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S Franks

Publications and source records attributed to S Franks.

At least 37 records · Page 2Linked to original sources
PubMed1999

Insulin action in the normal and polycystic ovary.

Insulin has a stimulatory effect on steroidogenesis by granulosa cells of normal and polycystic ovaries and interacts with gonadotropins in an additive or, as in the case of LH, a synergistic manner. These actions seem to be mediated specifically by the insulin receptor rather than by cross-reaction with the type I IGF receptor, even in tissue obtained from women with PCOS with biochemical evidence of insulin resistance. The authors suggest that hyperinsulinemia makes a significant contribution to premature arrest of follicle growth, which is characteristic of anovulation in women with PCOS, and that the interaction of insulin with LH is a key element in this process. Insulin may also have a role in amplifying LH-induced androgen production by theca cells, which may help explain the prominence of symptoms of hyperandrogenism in obese subjects with PCOS. The results of recent clinical studies of insulin-sensitizing agents such as metformin and the thiazoladinedione troglitazone in PCOS have provided encouragement that improvement of insulin sensitivity and consequent lowering of circulating insulin levels by these agents may be of therapeutic value in the management of both anovulation and hirsutism.

Drug Interactions↗
PubMed1999

The prevalence of polycystic ovaries in women with infertility.

Polycystic ovaries (PCO) are highly prevalent in women presenting with hirsutism or recurrent miscarriage but the functional significance of PCO in ovulatory women presenting with infertility remains unclear. We examined the prevalence of PCO, on ultrasonography, among women presenting with infertility. Among 289 couples classified in four main diagnostic categories, PCO were found in 81 (83%) of 98 anovulatory patients, 40 (53%) of 76 patients whose partners had sperm dysfunction, 26 (50%) of 52 patients with tubal disease and in 28 (44%) of 63 patients with unexplained infertility. By comparison, in a control group of 67 parous volunteers, 19 (28%) were found to have PCO. PCO patients with unexplained infertility had higher midfollicular luteinizing hormone and testosterone compared with the group with normal ovaries. The prevalence of PCO was significantly higher in each of the infertility groups than in controls, and a similar tendency (not significant) was observed among women with unexplained infertility. Ovulatory PCO women with infertility had higher testosterone concentrations in comparison with PCO controls. In summary, the prevalence of PCO among ovulatory women with infertility is higher than that in the normal population, suggesting that PCO may, perhaps by virtue of an effect of hyperandrogenaemia, contribute to the causes of subfertility in women with regular menses.

Adult↗
PubMed1999

Effects of follicle-stimulating hormone and serum substitution on the in-vitro growth of human ovarian follicles.

In-vitro maturation (IVM) of human ovarian follicles and oocytes could benefit infertile women, and allow the development of in-vitro systems for the study of human follicular development. Little is known about the initiation of growth of primordial follicles and the regulation of early folliculogenesis. An ovarian tissue-slice culture system was used to examine the effects of media composition, follicle stimulating hormone (FSH) and serum substitution on the development of small human follicles in vitro. Human ovarian cortex biopsies were cut into small pieces and cultured for 5, 10 or 15 days. Control (non-cultured) and cultured tissue was fixed, serially sectioned, and stained. The follicles contained within the tissue pieces were counted, measured, and assessed for stage of development and viability. Comparison of the ability of alpha-minimum essential medium (alpha-MEM), Waymouth's, or Earle's balanced salt solution (EBSS) culture media (all with 10% human serum) to support follicle growth demonstrated significantly increased initiation and growth of follicles in alpha-MEM during the first 10 days of culture. The supplementation of alpha-MEM with 300 mIU/ml FSH significantly reduced levels of atresia and increased the mean diameter of healthy follicles. Follicles in tissue cultured for 10 days with human serum albumin and ITS (insulin/transferrin/selenium mix) were significantly larger, more developed and showed significantly less atresia than those cultured with serum alone. Primordial to small preantral follicles can be grown under serum-substituted conditions in tissue-slice culture, and are responsive to FSH, which is thought to be acting mainly as a survival factor at these early stages.

Adult↗
PubMed1999

Oral contraceptive use: implications for cognitive and emotional functioning.

This study investigated the role of oral contraception use versus nonuse as a moderator variable differentially influencing cognitive-emotional processes. Seventy-six healthy women (29 users and 47 nonusers; 18 to 48 years old), completed the State-Trait Anger Expression Inventory, the Clinical Analysis Questionnaire, the Rotter Scale of locus of control, the Daily Hassles Scale, and a Repertory Grid. A subsample (N = 33) also volunteered for a blood draw. Hormonal levels of progesterone and estrogen mostly were unrelated to cognitive and emotional measures, and contraindicated the "chemical suppression" proposition. Alternatively, when cognitive-emotional functioning was examined separately for users and nonusers, cognitive factors including the appraisal of stress, loci of control, and self-integration were implicated with specific patterns of negative affect and much more so for users than for nonusers. For the most part, oral contraceptive use versus nonuse seemed to influence the saliency rather than the nature of cognitive-emotional patterns. Discussion focused on oral contraceptive use as a moderator variable and the need for longitudinal research to clarify the evolving, biopsychosocial influence of hormonal regulatory treatment.

