacuum aspiration. Women seeking therapeutic abortion of pregnancy (less than or equal to 56 days amenorrhoea) were allocated to one of four treatment groups: (1) vacuum aspiration (n = 28); (2) 1 mg vaginal pessary of a prostaglandin analogue (gemeprost) every 3 h for up to 5 pessaries (n = 30); (3) the antigestogen (RU 486--mefipristone) 150 mg per day for 4 days by mouth (n = 20); (4) RU 486 in the same dose as group 3 together with 1 mg gemeprost on day 3 (n = 19). Complete abortion occurred more often in women treated with vacuum aspiration (96%), gemeprost alone (97%) and RU 486 plus gemeprost (95%) than in those treated with RU 486 alone (60%). In women receiving up to five gemeprost pessaries alone vomiting occurred in 7 (23%) and diarrhoea in 10 (33%); 16 (53%) required parenteral opiates for relief of pain. Side-effects and analgesic requirements were much reduced in the women who received RU 486 alone or in combination with a single gemeprost pessary. There was no difference in the number of days of vaginal bleeding after abortion between the four groups although there was wide individual variation (mean 10 days, range 1-34). These results confirm that medical induction of abortion in early pregnancy with prostaglandin vaginal pessaries is as effective as vacuum aspiration and that the dose can be reduced five-fold without loss of efficacy when used in combination with RU 486.

The return to ovulation following early abortion (less than or equal to 56 days amenorrhea) has been assessed after both vacuum aspiration under general anesthesia (N = 14) and menstrual induction with 16,16 dimethyltrans-delta 2PGE1 methyl ester in pessary form (N = 18). The urinary excretion of hCG, total estrogen and pregnanediol was similar in each group. There was an initial rapid decline in hCG excretion (t1/2 48 h), reaching 10% of the pre-treatment value after 6 days. Twenty-nine (91%) women showed a luteal phase rise in pregnanediol excretion, with ovulation occurring on day 29 (16-37) and 24 (16-32) in the vacuum aspiration and prostaglandin groups, respectively (median (range) NS). The wide range in the return of ovarian activity was related to the variation in decline of progesterone secretion (as reflected by excretion of pregnanediol) by the corpus luteum. Asynchrony between the ovarian and menstrual cycles resulting from a delay to ovulation presents a major constraint to the use of early pregnancy interruption as a routine method of fertility control.

Abortion was attempted in 39 women in early pregnancy (less than 56 days amenorrhea) with the progesterone antagonist RU486 alone (150 mg per day for 4 days) or in combination with a PG analogue, 16,16-dimethyl-trans-delta 2-PGE1 (Gemeprost) in the form of a 1 mg vaginal pessary. Complete abortion was also attempted in 5 women who received RU486 together with 2 X 1 mg PG pessaries. Vaginal bleeding followed by complete abortion occurred in 18 of 19 women who received RU486 + 1 mg PG pessary as compared to only 12 of 20 women who received RU486 alone (P less than 0.01). All women who received RU486 + 2 mg Gemeprost had a complete abortion. The onset of crampy abdominal pain (median: 3 vs 4 days) and vaginal bleeding (3 vs 3 days) was similar in the RU486 and RU486 + PG groups, respectively. Slightly less than half the patients in both groups had nausea and/or vomiting, but the incidence did not differ from that occurring prior to treatment. The mean duration (range) of vaginal bleeding [RU486 alone: 10 (0,29) days and RU486 + PG: (5,34) days], and the measured blood loss [RU486: 53 (2,227) ml and RU486 + PG: 81 (32,222) ml] did not differ significantly between the two treatments. It is concluded that the combination of RU486 and a single PG vaginal pessary is a highly effective means of inducing therapeutic abortion in early pregnancy and offers an alternative to surgery.

