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Biomedical subjects

I T Cameron

Publications and source records attributed to I T Cameron.

At least 19 recordsLinked to original sources
PubMed1992

Presence of messenger ribonucleic acid for endothelin-1, endothelin-2, and endothelin-3 in human endometrium and a change in the ratio of ETA and ETB receptor subtype across the menstrual cycle.

The aim of the present study was to determine whether mRNA for the three endothelin peptides (endothelin-1, endothelin-2, and endothelin-3) and the two known receptor subtypes (ETA and ETB) was present in human endometrium at different stages of the menstrual cycle (menstrual, early and mid-proliferative, and early, mid-, and late secretory). Endometrium was obtained from women undergoing surgery for benign disease, and total RNA was extracted using a guanidinium isothiocyanate method. mRNA for endothelin peptide and receptor was detected using the reverse transcriptase-polymerase chain reaction with nested oligonucleotide primers. mRNA for endothelin-1, endothelin-2, and endothelin-3 was demonstrated throughout the menstrual cycle, and three splice variants of mRNA encoding endothelin-3 were found in all samples. The ratio of ETA to ETB receptor mRNA was found to change throughout the menstrual cycle. In the proliferative phase, amplified cDNA product was almost exclusively confined to the ETA receptor, whereas an increase in the amplified product of the ETB receptor cDNA was seen in the secretory and menstrual phases. These studies show that mRNA for endothelin-1, endothelin-2, and endothelin-3 is present in human endometrium at all stages of the menstrual cycle and suggest that different physiological actions of the endothelin peptides may be mediated through changes in the ratio of the ETA and ETB receptor subtypes.

Base Sequence↗
PubMed1992

Endothelin-like immunoreactivity in human endometrium.

Endothelin-like immunoreactivity (ET-IR) was detected immunocytochemically in glandular epithelium and vascular endothelium of human endometrium and myometrium. Primary antibody was raised in rabbits against the carboxy-terminal heptapeptide of endothelin 1 (ET-1), ET-1(15-21), and compared with antibodies raised against the cyclized amino-terminal, ET-1(2-13), and commercially obtained antibodies against the whole ET-1 or ET-3 molecule. Binding was visualized using the peroxidase technique in sections counter-stained with haemalum. Staining was seen in each of 15 sections from eight women in the proliferative (five) or secretory (three) phase of the cycle. Intense staining was present in the cytoplasm of endometrial glands and vascular endothelium, and was greatest at the endometrial-myometrial junction. The pattern of staining was similar with all primary antibodies tested. The demonstration of ET-IR in endometrium suggests that the endothelins may play a role in control of the uterine vascular bed.

Endometrium↗
PubMed1992

Activation of phospholipase A2 and phospholipase C by endothelin-1 in human endometrium.

Human endometrium contains specific binding sites for iodinated endothelin (ET)-1, ET-2 and ET-3, and ET-1 stimulates prostaglandin (PG) F2 alpha synthesis from explants of proliferative endometrium in short-term culture. This study has investigated the cellular responses of normal proliferative endometrium to ET-1. Radioimmunoassay was used to measure PG release and Dowex anion-exchange column chromatography was utilized to assess the accumulation of inositol phosphates. Endothelin-1 induced a significant increase in PGF2 alpha release (basal median: 1465 pg/mg per 60 min (range: 541-3935 pg/mg per 60 min); ET-1-stimulated: 1813 pg/mg per 60 min (1021-5714 pg/mg per 60 min); P < 0.04 using Wilcoxon signed rank test). The effect of ET-1 was attenuated in the presence of the phospholipase A2 inhibitor quinacrine. Endothelin-1 induced a rapid, transient and concentration-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), measured by the accumulation of tritiated inositol phosphates. Following a 1-min stimulation with ET-1 (100 nmol/l), [3H]inositol mono-, bis- and trisphosphate fractions increased from median values of 490.0 d.p.m./mg dry wt (range: 348.0-807.0 d.p.m./mg dry wt), 120.0 d.p.m./mg dry wt (93.6-144.1 d.p.m./mg dry wt) and 67.0 d.p.m./mg dry wt (54.2-85.0 d.p.m./mg dry wt) to 939.0 d.p.m./mg dry wt (635.9-1596.0 d.p.m./mg dry wt; P < 0.03), 145.0 d.p.m./mg dry wt (127.0-293.9 d.p.m./mg dry wt; P < 0.05) and 146.0 d.p.m./mg dry wt (77.5-187.0 d.p.m./mg dry wt; P < 0.03) respectively. These results suggest that ET-1 activates the phospholipase A2 and PtdIns(4,5)P2-specific phospholipase C in human proliferative endometrium, resulting in the generation of PGF2 alpha and second messengers respectively which are pivotal to endometrial function.

