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Biomedical subjects

S Franks

Publications and source records attributed to S Franks.

At least 109 records · Page 6Linked to original sources
PubMed1991

Correlation of plasma insulin and insulin-like growth factor-I with indices of androgen transport and metabolism in women with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is said to be associated with hyperinsulinaemia. Insulin stimulates androgen production by ovarian tissue in vitro and previous studies have identified a positive correlation of insulin with androstenedione. The aim of the present study was to discover whether insulin levels correlate with clinical presentation and with markers of androgen transport and metabolism in women with PCOS. DESIGN: Within-group analysis of clinical and biochemical characteristics of a consecutive series of women with PCOS, focusing on correlations of plasma insulin with clinical presentation and androgens. Insulin levels were also compared with a control group of normal women. PATIENTS: Forty-seven women who presented with hirsutism, cycle abnormalities or both, with ultrasound proven PCOS, were recruited. Mean age was 26.6 +/- 0.7 years (mean +/- SEM), BMI 27.3 +/- 1.2 kg/m2. MEASUREMENTS: Plasma insulin levels were measured at 30-minute intervals for 3 hours following a 75 g glucose load. Blood was also taken for measurement of testosterone (T), androstenedione (A), free testosterone (fT), sex hormone binding globulin (SHBG) and insulin-like growth factor-I (IGF-I). Androsterone glucoronide (AG), a marker of peripheral androgen metabolism, was also measured. RESULTS: Neither basal insulin nor the sum of insulin measurements during the glucose tolerance test (sumINS) in women with PCOS were significantly different from a control group with normal ovaries. Within the PCOS group, basal insulin was greater in women with irregular cycles or amenorrhoea than in those with regular ovulatory menses (8.0 +/- 1.1 vs 3.1 +/- 1.5 mU/l, P less than 0.01) despite similarly raised androgen levels. Both basal insulin and sumINS correlated with BMI in women with PCO (r = 0.37, P less than 0.05 and r = 0.64, P less than 0.01 respectively) but not in controls. There was no significant correlation between insulin or IGF-I levels and T, A or AG despite a positive correlation of AG (but no other androgen) with BMI. SHBG showed an inverse correlation and fT correlated positively with sumINS (r = -0.51, P less than 0.01; r = 0.39, P less than 0.05). Regression analysis of each of the androgens on the other variables demonstrated no significant relationship between insulin and androgens. CONCLUSIONS: These data suggest that, in vivo, the major effect of insulin on androgen secretion is mediated by changes in SHBG rather than by direct stimulation of ovarian androgen production. Higher insulin concentrations in anovulatory compared with ovulatory women with hyperandrogenaemia may indicate that insulin resistance in the ovary contributes to the mechanism of anovulation in PCOS.

Adult↗
PubMed1991

Phospholipase activity in the endometrium of women with normal menstrual blood loss and women with proven ovulatory menorrhagia.

The activity of phospholipase A2 types 1 and 2 and phospholipase C was measured in the endometrium of women with ovulatory menorrhagia and in those with normal menstrual blood loss. In both groups of subjects phospholipase A2 type 1 activity was significantly higher in the secretory phase than in the proliferative phase (P less than 0.001). The median activity (pmol/mg protein/min) for the proliferative phase was 27.6 in normal subjects and 40.4 in women with ovulatory menorrhagia and for the secretory phase the median activity was 144.5 in normal women and 138.1 in women with ovulatory menorrhagia. There was no difference between the two groups of women at either stage of the cycle. Phospholipase A2 type 2 activity was also higher in the secretory phase than in the proliferative phase (P less than 0.05 for normal subjects and P less than 0.001 for women with menorrhagia). The median activity (pmol/mg protein/min) for the proliferative phase was 94.4 (normal subjects) and 56.6 (women with menorrhagia) and for the secretory phase 148.3 (normal subjects) and 142.5 (women with menorrhagia). The activity of phospholipase A2 type 2 was significantly lower in the proliferative phase of women with ovulatory menorrhagia compared with normal subjects (P less than 0.05). Phospholipase C activity (nmol/mg protein/min) was significantly higher in women with ovulatory menorrhagia (median 8.2) compared with women with normal blood loss (median 5.5) (P less than 0.01).

Endometrium↗
PubMed1991

Obesity and polycystic ovary syndrome.

