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Biomedical subjects

P Hardiman

Publications and source records attributed to P Hardiman.

At least 19 recordsLinked to original sources
PubMed2005

The association between polycystic ovaries and endometrial cancer.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are assumed to be at increased risk of endometrial cancer (EC), albeit of a more differentiated type with better prognosis than in normal women. This study was designed to test these assumptions, as evidence for them is lacking. METHODS: The prevalence of polycystic ovaries (PCO), as a marker of PCOS, was investigated in ovarian sections from 128 women with EC and 83 with benign gynaecological conditions. The expression of the prognostic markers p53, Ki67, Bcl2 and cyclin D1 was also investigated by immunohistochemistry in endometrial tumours from 11 women with PCO and 16 with normal ovaries. RESULTS: Overall, PCO were similarly prevalent in women with EC (8.6%) and benign controls (8.4%); however, in women aged <50 years, PCO were more prevalent in women with EC (62.5 versus 27.3%, P = 0.033). Cyclin D1-expressing endometrial tumours tended to be more prevalent in women with PCO compared to normal ovaries (36.4 versus 6.25%, respectively, P = 0.071). Bcl2-, p53- and Ki67-expressing tumours were similarly prevalent. CONCLUSIONS: The association between PCOS and EC appears confined to premenopausal women. The tendency for cyclin D1-expressing endometrial tumours to be more prevalent in women with PCO challenges the assumption that EC prognosis is improved in women with PCOS.

Adult↗
PubMed2005

Microvascular dysfunction in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with multiple cardiovascular risk factors and an increased prevalence of arterial dysfunction. However, microvascular dysfunction in PCOS has not been assessed. METHODS: Subjects comprised 12 women with PCOS and 12 age-matched controls with normal ovaries. Microvascular function was assessed by observing forearm skin microvascular erythrocyte flux responses, to cumulative iontophoretic doses of 1% (w/v) acetylcholine (ACh) and 1% (w/v) sodium nitroprusside (SNP), using laser Doppler imaging. RESULTS: Basal microvascular perfusion was comparable in PCOS and controls. The increase in skin microvascular perfusion in response to ACh was however generally blunted in PCOS women (P = 0.018). Peak ACh-induced erythrocyte flux was also less (p < 0.04) in PCOS women (125.1 +/- 21.7, i.e. 5.3-fold basal flux) than in controls (200.8 +/- 28.5, i.e. 8.3-fold basal flux). Analysis of covariance indicated this effect was unrelated to differences in body mass index or serum testosterone but serum insulin may be a weak confounder. No differences were noted between the PCOS and control groups in their response to SNP. CONCLUSION: Despite its limited sample size studied, this is the first demonstration that women with PCOS exhibit microvascular endothelial dysfunction, indicated by an inhibited vasodilatory response to ACh.

Acetylcholine↗
PubMed2004

Cell cycle and apoptotic proteins in relation to ovarian epithelial morphology.

OBJECTIVE: To assess the relationship between the expression of cell cycle and apoptotic proteins and the morphological appearance of the surface epithelium in non-neoplastic ovaries. METHODS: The subjects for this study were 79 women who had undergone oophorectomy for benign conditions at the North Middlesex Hospital, London, and Royal Free Hospital, London, and whose ovaries had been reported on routine histology as entirely normal or containing physiological cysts or endometriosis. The epithelial morphology was reassessed on haematoxylin and eosin-stained paraffin wax sections using nine cytological and architectural parameters associated with premalignant intraepithelial changes. A 'score' was obtained for each ovary. Expression of p53, Ki67, cyclin D1 and Bcl-2 in the surface, cystic and endometriotic epithelium was assessed in corresponding sections using standard immunohistochemistry. RESULTS: The median score for the morphological changes was significantly higher in the sections, which expressed p53 compared to those which did not. This difference remained significant in a subanalysis of the sections, which did not contain endometriosis. No relationship was identified between the morphological score and the expression of Ki67, Bcl-2 and cyclin D1. CONCLUSION: Increased intraepithelial abnormality as assessed by an epithelial morphological score of ovarian sections is associated with expression of the p53 cell cycle protein. This lends credence to the hypothesis that the ovarian surface or cystic epithelium goes through an identifiable precursor or "premalignant" phase before the development of invasive disease. Further work is required to characterise the changes that take place before the development of malignancy in ovarian epithelium.

Apoptosis↗
PubMed2004

Polycystic ovary syndrome, diabetes and cardiovascular disease: risks and risk factors.