Endometrium↗
PubMed1991

Endothelin-1 stimulates prostaglandin F2 alpha release from human endometrium.

Despite a key role in the pathogenesis of menorrhagia, the factors controlling the uterine vascular bed are poorly understood. This study has assessed the effects of the potent vasoconstrictor endothelin (ET)-1 on prostaglandin (PG) release from human endometrial explants in short-term culture. There was no significant difference between the production of PGF2 alpha in proliferative and secretory tissue (1709 and 2434 pg/mg/h--median values, range 70,3745 and 219,6700 pg/mg/h). Less PGE was released than PGF2 alpha, and the amount did not vary with the phase of the menstrual cycle (308 and 296 pg/mg/h (range 65,387 and 105,429) for proliferative and secretory tissue). ET-1 (10 and 100 nM) and arachidonic acid (AA, 30 microM), stimulated PGF2 alpha release from proliferative, but not secretory endometrium, by 78%, 86% (P less than 0.01) and 80% respectively, compared with control tissue. No effect was seen on PGE release. ET-1 may play a role in the local control of the endometrial vascular bed either directly, or via the release of PGF2 alpha.

Adult↗
PubMed1991

Epidermal growth factor in human endometrium: proliferative effects in culture and immunocytochemical localization in normal and endometriotic tissues.

Endometrial proliferation is stimulated by oestradiol. The precise mechanism is poorly understood, but may be mediated by epidermal growth factor (EGF). The aim of the present study was to assess the effects of oestradiol and EGF on glandular and stromal proliferation in human endometrial cell cultures, and to determine the localization of EGF-like immunoreactivity (EGF-IR) using immunocytochemistry in normal and endometriotic tissue. Endometrium was obtained from women undergoing curettage or hysterectomy for benign disease, or laparoscopy for endometriosis. For tissue culture experiments, enriched glandular and stromal cells were prepared by digestion with collagenase and DNAase, and cultured for 4 days with oestradiol or EGF, both alone and in combination. Immunocytochemical studies were performed using sheep primary antibody against EGF, with binding visualized using the unlabelled antibody--enzyme method. In combination, oestradiol and EGF increased mean cell counts from 1.15 +/- 0.06 and 1.36 +/- 0.05 x 10(5)/ml to 1.68 +/- 0.1 (+46%) and 1.94 +/- 0.16 (+43%) x 10(5)/ml, in proliferative and secretory gland preparations respectively (n = 10, P less than 0.01). No effect was seen in stromal cell preparations; however the stimulation in gland preparations was further augmented after the addition of stromal-conditioned medium. EGF-IR was detected in endometrium from normal women, and in normal and ectopic endometrium from women with endometriosis. EGF-IR was seen in glands and stroma and was not related to the phase of the menstrual cycle. EGF may play a role in the oestrogen-stimulated proliferation of normal and endometriotic endometrium.

Animals↗
PubMed1991

Binding sites for iodinated endothelin-1, endothelin-2 and endothelin-3 demonstrated on human uterine glandular epithelial cells by quantitative high-resolution autoradiography.

Quantitative in-vitro receptor autoradiography has been used to localize and compare the anatomical distribution of binding sites for iodinated endothelins (ET-1, ET-2 and ET-3) in human uterus. Binding sites for the three iodinated isoforms had a similar gross anatomical distribution. The density of binding sites was significantly higher in the endometrium compared with the myometrium and greatest at the endometrial-myometrial junction. In cross-competition experiments, unlabelled ET-1, ET-2, ET-3, sarafotoxin S6b and mouse vasoactive intestinal contractor (1 mumol/l) competed for the binding sites of all the iodinated peptides suggesting that ETs may bind to the same receptor. However, preproendothelin(110-130) (endothelin-like peptide) or preproendothelin(124-130) and other non-endothelin vasoactive peptides tested as a concentration of 1 mumol/l did not compete. Micro-autoradiography revealed that high densities of iodinated ET-1, ET-2 and ET-3 binding sites were localized to glandular epithelial cells and blood vessels with lower levels in the myometrium and vascular smooth muscle, suggesting that these potent vasoactive and proliferative agents could play a role in the control of menstruation.

Adult↗
PubMed1991

Localization and endogenous concentration of endothelin-like immunoreactivity in human placenta.

