Goserelin therapy before surgery for uterine fibroids.
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Adult↗
Biomedical subjects
D T Baird
Publications and source records attributed to D T Baird.
A model for follicular selection and ovulation: lessons from superovulation.
A model for selection of the preovulatory follicle during the normal ovarian cycle is proposed. During menstruation the concentration of FSH rises to a level high enough to "activate" a single small antral follicle (2-4 mm dia.) so that it can produce large amounts of oestradiol. As the follicle develops, the concentration of FSH is suppressed below this threshold level by the secretion of oestradiol and inhibin. The dominant follicle becomes increasingly sensitive to FSH so that it continues to develop in an environment which inhibits development of other follicles. Multiple ovulation can be achieved by extending the period during which the level of FSH remains above this threshold level (e.g. during treatment with clomiphene or gonadotrophins). Although multiple ovulation occurs when the gate is widened in this way, the follicles are never completely synchronous as they continue to grow at approximately the same rate. Current evidence suggests that ovulation occurs at random between the two ovaries in successive cycles and that the corpus luteum exerts an inhibitory effect on folliculogenesis by suppressing the secretion of FSH and LH. These observations are compatible with the hypothesis that while small antral follicles are recruited continuously, at all stages of reproductive life, selection of the dominant follicle requires the unique gonadotrophic environment which is only present in the early follicular phase. The follicle of the month is, therefore, selected by chance because it is at the right place at the right time.
Animals↗
The effects of danazol, mefenamic acid, norethisterone and a progesterone-impregnated coil on endometrial prostaglandin concentrations in women with menorrhagia.
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.
Biopsy↗
Prostaglandin-induced pregnancy termination: further studies using gemeprost (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) vaginal pessaries in the early second trimester.
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.
Abortifacient Agents↗
Endometrial prostaglandins in women with abnormal menstrual bleeding.
Endogenous prostaglandin (PG) concentrations (6oxo PGF1 alpha, PGE, PGF2 alpha) have been measured by radioimmunoassay in the endometrium of women with objectively assessed menstrual blood loss (MBL). The concentration of PGE and "total" PG (6oxo PGF1 alpha + PGE + PGF2 alpha) was greater in the endometrium of those women with heavy menses (median MBL 152 ml (range 86,432) n = 16) than in those individuals with a normal menstrual loss (MBL 59 ml (18,78) n = 18). The concentrations of PGE and PGF2 alpha were similar in each group, but the concentration of 6oxo PGF1 alpha was significantly less than that of both PGE and PGF2 alpha. In 19 individuals, specimens of endometrium were incubated for 1 and 2 hours in modified 199 medium to assess PG release. There was a direct correlation between endogenous PG content and the production of 6oxo PGF1 alpha, PGE, PGF2 alpha and "total" PG in the first hour, which persisted for the second hour with PGF2 alpha and "total" PG. Endometrial PGs may play a role in the mechanism underlying menstruation; however the observed relationship between the prostanoids and MBL will vary with different experimental methods.
6-Ketoprostaglandin F1 alpha↗
Shrinkage of uterine fibroids during therapy with goserelin (Zoladex): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot.
Thirteen premenopausal women with uterine fibroids were treated for a maximum of 6 months with a long-acting agonist of luteinizing hormone-releasing hormone (LH-RH), goserelin (Zoladex depot, ICI Pharmaceuticals, Macclesfield, UK) 3.6 mg, administered subcutaneously every 28 days. A 55% reduction (range, 38% to 84%) in uterine volume assessed by ultrasound was obtained. The greatest reduction (30%) was apparent within the first treatment cycle regardless of whether treatment was started in the early follicular or the luteal phase. Fibroid regression was inversely correlated with urinary estrogen concentration. Treatment was well tolerated and only one subject withdrew from the study before its scheduled completion. Following cessation of therapy, ovulatory menstruation returned within 3 months in the majority of the subjects, but this was accompanied by a rapid regrowth of the fibroids. This medical approach to the management of fibroids merits further investigation but as yet cannot be regarded as an alternative to surgery.
Adult↗
Clinical applications of LHRH analogues.