Our studies show that obese women with polycystic ovary syndrome are more likely to have hirsutism and menstrual disturbances than are lean women with PCOS. The most obvious biochemical differences between obese and lean women with PCOS is that SHBG concentrations are much lower in women with obesity. The SHBG levels are inversely related to insulin, and insulin has been shown to have a direct inhibitory action on SHBG secretion. Other factors, however, may contribute to the mechanism of the increased prevalence of hirsutism and anovulation in obese women with PCOS, such as a direct effect of insulin or increased activity of 5 alpha-reductase in peripheral tissues. Finally we have been able to show that weight reduction of more than 5% is associated with an improved biochemical profile and, importantly, with restoration of fertility.

Endocrine Glands↗
PubMed1991

Release of arachidonic acid from human endometrial cells in culture mediated by calcium ionophore (A23187) or fluoride.

Primary cultures of endometrial glands and stromal cells were labelled with [14C]-arachidonic acid for 4 h before exposure to either the calcium ionophore, A23187 (which activates phospholipase A2 (PLA2) by increasing intracellular calcium concentrations) or sodium fluoride (which activates a G-protein). Calcium ionophore (0.5-50 mumol/l) stimulated a dose- and time-dependent release of arachidonic acid from endometrial glands. Incubation with ionophore (10 mumol/l) for 1 h released 22% of the incorporated arachidonic acid. There was a corresponding decrease in phospholipids and no loss from triglycerides. Stromal cells were unresponsive to ionophore. Fluoride (10 mmol/l) stimulated a release of arachidonic acid from stromal cells and endometrial glands (6.5% of the total arachidonic acid incorporated). In stromal cells, arachidonic acid was released from triglycerides in Day-1 cultures and from phospholipids in Day-2 cultures. In both Day-1 and Day-2 cultures of endometrial glands, arachidonic acid was released from phospholipids, but not from triglycerides. Among the phospholipids, phosphatidylcholine was always the major source of arachidonic acid. Arachidonic acid release from endometrial glands and stromal cells may be mediated by activation of PLA2 (or phospholipase C) via a G-protein, but in glands calcium ionophore may have a direct effect on PLA2. The response to calcium ionophore may reflect the differences in calcium requirements of the two endometrial PLA2 isoenzymes.

Arachidonic Acid↗
PubMed1990

Uptake, distribution and release of 3H-arachidonic acid from human endometrium.

The lysophosphatide acyltransferase blocking agent ethylmercurisalicylate (merthiolate) was used to investigate the uptake and release of arachidonic acid from explants of human endometrium in short term tissue culture. Tissue explants were (a) incubated with 3H-arachidonic acid for 1-24 h in the presence or absence of 0.5-50 microM merthiolate, and (b) prelabelled with 3H-arachidonic acid for 18 h followed by incubation with or without 50 microM merthiolate for 1-24 h. Neutral lipids, phospholipids and arachidonic acid were separated by thin layer chromatography and uptake and release of 3H-arachidonic acid expressed as % total uptake. The triglyceride pool was the main target for arachidonic acid uptake. Incorporation increased from 9.1% at 1 h to 56.6% at 24 h. Uptake into phospholipids increased from 8.1% at 1 h to 19.6% at 24 h with phosphatidylcholine accounting for 3.8% and 8.8% respectively. Incubation with 50 microM merthiolate rapidly reduced uptake into triglycerides (to 1.8% at 1 h and 0.9% at 24 h), whereas the effect on uptake into phospholipids (5.9% at 1 h, 3.4% at 24 h) was much less marked. There was a dose related inhibition of arachidonic acid incorporation into both triglycerides and phospholipids, but a lower dose of merthiolate (1 microM) was required to reduce uptake into triglycerides than into phospholipids (5 microM). Uptake into mono- and diglycerides was low and unaffected by merthiolate. Incubation of prelabelled tissue with 50 microM merthiolate resulted in a 20% increase in the release of arachidonic acid from triglycerides and a corresponding accumulation of labelled monoglyceride.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1990

Common problems in induction of ovulation.

There are many groups of women with anovulatory infertility who respond abnormally to conventional treatment. It is important to diagnose the underlying disorder correctly before commencing treatment. In this chapter we have discussed the various treatment modalities available and how they may be adapted to fit the particular clinical needs. In women who are profoundly hypo-oestrogenic, the 'priming' of the ovary using prolonged low-dose gonadotrophins offers a possible solution if both subcutaneous and intravenous pulsatile GnRH therapy has failed. It may also reduce the incidence of multiple pregnancies in these women. Growth hormone seems to augment the response to gonadotrophin in these women and may prove a useful adjunct to therapy once further experience of its use has been reported. Women with PCO have been a difficult group to treat because of their tendency to hyperstimulate. The low-dose gonadotrophin regimen outlined in this chapter overcomes the majority of these problems without reducing the rate of conception. This group continue to have an increased incidence of miscarriage. The introduction of combined therapy of hMG with a GnRH analogue may improve this situation, but the data from randomized controlled studies are still awaited. Ovarian failure remains an untreatable cause of infertility. A few women may become pregnant spontaneously, but these are the exception rather than the rule. Hormone replacement therapy should be offered to all these women because of the long-term problems of osteoporosis and cardiovascular disease. Products containing a low dose of oestrogen (e.g. Premarin 0.625 mg) will not interfere with ovulation if there should be a spontaneous resumption of ovarian activity.