The aim of this study was to investigate the localization of endothelin-like immunoreactivity (ET-IR) in human placenta, chorion and amnion and to compare the endogenous concentration of immunoreactive endothelin (ET) in these tissues before and after the onset of labour. ET-IR was detected in the endothelium of stem vessels in placental villi, as well as in decidual stromal cells in the basal maternal plate, by immunocytochemistry using primary polyclonal rabbit antibody. A specific radioimmunoassay was used to detect endogenous concentration of ET in homogenized placental tissues. The endogenous concentration of ET-IR was significantly greater in amnion than in chorion and placenta (amnion 249 +/- 13 fmol/g; chorion 190 +/- 11 fmol/g; placenta 169 +/- 14 fmol/g; means +/- S.E.M.; n = 12; P less than 0.01). No significant difference was seen before or after the onset of labour. The detection of ET-IR in placenta, chorion and amnion suggests that the ETs may play a role in the paracrine control of human uterine function.

Amnion↗
PubMed1990

The effects of mefenamic acid and norethisterone on measured menstrual blood loss.

Although there are numerous medical treatments for menorrhagia, in many instances neither the precise diagnosis nor the response to therapy have been assessed objectively. Menorrhagia (menstrual blood loss more than 80 mL per cycle) was diagnosed objectively in 32 (44%) of 72 women with a subjective complaint of heavy menses. All of the 32 women had ovulatory cycles. After random allocation to treatment with either mefenamic acid (500 mg three times daily during menses, N = 17) or norethisterone (5 mg twice daily on days 19-26 of the cycle, N = 15) for two additional cycles, the median menstrual blood loss was reduced from 123 mL (range 86-237) to 81 mL (22-193) (P less than .001) and from 109 mL (81-236) to 92 mL (43-189) (P less than .002) with mefenamic acid and norethisterone, respectively. Apart from a decrease in the median number of days of bleeding, from 7 (5-8) to 5 (3-8) in those women treated with mefenamic acid, no other differences were seen between the groups. We conclude that mefenamic acid and norethisterone were similarly effective in reducing the degree of menstrual blood loss in women with proved menorrhagia, but that 52 and 67% of the women, respectively, remained menorrhagic after 2 months of treatment.

Adult↗
PubMed1989

Dysfunctional uterine bleeding.

The diagnosis of DUB is made by the exclusion of organic disease as a cause of the abnormal menses; the condition accounts for about 80% of cases of menorrhagia. Of these, over 80% will have no abnormality of the hypothalamo-pituitary-ovarian axis, and it is likely that the disorder is the result of local endometrial factors. There appears to be not only a preponderance of vasodilatory prostaglandins in the endometrium of women with menorrhagia, but also an excessive increase in fibrinolytic activity within the uterine cavity. Once a diagnosis has been reached with the aid of history, examination, haematological and endocrine investigations, and dilatation and curettage when appropriate, medical treatment is the usual first line approach. Non-steroidal anti-inflammatory drugs such as mefenamic acid, or antifibrinolytic agents such as tranexamic or epsilon aminocaproic acids, will reduce blood loss by between 25 and 50%. Though the former drugs are relatively free from side-effects in healthy women, intracranial thrombosis has been reported with the latter (Agnelli et al, 1982). Medications which suppress ovarian function, such as danazol or gonadotrophin releasing hormone analogues, are highly effective in lessening, or inhibiting, menstrual loss, but at the expense of side-effects and convenience respectively. The combined contraceptive pill may reduce blood loss by 50% but is not appropriate for older women. Cyclical gestagens such as norethisterone have been widely employed, particularly for the treatment of anovulatory cycles, but their place in the management of ovulatory DUB is less clear. If medical treatment fails hysterectomy should be considered, though less invasive surgical methods of endometrial ablation are being developed. Finally, it should be remembered that in the absence of associated signs or symptoms of iron-deficiency anaemia, heavy menstrual bleeding is a subjective complaint and up to 50% of women describing menorrhagia will have a measured monthly blood loss within normal limits.

Female↗
PubMed1989

Oocyte donation: a review.