What is the current state of clinical application of inhibition of gonadal activity with LHRH agonists or antagonists? It seems unlikely in the short term that antagonists will be widely applied due to the short-acting nature of the present compounds and their troublesome side-effects. In contrast clinical studies with a number of agonists have demonstrated their efficacy in producing a hypogonadal state safely with rapid recovery following cessation of therapy. Although nasal administration may be suitable for short-term suppression (up to 28 days) it seems likely that long-acting depot preparations will be useful for more prolonged suppression. Perhaps the easiest application to determine will be the profound suppression required to produce medical castration in hormone-dependent tumours. The combination of agonist and receptor blocker is attractive particularly when the receptor blocker like cyproterone acetate also suppresses the release of LH, FSH and adrenocorticotrophic hormone. In cancer of the prostate and breast the side-effects due to inhibition of secretion of testosterone and oestradiol are tolerable although the only benefit over castration is the avoidance of minor surgery. The agonists should improve significantly the existing treatment for precocious puberty, endometriosis, uterine fibroids, polycystic ovary syndrome (PCO) and induction of ovulation although large scale trials comparing different therapies and doses are required. Finally, the concept of combination therapies to block further the influence of steroid hormones suggests challenging possibilities for even more effective therapy.
Administration, Intranasal↗
Relative ability of modified versions of the hamster oocyte penetration test, incorporating hyperosmotic medium or the ionophore A23187, to predict IVF outcome.
This study was designed to assess the relationship between IVF outcome and the results obtained with two modified versions of the zona-free hamster oocyte penetration test in which the spermatozoa were pre-incubated with either hyperosmotic medium or the divalent cation ionophore A23187. When the former system was used, a poor correlation with IVF outcome was observed. Samples screened prior to IVF exhibited a 60% false negative rate (failed penetration test, successful IVF), while for those assessed concurrently with IVF, the equivalent figure was 85.7%. Addition of A23187 optimized the penetration system giving higher levels of sperm--oocyte fusion and a more accurate prediction of the capacity of the spermatozoa to fertilize human ova in vitro. With this system the false negative rate was 4.3% for screened samples and 0% for those assessed simultaneously with IVF. These results suggest that the A23187-enhanced system may be of value as a screening criterion for IVF.
Animals↗
Post-fertilization polyploidy in human preimplantation embryos fertilized in-vitro.
The development of in-vitro fertilization (IVF) and embryo transfer (ET) as a treatment for certain forms of infertility has emphasized the need for more information on why so many preimplantation embryos fail to develop beyond the very early cleavage stages. Analysis of nuclei from embryos that had ceased to grow or that were morphologically abnormal was carried out using one of two techniques: measurement of the DNA content of their nuclei, or observation of the number of Y chromosomes per nucleus. It was found that there was a correlation between the length of time in culture and abnormal development of polyploidy in a number of the cells. On the other hand, a small proportion of polyploid cells observed in a morphologically normal expanded blastocyst probably represents the normal precursors of polyploid trophoblast cells as observed in other mammalian species.
Blastocyst↗
Suppression of ovarian activity by Zoladex depot (ICI 118630), a long-acting luteinizing hormone releasing hormone agonist analogue.
A long-acting LHRH agonist, Zoladex depot 3.6 mg, was administered as a monthly s.c. injection to seven premenopausal volunteers for a maximum of 6 months, starting in the luteal phase of the cycle. Transient stimulation of gonadotrophin release was observed 24 h after the initial depot, followed by sustained suppression of plasma LH, while FSH levels returned to the normal range. Plasma oestradiol concentrations fell to early follicular phase values within 14 d. Twice-weekly monitoring of urinary oestrone-3-glucuronide and pregnanediol demonstrated inhibition of ovulation and almost complete suppression of ovarian follicular activity throughout therapy. All the subjects became amenorrhoeic. Mean plasma testosterone concentrations were also significantly reduced while androstenedione remained within the pretreatment range. SHBG concentrations were not significantly reduced. After cessation of therapy, postovulatory menstruation occurred within 80 d of administration of the last depot.
Adult↗
Evidence for gonadal desensitization after pulsatile therapy in women with amenorrhoea?