The hospital records of 548 consecutive patients undergoing midtrimester pregnancy termination by the local administration of prostaglandins (PGs) have been reviewed. Most women (352 or 64%) were single and 322 (59%) were pregnant for the 1st time. 2/3 of the patients (361 or 66%) were between 12-16 weeks pregnant, whereas 7 (1%) were considered to be more than 20 weeks pregnant. In 401 cases (92%), abortion was performed under Item 2 of the 1967 Abortion Act, although Item 4 was cited in 34 (81%) of those individuals with a pregnancy of greater than 17 weeks duration. Apart from 10 women (2%) in whom severe hemorrhage was documented, the major complication rate was less than 1%. The use of local PGs provides a safe, effective treatment method for therapeutic abortion in the 2nd trimester.

A translocation of genetic material involving the long arm of the X chromosome and the heterochromatic portion of the Y chromosome is reported in a young woman. The phenotypic effect of this translocation and loss of almost half of the long arm of the X chromosome is described.

The development of anti-progesterones has provided a probe to examine the role of progesterone both in the normal cycle and in pregnancy. The most widely used of these agents, mifepristone, appears to act both directly at the endometrial progesterone receptor, and centrally by reducing circulating gonadotrophin concentrations. In addition, ovarian steroidogenesis may be modified. The clinical application of these agents for the interruption of pregnancy will be considered in the following chapters.

Endometrial stromal cells and isolated endometrial glands obtained from women during days 6-26 of the ovarian cycle were cultured for 24 h in the presence of the progesterone antagonists 17 beta-hydroxy-11 beta-[4-dimethylaminophenyl]17 alpha-[1-propynyl] estra-4,9-dien-3-one (RU486) and 17 beta-hydroxy-11 beta-[4-dimethylaminophenyl] 17 alpha-[3-hydroxy-1-propenyl]estra-4,9-dien-3-one (ZK 98734). Both steroids stimulated prostaglandin F2 alpha (PGF2 alpha) production by stromal cells in a dose-dependent manner, in doses ranging from 10-1000 nM. Progesterone (100 nM) inhibited RU486 stimulation, except at the highest dose of antiprogestin. PGE2 was produced in smaller amounts than PGF2 alpha, but, when measurable, it also increased in the presence of RU486. In contrast, RU486 did not increase PG production by endometrial glands. In an experiment to determine the effect of pretreatment, stromal cells were incubated for 24 h with 1000 nM progesterone or RU486 (all with 100 nM 17 beta-estradiol) with either 30 or 6 microM arachidonic acid. These six batches of cells were incubated for a second 24 h with either progesterone or antiprogestin. Cells pretreated with the higher dose of arachidonic acid had a marked increase in PGF2 alpha production during the second 24 h only when also pretreated with progesterone. This finding suggests that progesterone allows an accumulation of PG precursor in a suitable accessible pool. Pretreatment with progesterone also allowed a greater conversion of PG to its 13,14-dihydro-15-keto metabolite. These results suggest that antiprogesterone steroids may act as menstrual regulators by: stimulating endogenous PG production within the endometrial stromal cells and inhibiting PG catabolism.

In most developed countries in which therapeutic abortions are legal, termination of pregnancy is performed at between 8 and 12 weeks of gestation. Because the complication rate after this procedure rises with increasing gestation, there would be many advantages in inducing abortion before the eighth week ('menstrual induction'). With the increasing availability of highly sensitive methods of detecting human chorionic gonadotropin, pregnancy can now be diagnosed as early as 10-14 days after conception. The uterus can be surgically evacuated safely and simply by suction aspiration under local anaesthesia. However, a safe and effective method of inducing abortion by medical means would be a useful and cheaper alternative. Of the potentially useful compounds, only derivatives of prostaglandins E and F administered by vaginal pessary have so far been shown to be effective. Although the rate of haemorrhage and infection is low, 10-30% of women experience moderate side-effects of pelvic pain, diarrhoea and/or vomiting. The possibilities are discussed of reducing the incidence of side-effects by different methods of release or using prostaglandins in combination with other compounds such as antigestogens which might lower the therapeutic threshold.