Polycystic ovary syndrome is one of the most common endocrine disorders in the human, affecting approximately 10% of women of reproductive age. Although originally considered a gynaecological disorder, the syndrome is associated with a wide range of endocrine and metabolic abnormalities, including insulin resistance. Affected women are at an increased risk of developing gestational and non-insulin dependent diabetes and there is an association with cardiovascular risk factors including obesity, hypertension, dyslipidaemia, hyperhomocysteinaemia, increased intima media thickness and impaired vascular elasticity. The effect on cardiovascular mortality is currently unclear. However, in view of the proven links with diabetes and the cardiovascular risk markers, this condition should be considered within the province of physicians as well as gynaecologists.

Adult↗
PubMed2003

Antioxidants and reactive oxygen species in follicular fluid of women undergoing IVF: relationship to outcome.

BACKGROUND: The role of free radicals and reactive oxygen species (ROS) in female reproductive function is still unclear. The present study was designed to investigate their relationship with ovulation, fertilization and conception. METHODS: Follicular aspirates obtained from women undergoing IVF following controlled ovarian stimulation were evaluated using the ferric reducing antioxidant power (FRAP) assay for baseline total antioxidant capacity (TAC). Both the baseline TAC and the decline in TAC over 72 h (two-point assay) were used as markers of oxygen radical activity. RESULTS: A total of 303 follicular aspirates from 63 women were analysed. Two hundred and eighteen (71.9%) yielded oocytes, 169 (77.5%) of these fertilized and 134 (79.3%) of these embryos survived until the time of embryo transfer. Baseline TAC was no different in follicular fluid whether the follicle contained an oocyte or not, but was significantly higher in fluid from follicles whose oocyte successfully fertilized and significantly lower in fluid from follicles where the resultant embryo survived to transfer. The decline in TAC was lower when the oocytes fertilized and higher in association with embryo viability, but the differences were not statistically significant. CONCLUSIONS: These results provide further evidence that ROS play a role in female reproductive function.

Antioxidants↗
PubMed2002

Polycystic ovaries.

Transvaginal ultrasound is currently the gold standard for diagnosing polycystic ovaries. The results of studies using ultrasound suggest a prevalence in young women of at least 20%. Between 5% and 10% of these women with polycystic ovaries shown on ultrasound will have the classical symptoms of polycystic ovary syndrome such as infertility, amenorrhoea or signs of hirsutism and obesity, as originally described by Stein and Leventhal in 1935. However, the significance of polycystic ovaries in asymptomatic women is still under investigation, as is the role of Doppler (pulsed and colour) and three-dimensional ultrasound. Ultrasound has also contributed to our understanding of the local and systemic haemodynamic changes associated with polycystic ovaries, although the relationship of these changes to morbidity and mortality is unknown.

Adult↗
PubMed2000

Internal carotid-artery response to 5% carbon dioxide in women with polycystic ovaries.

Although polycystic ovary syndrome is associated with hypertension, hyperlipidaemia, and insulin resistance, mortality from cerebrovascular disease is not increased. We previously reported lower downstream resistance in the internal carotid artery in women with polycystic ovary syndrome. This study was designed to assess vascular reactivity by measuring the response to inhalation of 5% carbon dioxide. We studied 34 young women with polycystic ovary syndrome, 15 with symptomless polycystic ovaries, and 18 controls.

Administration, Inhalation↗
PubMed2000

Lipid effects of hormone replacement therapy with sequential transdermal 17-beta-estradiol and oral dydrogesterone.

OBJECTIVE: To assess the effects on lipid and lipoprotein levels of a combination therapy of matrix patch and oral sequential dydrogesterone. METHODS: The lipid effects of transdermal estradiol (E2) (80 microg/day continuously) and oral dydrogesterone (10 mg from days 15-28 of each cycle) were assessed in a multicenter, prospective, open, baseline-controlled study. Subjects were 42 healthy, postmenopausal women who had not had hysterectomies. Fasting blood samples were taken at baseline, day 14 of cycle 3 (estrogen alone), and day 25 of cycle 6 (estrogen and progestogen). The main outcome measures were changes from baseline in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides after six cycles. RESULTS: Thirty-six subjects completed six cycles and in the 28 with complete data, HDL cholesterol increased by 10.6% from 65.25 to 72.2 mg/dL (95% confidence interval [CI] 2.32, 11.58, P = .005) and LDL cholesterol fell by 5.1% from 130.9 to 124.3 mg/dL (95% CI 13.9, 1.16, P = .07). There was a nonsignificant decrease in LDL cholesterol from 130.9 at baseline to 124.3 mg/dL at 6 months and in triglycerides from 110.6 to 107.1 mg/dL. CONCLUSION: Sequential treatment with transdermal E2 and oral dydrogesterone increased HDL cholesterol, without the accompanying increase in triglycerides that occurs with oral estrogen replacement therapy.