Oocyte donation provides an option for achieving pregnancy in women lacking functioning gonads, or in whom IVF techniques have failed to harvest adequate oocytes, or those who do not wish to use their own gametes because of hereditary disease. In agonadal women, artificial menstrual cycles are required before proceeding to gamete donation. A fixed cyclical steroid replacement schedule of oestradiol (E2) valerate and progesterone (P4) pessaries was initially used, but the need for synchrony between donor and recipient cycles, and the narrow window for implantation limited the transfer of fresh embryos. Donor-recipient cycle asynchrony can be overcome by using frozen-thawed embryos, or by extending the follicular phase in the recipient to widen the transfer window. Twenty-two pregnancies have now been achieved by the Monash/Epworth group, resulting in the birth of 13 healthy infants. There were no statistically significant differences in pregnancy rates (per transfer) between transfers in natural cycles (14%, four pregnancies) and steroid replacement cycles (24%, 16 pregnancies). Five pregnancies (36%) were established in women treated with 2 mg of E2 daily 13-18 days before embryo transfer with P4 starting on the day of or the day following oocyte retrieval. E2 was continued for a median of 85 days (range 49-110) and P4 for a median of 86 days (range 49-133) after the supposed last menstrual period. All but one delivery was by caesarean section. There were no perinatal deaths and no ectopic pregnancies.

Embryo Transfer↗
PubMed1988

Anti-progesterones: background and clinical physiology.

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.

Abortifacient Agents↗
PubMed1988

Early pregnancy termination: a comparison between vacuum aspiration and medical abortion using prostaglandin (16,16 dimethyl-trans-delta 2-PGE1 methyl ester) or the antiprogestogen RU 486.

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.

Abortion, Therapeutic↗
PubMed1988

Vaginal progesterone administration before ovulation induction with exogenous gonadotropins in polycystic ovarian syndrome.

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.

Administration, Intravaginal↗
PubMed1988

Occult ovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations.

Ten women with infertility, regular menses, and elevated plasma FSH concentrations after a failed in vitro fertilization attempt were studied throughout a spontaneous menstrual cycle. Plasma estradiol, progesterone, inhibin, LH, and FSH concentrations were measured by RIA on days 1, 8, 15, and 22 and compared with the ovarian steroid and gonadotropin profiles obtained from seven endocrine-normal women. The elevated FSH concentrations in the hypergonadotropic group were not associated with significant changes in E2 and P4, but an increase in LH concentrations was found on days 1, 8, and 22 (medians of 18 and 4, 17 and 6, and 7 and less than 3 U/L for the hypergonadotropic and normal groups, respectively; P less than 0.01). Their plasma inhibin concentrations [213, 242, 747, and 561 U/L (median values on days 1-7, 8-14, 15-21, and 22-28)] were normal. Autoantibodies to adrenal, thyroid, or ovary were present in five (50%) women, and antiovarian antibodies were present in 4. Two women gave a family history of thyroid disease, and one woman was hypothyroid. Repeat assessment 3-6 months revealed persistently elevated FSH concentrations in five (63%) of eight women; the other three had normal ovarian steroid and gonadotropin concentrations. The triad of infertility, regular menses, and elevated plasma FSH concentrations describes a group of women with occult ovarian failure, a condition of compensated granulosa cell function, which may be an early stage of premature ovarian failure. These women with occult ovarian failure had an impaired response to ovarian hyperstimulation and may be at increased risk of developing polyglandular autoimmunity.

Adult↗
PubMed1988

The return to ovulation following early abortion: a comparison between vacuum aspiration and prostaglandin.

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, Induced↗
PubMed1988

Prostaglandins and antigestagens for the interruption of early pregnancy.

During pregnancy the uterus is maintained in a quiescent state by the secretion of progesterone. Antigestagens antagonize the biological action of progesterone by binding to the nuclear receptor in the target organs. Administration of the antigestagen mifepristone to women induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. In addition, the sensitivity of the myometrium to exogenous prostaglandins is markedly increased. Although mifepristone will induce bleeding in the majority of women in early pregnancy, the incidence of incomplete abortion or ongoing pregnancies increases with increasing gestational age and is too high to be clinically useful as an agent for therapeutic abortion. However, a single dose of mifepristone (400-600 mg) followed by a vaginal pessary of a prostaglandin analogue (0.5-1.0 mg), gemeprost, induced complete abortion in 95 of 100 women of gestational age less than 42 days (less than or equal to 56 days amenorrhoea). The incidence of diarrhoea (15%) and abdominal pain requiring opiate analgesia (10%) was much lower than when abortion was induced with prostaglandin alone. Vaginal bleeding continued for 13.8 +/- 0.8 days after administration of the prostaglandin. A combination of an antigestagen with a small dose of a prostaglandin analogue is an effective alternative to vacuum aspiration for the therapeutic termination of early pregnancy.

Abortifacient Agents↗