Sixteen women with primary and secondary amenorrhoea were treated with pulsatile GnRH administered subcutaneously. Ovulation was successfully induced in 6/8 women with hypogonadotrophic hypogonadism; and in 2/2 women with idiopathic hyperprolactinaemia; but in only 3/6 women with amenorrhoea associated with an elevated LH:FSH ratio. Using serial blood sampling, we were unable to demonstrate the establishment of a physiological pattern of gonadotrophin secretion in the presence of an apparently normal menstrual cycle. Nor did we observe a consistent relationship between injection of GnRH and the resultant gonadotrophin response. A reduction or total cessation of both pituitary and gonadal sensitivity to GnRH was observed in four women. Possible reasons for these findings are discussed.
Adult↗
Luteal phase after ovarian hyperstimulation.
The luteal phase was investigated in 17 women with normal menstrual cycles and tubal infertility who were superovulated with clomiphene (9 cycles), clomiphene plus pulsatile human menopausal gonadotrophin (hMG) (12 cycles) and clomiphene plus pulsatile follicle stimulating hormone (FSH) (11 cycles) during an in-vitro fertilization programme. Follicles were aspirated 34-36 h after the onset of the endogenous LH surge. Urinary total oestrogen levels during the first 6 days of the luteal phase were significantly higher, the duration of the luteal phase was significantly shorter and the luteal levels of urinary pregnanediol were significantly lower in the two combination treatment cycles than in the clomiphene only cycles. When the three treatment groups were combined the mid-luteal peak pregnanediol levels and the duration of the luteal phase showed significant negative correlations with plasma or urinary oestrogen levels during the follicular and the luteal phase. It is suggested that the luteal function in cycles superovulated with clomiphene/hMG or clomiphene/FSH is disrupted and this is related to the high amounts of circulating oestrogen.
Clomiphene↗
Production of inhibin bioactivity by human granulosa-lutein cells: stimulation by LH and testosterone in vitro.
Granulosa-lutein cells from human preovulatory ovarian follicles were cultured for up to 12 days to determine their capacity for production of inhibin in vitro. Using a highly sensitive sheep pituitary cell bioassay we observed time-related changes in basal inhibin production, maximal during the first 4 days of culture (48 +/- 15 units/million cells every 2 days, means +/- S.E.M.; n = 5 patients) falling to values five times lower by day 12. After 4-6 days of culture in the presence of human LH (hLH) inhibin production was enhanced in proportion to the hLH dose (maximum five fold at 10 ng/ml); hFSH over the same dose-range had no effect. Progesterone production in response to hLH followed a similar pattern to that of inhibin and was also unresponsive to hFSH. In the absence of exogenous aromatase substrate, basal and gonadotrophin-stimulated oestradiol production was negligible after the first 4 days. Addition of testosterone (1 mumol/l) to the culture medium increased oestrogen formation several hundred-fold with no effect on progesterone production. Inhibin production was also increased by 50-100% in the presence of testosterone. These results demonstrate that LH and testosterone stimulate the production of inhibin by granulosa-lutein cells in vitro. It is suggested that inhibin production occurs under hormonal control in the corpus luteum as well as in the preovulatory follicle in the human ovary.
Biological Assay↗
Specific binding sites for LH/chorionic gonadotrophin, low-density lipoprotein, prolactin and FSH in homogenates of human corpus luteum. I: Validation of methods.
The specific binding of 125I-labelled human chorionic gonadotrophin (hCG), human low-density lipoprotein (hLDL), human FSH (hFSH) and human prolactin (hPRL) to homogenates of human corpus luteum tissue was measured. Specific binding of 125I-labelled hCG was dependent on the temperature and duration of incubation, was inhibited by divalent metal ions or chelating agents, and increased linearly with homogenate concentration. Recovery of bound hormone was more effective using Millipore filtration or polyethylene glycol precipitation compared with centrifugation alone. Binding of 125I-labelled hCG was inhibited specifically by low levels of hCG and human LH (hLH) but not by ovine LH or bovine LH. Incubation of human luteal tissue with ice-cold citrate buffer (pH 3) released more than 90% of specifically bound 125I-labelled hCG within 5 min. This treatment inactivated LH receptors, but did not affect the immunoactivity of hLH released, enabling the measurement of released hormone by radioimmunoassay. Scatchard plots of binding of 125I-labelled LDL to human corpus luteum demonstrated a single class of binding sites. Binding was saturable, increased linearly with increasing concentration of homogenate, and was displaceable by low concentrations of unlabelled LDL. Binding of 125I-labelled hPRL to human luteal homogenates was increased by Mg2+ and was specific for lactogenic hormones (human prolactin, human growth hormone and ovine prolactin). Binding of 125I-labelled hFSH was not dependent on divalent metal ion concentration (in marked contrast to hFSH binding to immature pig granulosa cell receptors) and was displaced by hFSH preparations but not by hPRL, ovine LH or hCG at 1 microgram/ml. These results establish optimal conditions and hormone specificities for the measurement of human luteal gonadotrophin and LDL receptors, and methods for the estimation of hLH/hCG endogenously bound to human corpus luteum tissue.