Adult↗
PubMed2000

Internal carotid artery haemodynamics in women with polycystic ovaries.

Although polycystic ovarian syndrome (PCOS) is associated with risk factors for cerebrovascular disease, the available evidence does not demonstrate increased stroke mortality, and it has been suggested that some protective mechanisms must be operating in these women. Haemodynamic changes have been demonstrated in the pelvic vessels and aorta in this syndrome, but there have been no studies of the cerebral circulation. Since insulin resistance is a central feature of PCOS, it is of interest that cerebral blood flow may be altered in diabetic subjects. The present study was designed to assess internal carotid artery haemodynamics in women with PCOS, asymptomatic women with polycystic ovaries (PCO women) and healthy controls. Mean internal carotid pulsatility index, measured using pulsed Doppler ultrasound under standardized conditions, was significantly lower in 35 PCOS and 15 PCO women than in the 18 controls. This was also shown on multiple regression analyses. Peak systolic velocity did not differ between groups. In view of the difficulty of interpreting pulsatility index in low-impedance vascular beds, the 'back' pressure was calculated and found to be lower in women with polycystic ovaries. This is the first demonstration of lower pulsatility index and back pressure (suggestive of reduced vascular tone) in the cerebral circulation of these women, independent of blood pressure, insulin resistance and other endocrine or metabolic factors. Changes in internal carotid haemodynamics may offset the risk of cerebrovascular disease commonly associated with polycystic ovaries.

Adolescent↗
PubMed2000

Thyroid hormone receptor gene expression in first trimester human fetal brain.

Maternal thyroid hormone is transferred to the fetus early in pregnancy and is postulated to regulate brain development. Thyroid hormone nuclear receptor (TR) proteins are present in fetal brain, but their isoformal composition is unknown. We therefore investigated the ontogeny of TR isoforms and related splice variants in first trimester human fetal brain (n = 9) by semi-quantitative reverse transcriptase-polymerase chain reaction analysis. Expression of the TRbeta1, TRalpha1 and c-erbAalpha2 isoforms was detected from 8.1 weeks gestation (wg). An additional truncated species was detected with the c-erbAalpha2 primer set, consistent with the c-erbAalpha3 splice variant previously described in the rat. All c-erbAalpha-derived transcripts were co-ordinately expressed and increased (ca. 8-fold) between 8.1 and 13.9 wg. A more complex ontogenic pattern was observed for TRbeta1, suggestive of a nadir between 8.4 and 12.0 wg. These findings point to an important role for the TRalpha1 isoform in mediating maternal thyroid hormone action during first trimester human fetal brain development.

Adult↗
PubMed1998

Uterine artery blood flow parameters in women with dysfunctional uterine bleeding and uterine fibroids: the effects of tranexamic acid.

The objective of this study was to investigate the effects of tranexamic acid on uterine vascular resistance in women with dysfunctional uterine bleeding and in women with menorrhagia associated with fibroids. A longitudinal, prospective study was carried out in premenopausal women referred to a gynecological outpatient department with a complaint of menorrhagia. We studied 24 women with dysfunctional uterine bleeding (mean age 38.8 years; normal ultrasound examination, hysteroscopy and endometrial biopsy) and 12 women (mean age 42.8 years) with at least one fibroid greater than 2.0 cm on ultrasound examination. None were on any form of oral contraception or other medication which could influence uterine vascular resistance. All women had normal coagulation and thyroid function tests. Transvaginal scanning was performed using an Aloka SSD 650 machine with a 5-MHz probe and pulsed Doppler. Pulsatility index (PI) and resistance index (RI) were measured from the left and right uterine arteries before and during the second month of treatment with tranexamic acid (1 g orally three times a day). Menstrual blood loss was assessed using a validated pictorial blood chart. In women with dysfunctional uterine bleeding, the mean PI and RI fell significantly with treatment (PI 2.20-1.94, p = 0.0001; RI 0.81-0.77, p = 0.003). There was a reduction of approximately 30% in menstrual blood loss with treatment (210.0-137.6 ml, p = 0.0001). In women with uterine fibroids, there was no significant change in either the PI or the RI with treatment and there was no significant reduction in menstrual blood loss. We conclude that tranexamic acid significantly reduces uterine artery vascular resistance in women with dysfunctional uterine bleeding. This effect is unlikely to be a mechanism for the action of tranexamic acid in reducing menstrual blood loss but may have important implications for women taking this treatment in the long term.