Anovulation↗
PubMed1990

Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases.

Two hundred and sixty-three women with ultrasound-diagnosed polycystic ovary syndrome were studied of whom 91 (35%) were obese (BMI greater than 25 kg/m2). Obese women with PCOS had a greater prevalence of hirsutism (73% compared with 56%) and menstrual disorders than non-obese subjects. Total testosterone and androstenedione concentrations in serum were similar in the two subgroups but SHBG concentrations were significantly lower, and free testosterone levels higher, in obese compared with lean subjects. In addition, concentrations of androsterone glucuronide, a marker of peripheral 5 alpha-reductase activity, were higher in obese than in non-obese women with PCOS. There were no significant correlations of either SHBG or free testosterone with androsterone glucuronide suggesting that obesity has independent effects on transport and on metabolism of androgen. There were no significant differences between the subgroups in either baseline gonadotrophin concentrations or the pulsatile pattern of LH and FSH secretion studied over an 8-h period. There was, however, an inverse correlation of FSH with BMI, but only in the obese subgroup. In conclusion, the increased frequency of hirsutism in obese compared with lean women with PCOS is associated with increased bio-availability of androgens to peripheral tissues and enhanced activity of 5 alpha-reductase in obese subjects. The mechanism underlying the higher prevalence of anovulation in obese women remains unexplained.

Androgens↗
PubMed1990

Inhibition of oestradiol production by epidermal growth factor in human granulosa cells of normal and polycystic ovaries.

Anovulation in women with polycystic ovary syndrome results from a disorder of FSH-mediated follicular maturation which may involve paracrine modulation of FSH action by intra-ovarian factors. Epidermal growth factor (EGF) is a potent inhibitor of FSH-stimulated oestradiol production in the rat and has also been shown to inhibit aromatase activity in human granulosa cells obtained after superovulation. The purpose of this study was to investigate the action of EGF on granulosa cell function in human ovaries which had not been previously exposed to treatment with exogenous gonadotrophins and to compare the responses in tissue obtained from normal and from polycystic ovaries. Granulosa cells were obtained from antral follicles less than 10 mm in diameter after dissection of unstimulated normal or polycystic ovaries (PCO). Cells were pooled, washed, plated and incubated for 48h in the presence of 10(-7) M testosterone and various doses of human FSH. FSH dose responses were obtained with or without the addition of purified EGF (50 pg/ml). Testosterone in the absence of FSH resulted in a fourfold (range 2-7.5) increase in oestradiol accumulation in the medium after incubation of granulosa cells from both normal and polycystic ovaries. This increase was reversed by addition of EGF. FSH treatment stimulated a dose-related increase in oestradiol regardless of the origin of the granulosa cells. The peak E2 response to FSH, obtained at a dose of 1-2.5 ng/ml was a 20-fold increase above testosterone alone (range 4-55) in cells from PCO compared to sixfold (2.5-13) in cells from normal ovaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1990

Uterine size and endometrial thickness and the significance of cystic ovaries in women with pelvic pain due to congestion.

In a group of 55 women with chronic pain due to pelvic congestion measurement by ultrasound revealed they had a larger uterus and thicker endometrium as compared with a group of normal women matched for age, parity and the presence of polycystic ovaries found on ultrasound scanning. Many women with pelvic congestion (56%) were found on ultrasound to have cystic changes in their ovaries which ranged from a classic polycystic pattern to the appearance of clusters of 4-6 cysts in bilaterally enlarged ovaries. It is suggested that uterine enlargement and thickening of the endometrium are caused by oestrogen, either from the effects on the target organs of an increased concentration or of hypersensitivity to oestrogen.

Adult↗
PubMed1990

Effect of insulin-like growth factor-type I (IGF-I) and insulin on the secretion of sex hormone binding globulin and IGF-I binding protein (IBP-I) by human hepatoma cells.