Adolescent↗
PubMed1999

A new contributing factor to polycystic ovary syndrome: the genetic variant of luteinizing hormone.

Although the etiology of polycystic ovary syndrome (PCOS) is still unclear, LH is considered to play a central role in its pathogenesis. An immunologically anomalous form of LH, with two point mutations in the LHbeta gene, has been recently described. This genetic variant of LH (v-LH), of wide geographic distribution, is functionally different from wild-type (wt) LH. To assess the role of the v-LH in PCOS, we analyzed its frequency in groups of PCOS patients from Finland, The Netherlands, the United Kingdom, and the United States. The LH status was determined by two immunofluorometric assays from a total of 1466 subjects. The carrier frequency of the v-LH allele in the whole study population was 18.5%, being highest (28.9%) in Finland and lowest (11.2%) in The Netherlands. In the individual countries, the frequency of v-LH was similar in obese and nonobese controls, but in The Netherlands and Finland, it was 5- to 7-fold lower in obese PCOS subjects compared with that in the other groups (2-4.5% vs. 10.3-33.3%; P < 0.05). A similar tendency was found in the United States (5.7% vs. 11.1-25.0%), but not in the United Kingdom. The overall high prevalence of v-LH in healthy women and women with PCOS suggests that it is compatible with fertility. The similar frequency of v-LH in healthy nonobese and obese women indicates that obesity per se is not related to the variant. In contrast, the lower frequency of v-LH in obese PCOS patients suggests that v-LH somehow protects obese women from developing symptomatic PCOS. However, the regional differences in this finding between patients with apparently similar diagnostic criteria emphasizes the multifactorial nature of this syndrome, and that its pathogenesis may vary according to the genetic background. Although the definitive role of v-LH in PCOS remains to be proven, its determination may improve the prediction of risk of PCOS, especially in obese women.

Adolescent↗
PubMed1999

Genetic abnormalities in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a very common endocrinopathy and is the major cause of anovulatory infertility. It is also associated with an increased risk of non insulin dependent diabetes (NIDDM) in later life. Despite the importance of PCOS to women's health, little is known about its aetiology. Because of the well-known familial clustering of cases of PCOS, recent studies in our department have focused on clinical and molecular genetic studies in an attempt to identify key genes which may be involved in its aetiology. We have found evidence that a polymorphism in the regulatory region of CYP11a (encoding P450 cholesterol side chain cleavage, also an important enzyme in the steroidogenic pathway) is associated with and linked to PCOS. In examination of the insulin gene (INS), we have shown, in three separate populations, that class III alleles in the INS-VNTR (the minisatellite in the regulatory region of the insulin gene) are associated with PCOS. Variation in this element has also been implicated in the aetiology of NIDDM. We propose that PCOS is an oligogenic disorder in which a small number of key genes interact with environmental factors (notably dietary), the balance of which factors determine, the typically heterogeneous, clinical and biochemical phenotype.

Cholesterol Side-Chain Cleavage Enzyme↗
PubMed1998

Genetics of polycystic ovary syndrome.

We have found evidence for the involvement of two major genes in the aetiology of PCOS. The results of both linkage and association studies suggest that CYP11a (coding for P450 cholesterol side chain cleavage) and the insulin VNTR regulatory polymorphism are important genes in the aetiology of PCOS and may explain, in part, the heterogeneity of the syndrome. Differences in expression of CYP11a could account for variation in androgen production in women who have polycystic ovaries and those subjects who are homozygous for III alleles at the insulin gene VNTR locus are more likely to be hyperinsulinaemic. It is likely that other genes are involved in the aetiology of PCOS. Recent results lend weight to the idea that PCOS represents a complex trait in which several genes--but perhaps a relatively small number of key genes--contribute, in conjunction with nutritional factors, to the observed clinical and biochemical heterogeneity.

Androgens↗
PubMed1998

Growth hormone and ovarian function.