Animals↗
Specific binding sites for gonadotrophin-releasing hormone, LH/chorionic gonadotrophin, low-density lipoprotein, prolactin and FSH in homogenates of human corpus luteum. II: Concentrations throughout the luteal phase of the menstrual cycle and early pregnancy.
Corpora lutea were obtained from 52 women undergoing laparotomy during the luteal phase of the menstrual cycle. In addition, stromal, thecal and granulosa cell preparations were obtained from seven women undergoing ovariectomy during the late follicular-preovulatory phase of the cycle. The specific binding of a 125I-labelled gonadotrophin-releasing hormone (GnRH) agonist [D-Ser(But)6] GnRH(1-9)-ethylamide (buserelin) and of human chorionic gonadotrophin (hCG), human FSH (hFSH), human prolactin (hPRL) and human low-density lipoprotein (hLDL) to tissue homogenates was measured under optimal conditions. Bound LH/hCG was estimated by elution with acid-citrate buffer, followed by radioimmunoassay of released hormone. Binding of GnRH agonist, though variable, was highest in mid-luteal corpus luteum and high binding was also present in three out of four corpora lutea of pregnancy. Binding of LH/hCG increased significantly with luteinization, reaching maximal levels in the mid-luteal phase before falling significantly. Occupancy of LH receptors by bound LH was relatively constant throughout the luteal phase (10.7-35.3%), but occupancy increased to greater than 90% in corpora lutea from early pregnancy. Binding of hFSH was variable, with only five out of 50 corpora lutea having binding greater than 10 pg/micrograms DNA. Similarly, hPRL binding varied markedly with only six out of 44 having binding greater than 50 pg/micrograms DNA. Binding of LDL was highest in the early- to mid-luteal phases of the cycle. In corpora lutea from all stages of the menstrual cycle (excluding corpora albicantia), GnRH agonist binding was highly correlated with the levels of unoccupied and occupied LH receptors (P less than 0.001; n = 49 and n = 48 respectively) and with LDL receptors (P less than 0.002; n = 49). Binding of GnRH agonist was also correlated with PRL binding (P less than 0.05; n = 21) but not with FSH receptors (P greater than 0.4; n = 25). In addition, LDL binding was associated with PRL (P less than 0.005; n = 21) and FSH receptors (P less than 0.05; n = 25) and with endogenously bound LH (P less than 0.03; n = 48), but not with unoccupied LH receptors (P = 0.8; n = 49). Moreover, in corpora lutea from the mid-luteal phase, there was a strong association between GnRH agonist binding and LDL receptors (P less than 0.02; n = 23). The correlations between GnRH agonist binding and a number of important indices of luteal function suggest a physiological role for GnRH-like factors in the human corpus luteum.
Corpus Luteum↗
Local prostaglandin administration for mid trimester abortion: a retrospective analysis.
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.
Abortion, Induced↗
Does treatment with bromocriptine influence the course of hyperprolactinaemia?
Twenty-two women with hyperprolactinaemia without evidence of microadenoma, either untreated (n = 3), treated with bromocriptine for a total of less than 1 year (n = 12), or treated with bromocriptine for a total of more than 1 year (n = 7) were followed up by retrospective case-note review for at least 53 months. More than 50% of the women showed a fall in serum prolactin concentrations by more than 40% over the period of follow-up. The occurrence of a fall did not appear to be related to either length of treatment with bromocriptine or to the occurrence of pregnancy. Some women elected to remain untreated, despite symptoms, in preference to taking tablets and having to use contraception. The wisdom of leaving patients untreated in the light of these findings is discussed.
Adult↗
Therapeutic abortion in early pregnancy with antiprogestogen RU486 alone or in combination with prostaglandin analogue (gemeprost).
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.
Abortifacient Agents↗