Adult↗
PubMed1996

IGFBP-1 in the placenta, membranes and fetal circulation: levels at term and preterm delivery.

Samples of maternal blood, amniotic fluid, placenta, fetal membranes and umbilical venous blood were collected from 59 women at vaginal delivery (32-41 weeks gestation) and 15 women at delivery by Caesarean section (37-41 weeks gestation). Umbilical vein levels of IGFBP-1 were significantly lower in deliveries prior to the onset of labour (elective Caesarean section) than those during normal vaginal delivery. These levels were, in turn, significantly lower than those delivered by emergency Caesarean section. This difference was not seen in any of the other tissues examined. Concentrations of IGFBP-1 were lower in placenta and membrane extracts from preterm deliveries than in term deliveries. This difference was not observed in maternal or fetal serum or in amniotic fluid. This study confirms that the fetal membranes are a major source of IGFBP-1 and that fetal circulating levels are raised where there is evidence of fetal hypoxia. The absence of a comparable rise in levels in placenta, membranes or amniotic fluid suggests that the origin of this increase is from fetal tissue.

Amniotic Fluid↗
PubMed1996

Measurement of interleukin-1 alpha and interleukin-6 in pregnancy-associated tissues.

The concentrations of interleukin-1 alpha (IL-1 alpha) and IL-6 in pregnancy-associated tissues were investigated in term labour and delivery in the absence of labour (elective Caesarean section). Samples of amniotic fluid, placenta, fetal membranes, umbilical venous and, where possible, umbilical arterial blood were collected at delivery (37-41 weeks of gestation). Maternal blood was sampled during labour. Fluid and tissue extracts were assayed for IL-1 alpha and IL-6 by radioimmunoassay. Placenta and membranes were examined histologically for evidence of infection. Concentrations of IL-1 alpha and IL-6 in amniotic fluid and membrane extract, and IL-1 alpha in maternal and fetal blood, were raised after the onset of labour. Concentrations of both cytokines in the placenta remained unchanged. There was a good correlation between concentrations of both cytokines in amniotic fluid and membranes. There was also a significant correlation between concentrations of IL-1 alpha and IL-6 in amniotic fluid, placenta and membranes. It is suggested that the fetal membranes or maternal decidua, but not the placenta, internal fetal or maternal tissues, are the main sources of IL-1 alpha and IL-6 during labour.

Amniotic Fluid↗
PubMed1995

The effects of the somatostatin analogue octreotide on ovulatory performance in women with polycystic ovaries.

The elevated luteinizing hormone (LH) and androgen concentrations characteristic of women with polycystic ovaries (PCO) are considered crucial factors in their infertility. The somatostatin analogue octreotide lowers LH and androgen concentrations in women with PCO. The effects of octreotide given concurrently with human menopausal gonadotrophin (HMG) were therefore compared with that of HMG alone in 28 infertile women with PCO resistant to clomiphene. In 56 cycles of combined HMG and octreotide therapy there was more orderly follicular growth compared with the multiple follicular development observed in 29 cycles in which HMG was given alone (mean number of follicles > 15 mm diameter on the day of human chorionic gonadotrophin (HCG) administration: 2.5 +/- 0.2 and 3.6 +/- 0.4 respectively; P = 0.026). There was a significantly reduced number of cycles abandoned (> 4 follicles > 15 mm diameter on day of HCG) in patients treated with octreotide+HMG, so that HCG had to be withheld in only 5.4% of cycles compared to 24.1% with HMG alone (P < 0.05). The incidence of hyperstimulation was also lower on combined treatment. Octreotide therapy resulted in a more 'appropriate' hormonal milieu at the time of HCG injection, with lower LH, oestradiol, androstenedione and insulin concentrations. Although growth hormone concentration was similar on both regimens, significantly higher insulin growth factor-I concentrations were observed on the day of HCG in women on combined therapy than on HMG alone.

Adult↗