Dietary factors are known to modulate concentrations of sex hormone-binding globulin (SHBG). In the present study we have investigated the possibility that insulin like growth factor-type I (IGF-I) may be an additional regulator of SHBG using cultured human hepatoma cells which secrete SHBG. The inhibitory effect of insulin on SHBG secretion by these cells was confirmed but, in addition, IGF-I was shown to inhibit SHBG secretion by about 40% at a concentration of 100 nmol/l. A similar degree of inhibition was achieved using insulin at a concentration of 10 mumol/l. Insulin, but not IGF-I, was also found to inhibit the secretion of a low molecular weight IGF-binding protein (IBP-I), which is also secreted by hepatoma cells. It is concluded that IGF-I is an additional regulator of SHBG secretion by these cells and that it may be involved in regulating SHBG secretion in vivo in response to dietary factors.

Carcinoma, Hepatocellular↗
PubMed1990

Direct gonadotrophic effect of growth hormone on oestradiol production by human granulosa cells in vitro.

In-vitro studies in both rodents and man suggest that GH can stimulate ovarian steroidogenesis, but it is not clear whether this effect is mediated by changes in circulating concentrations of insulin-like growth factor-1 (IGF-1) or whether it is a direct action on the ovary (or, indeed, both). In this study the effects of biosynthetic human GH (hGH) on the production of oestradiol and IGF-1 by human granulosa cells in culture were examined using ovarian tissue (from both normal and polycystic ovaries) which had not previously been exposed to exogenous gonadotrophin therapy. Addition of hGH (1 or 10 ng/ml) to the incubation medium resulted in a significant (1.7 to 3.6 fold) increase in oestradiol accumulation after 48h in culture. Human GH also had a significant additive effect on the dose-related responsiveness of granulosa cell oestradiol production to hFSH. Concentrations of IGF-1 in the medium were undetectable in each of these experiments. These studies demonstrate that hGH has a potent, direct stimulatory effect on production of oestradiol by the human ovary which is independent of the effect of FSH. These findings have important implications for understanding the physiological role of hGH in human ovarian function as well as for therapeutic use of biosynthetic hGH for induction of ovulation.

Cells, Cultured↗
PubMed1989

17 beta-Hydroxysteroid oxidoreductase activity in the endometrium of normal women and patients with pelvic pain and polycystic ovaries.

17 beta-Hydroxysteroid oxidoreductase (17-OHSD) activity in the endometrium of women with pelvic pain syndrome (PPS) and/or polycystic ovaries (PCO) was compared with that of a control group. In both groups there was a 10-fold increase in 17-OHSD activity in secretory phase tissue compared with that of the proliferative phase, measured by both oxidative and reduction pathways, and a highly significant correlation between the two directions (P less than 0.001). In normal subjects, the ratio of activity measured under oxidative conditions: reducing conditions, at all stages of the cycle except late proliferative phase, was 2.1-2.9. In the late proliferative phase the ratio was 5.5 which was significantly different from other stages of the cycle. Similar ratios were found for the PPS/PCO group (proliferative phase 2.5, secretory phase 5.6); these were also significantly different (P less than 0.01). On the basis of this study oestrogen metabolism in the endometrium of women with PPS and/or PCO appears to be no different from that of normal subjects. Measurement of enzyme activity in high speed soluble and particulate fractions of endometrial homogenate indicated the presence of two activities with different cofactor requirements. Gel filtration chromatography of the soluble fraction revealed a single peak of activity coincident with a molecular weight of 30 kDa with a strong preference for NAD + as cofactor. These preliminary findings suggest the presence of both soluble and particulate forms of 17-OHSD activity in the endometrium.

Biomarkers↗
PubMed1989

Induction of ovulation with clomiphene citrate in women with polycystic ovary syndrome: the difference between responders and nonresponders.

To identify why some women with polycystic ovary syndrome (PCO) fail to respond to clomiphene citrate (CC), the authors have monitored the endocrine and ovarian response to CC 100 mg/day given for 5 days. Of 40 cycles studied in 27 women, 73% were ovulatory. In 8 of 9 anovulatory women, there was no follicular development despite a significant rise in serum gonadotrophin concentrations within 3 to 5 days of starting CC. There were no significant differences between the ovulatory and anovulatory groups in the peak response of either luteinizing hormone (LH) or follicle-stimulating hormone (FSH). The authors conclude that, in women with polycystic ovaries, the most common reason for the failure to ovulate is an absent ovarian response to an appropriate rise in serum FSH.

Adult↗