Growth and reproductive development are closely co-ordinated during puberty but there is also evidence that growth hormone (GH) may have a physiological role in adult ovarian function. Both GH and the insulin-like growth factors (IGFs) have been shown to augment granulosa cell proliferation and steroidogenesis in the human Graafian follicle, suggesting that GH may act as a 'co-gonadotrophin' at ovarian level. Furthermore, the intra-ovarian 'IGF system' (i.e. IGFs and IGF-binding proteins) may be implicated in folicular atresia and in disorders of follicular function associated with polycystic ovary syndrome (PCOS). The clinical importance of GH to ovarian function in the adult is illustrated by the finding that adjuvant GH treatment reduces the dose of exogenous gonadotrophin which is required to induce folliculogenesis in women with hypogonadotrophic hypogonadism. There is, however, no evidence that GH supplementation is of significant clinical benefit in the management of patients with other ovulatory disorders--including PCOS--or in superovulation protocols for in vitro fertilization.

Adult↗
PubMed1998

Regulation of epidermal growth factor receptor by androgens in human endometrial cells in culture.

Women with polycystic ovaries (PCO) have a thicker endometrium than women with normal ovaries. This cannot be due to unopposed oestrogen, as it occurs in ovulatory cycles. Androgens may be involved, as these are raised in women with PCO. The effects of steroids are partly mediated by growth factors and their receptors. The aim of this study was to investigate the effect of androgens on epidermal growth factor (EGF) receptor in human endometrium. Endometrium was enzymatically dispersed and glands and stromal cells separated. Cells were incubated in Ham's F10 medium supplemented with 5% charcoal-stripped fetal calf serum and either androgens or vehicle. Specific binding of [125I]-labelled EGF was measured. Testosterone and dihydrotestosterone (DHT) (10 micromol/l) increased EGF receptor concentration (control 100 +/- 9%, testosterone 196 +/- 23% control; control 100 +/- 1%, DHT 244 +/- 6% control) but did not alter receptor affinity. The effect of testosterone was inhibited by the anti-androgen hydroxyflutamide, but not by the antioestrogen ICI182780 nor the aromatase inhibitor 4-hydroxyandrostenedione. EGF receptor levels were increased by androstenediol (control 100 +/- 2%, androstenediol 120 +/- 10% control) but not by androstanediol, dehydroepiandrosterone (DHA), DHA sulphate or androstenedione. Testosterone and DHT increased EGF receptor concentrations in glandular epithelium (control 100 +/- 24%, testosterone 147 +/- 5%, DHT 185 +/- 30% control). These data suggest that androgens may have an effect on the endometrium via an increase in EGF receptor concentrations.

Androgens↗
PubMed1998

Potent inhibition of human ovarian steroidogenesis by insulin-like growth factor binding protein-4 (IGFBP-4).

Several studies have now documented the existence of IGFBPs in follicular fluid and their correlation with the health of the follicle. In particular, increased levels of IGFBP-4 have been reported in androgen-dominant atretic follicles and those from polycystic ovaries. The aim of this study was to elucidate the role of IGFBP-4 in ovarian steroidogenesis. Granulosa cells and theca tissue were incubated with or without LH or FSH in the presence or absence of IGFBP-4 (0.5-50 ng/ml). Inhibition by IGFBP-4 of estradiol production in the presence of testosterone alone was seen in three of four experiments. IGFBP-4 completely inhibited FSH-stimulated estradiol production in three experiments and caused 67% inhibition in a fourth. Similar results were obtained for theca, in which concurrent incubation with IGFBP-4 completely negated the stimulatory effects of LH on androstenedione production. The mechanism by which IGFBP-4 exerts these potent effects and the possibility that this may by IGF-independent are currently being investigated.

Androstenedione↗
PubMed1998

Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation.

Polycystic ovary syndrome is the most common cause of anovulatory infertility. Anovulation in polycystic ovary syndrome is characterized by the failure of selection of a dominant follicle with arrest of follicle development at the 5-10 mm stage. In an attempt to elucidate the mechanism of anovulation associated with this disorder we have investigated at what follicle size human granulosa cells from normal and polycystic ovaries respond to LH. Granulosa cells were isolated from individual follicles from unstimulated human ovaries and cultured in vitro in serum-free medium 199 in the presence of LH or FSH. At the end of a 48-h incubation period, estradiol (E2) and progesterone (P) were determined in the granulosa cell-conditioned medium by RIA. In ovulatory subjects (with either normal ovaries or polycystic ovaries), granulosa cells responded to LH once follicles reached 9.5/10 mm. In contrast, granulosa cells from anovulatory women with polycystic ovaries responded to LH in smaller follicles of 4 mm. Granulosa cells from anovulatory women with polycystic ovaries were significantly more responsive to LH than granulosa cells from ovulatory women with normal ovaries or polycystic ovaries (E2, P < 0.0003; P, P < 0.03). The median (and range) fold increase in estradiol and progesterone production in response to LH in granulosa cell cultures from size-matched follicles 8 mm or smaller were E2, 1.0 (0.5-3.9) and P, 1.0 (0.3-2.5) in ovulatory women and E2, 1.4 (0.7-25.4) and P, 1.3 (0.3-7.0) in anovulatory women. Granulosa cells from anovulatory (but not ovulatory) women with polycystic ovaries prematurely respond to LH; this may be important in the mechanism of anovulation in this common endocrinopathy.