The effects of four medical treatments have been assessed on menstrual blood loss (MBL) and endometrial prostaglandin (PG) concentrations in 30 women with objectively confirmed menorrhagia. Patients were randomly treated with danazol, 200 mg daily (n = 6), mefenamic acid, 500 mg three times daily during menses (n = 8), norethisterone, 5 mg twice daily from day 15-25 of the cycle (n = 8) or a progesterone-impregnated coil releasing 65 micrograms progesterone daily (n = 8). Endometrial biopsies were obtained in the mid-luteal phase before and after treatment in 23 cases, and assayed for PG content using radioimmunoassay. Treatment with norethisterone had no effect on either MBL or the concentration of PGs in the endometrium. MBL was significantly reduced after treatment with mefenamic acid (P = 0.05, n = 6) and the progesterone coil (P less than 0.05, n = 6), and was reduced in each of 4 cases treated with danazol in whom endometrial biopsies were available. Although there was no consistent change in endometrial PG concentrations in either the mefenamic acid or danazol groups, the lower MBL after insertion of the progesterone coil was associated with a reduced endometrial content of PGE, PGF2 alpha and "total" PG (6oxo PGF1 alpha + PGE + PGF2 alpha)-P = 0.05. Whereas the cyclooxygenase inhibitor mefenamic acid is likely to exert its effect on endometrial PGs at the time of menstruation itself, the continuous administration of progesterone throughout the menstrual cycle could result in both an impairment in estrogen receptor generation leading to reduced estrogen-mediated cyclooxygenase activity, and an increase in endometrial PG metabolism.

We studied the value of vaginal progesterone (P4) in suppressing serum LH concentrations and restoring normal luteal phase serum LH concentrations before administration of exogenous gonadotropins in anovulatory women with the polycystic ovarian syndrome (PCOS). P4 (50 mg every 12 h) was administered by vaginal suppository to 9 women (18 cycles) for 14 days before ovulation induction with human menopausal gonadotropin (hMG) and hCG. Serum LH, FSH, estradiol, P4, and PRL levels were measured daily. A biphasic effect on LH secretion occurred during P4 administration. Peak serum LH levels occurred on day 5 (125% of basal levels; P less than 0.05) of vaginal P4 suppository use, followed by a progressive fall (P less than 0.05) to 79% of basal levels, but serum LH levels were still higher than those in normal women despite achieving physiological luteal phase P4 concentrations. Ovulation occurred in 56% of cycles after P4 and hMG/hCG treatment and in 65% of control cycles after hMG/hCG alone. In 7 women, serum LH was measured at 10-min intervals for 6 h before and after vaginal P4 administration for 10 days. LH pulse frequency decreased from 7.4 +/- 1.1 to 4.4 +/- 1.2 pulses/6 h (P less than 0.01), and LH pulse amplitude increased from 3.8 +/- 1.8 to 6.1 +/- 2.9 IU/L (P less than 0.01) after P4 administration. We conclude that vaginal P4 (50 mg every 12 h) 1) produces serum P4 concentrations within the normal range for the luteal phase of the menstrual cycle; 2) elevates serum LH, but not FSH, within 5 days; 3) decreases LH pulse frequency and increases LH pulse amplitude after 10 days, but does not normalize serum LH values; and 5) fails to improve the results of subsequent ovulation induction with exogenous gonadotropins in patients with PCOS.

The use of gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries for the termination of pregnancy in the early second trimester has been further investigated. Of 113 women between 12 and 16 weeks gestation, 93 (82%) aborted within 24 hours of the administration of 4.4 +/- 0.1 1 mg gemeprost pessaries. The mean induction-abortion interval was 881 +/- 31 minutes. Successful abortion was achieved in 16 of the remaining 20 women after a second course of gemeprost pessaries without the need for oxytocin supplementation. There were no serious complications. Crampy abdominal pain and vaginal bleeding started after 275 and 756 minutes respectively. Twenty-two (19%) patients did not require pain relief during treatment, but 90 (80%) required parenteral opiates. Vomiting and diarrhoea occurred in 16 (14%) and 23 (20%) cases respectively. The safe induction of therapeutic abortion in 96% of women using vaginal prostaglandin alone offers an acceptable alternative to surgical evacuation in the early second trimester.