Adult↗
PubMed1998

Developmentally regulated responses of human granulosa cells to insulin-like growth factors (IGFs): IGF-I and IGF-II action mediated via the type-I IGF receptor.

In experimental animal models, insulin-like growth factors (IGFs) have been found to be more potent stimulators of ovarian function than insulin. In human theca cells, however, insulin, IGF-I, and IGF-II have similar effects on androgen production. The relative effects of insulin and IGFs on human granulosa cell steroidogenesis is unknown. Furthermore, it is unclear whether effects of IGF-II on steroidogenesis are mediated by the type-I or type-II IGF receptor. The effects of insulin, IGF-I, and IGF-II on human granulosa cell steroidogenesis were compared in vitro. As expected, insulin, IGF-I, and IGF-II enhanced steroidogenesis. Previously, IGF-II has been shown to enhance granulosa cell steroid production after insulin preincubation. In this study, an effect of IGF-II, independent of insulin priming, also was observed. In granulosa cell cultures from small antral follicles (< or = 13 mm), insulin and IGF-I stimulated steroid production to a similar degree, whereas IGF-II was less effective. In contrast, IGFs were more effective than insulin (IGF-I > IGF-II > insulin) in granulosa cells isolated from preovulatory follicles. IGF-I and IGF-II actions were mediated via the type-1 IGF receptor. The increased responsiveness of mature granulosa cells to IGFs may be an important mechanism by which granulosa cells increase their steroidogenic output in the preovulatory follicle.

Cells, Cultured↗
PubMed1997

Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Women with anovulatory PCOS have hyperinsulinaemia, insulin resistance, and dyslipidaemia, and the syndrome is associated with greatly increased risks of non-insulin-dependent diabetes mellitus and cardiovascular disease and it often clusters in families. The VNTR (variable number of tandem repeats) locus upstream of the insulin gene (INS) regulates insulin expression. We have studied INS VNTR as a candidate genetic locus for susceptibility to PCOS. METHODS: We evaluated linkage of PCOS to the INS VNTR locus on chromosome 11p15.5 in 17 families with several cases, and looked for an association between VNTR and PCOS in two additional clinic populations. VNTR genotypes were designated I/I, I/III, and III/III and linkage disequilibrium mapping was used to test the primary role of the VNTR. FINDINGS: In a group of PCOS/male pattern baldness families, we obtained positive evidence for linkage to 11p15.5 (p = 0.002). The INS VNTR III/III genotype was associated with an increased risk of PCOS in two independent case-control studies (odds ratios 8.20 [p = 0.005] and 5.70 [p = 0.043]). Multilocus linkage disequilibrium mapping suggests that VNTR itself is the predisposing locus. INTERPRETATION: Mapping of susceptibility to PCOS to the INS VNTR implies that PCOS is due, in part, to an inherited alteration in insulin production. The data suggest a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life.

Alleles↗
PubMed1997

Modelling the control of ovulation and polycystic ovary syndrome.

The control of ovulation in mammalian species appears to be a highly robust process. The primary mechanism is believed to be competition amongst a group of developing follicles, mediated by a hormonal feedback loop involving in the first instance the pituitary. Successful follicles reach maturity and ovulate, the remainder atrophy and die. A model of this control process has been derived by Lacker and his group. Based on simple qualitative assumptions about the hormonal feedback loop, this is able to reflect many of the basic physiological features of ovulation in mammals. However, a fundamental hypothesis of Lacker's work is that all follicles are identical and respond to hormonal signals in precisely the same way. Not only is this improbable, but it also leads to several aspects of the model which are qualitatively unrealistic, most notable of these is its inability to accurately model the condition known as Polycystic Ovary Syndrome. This common malfunction of the ovulatory control mechanism accounts for up to three-quarters of cases of anovulatory infertility in humans and its understanding is therefore of considerable medical significance. In this paper we extend the analysis of Lacker's model to the case of non-identical follicles; this allows us to obtain behaviour much closer to that observed in PCOS patients and to draw some tentative conclusions about the mechanisms underlying this condition.

Animals↗
PubMed1997

Mechanical isolation and in vitro growth of preantral and small antral human follicles.

OBJECTIVE: To develop a procedure for isolating small human follicles and to determine their growth requirements. DESIGN: Preantral and early antral follicles were isolated manually, allocated randomly to experimental groups, and cultured for a few weeks. SETTING: Patients giving informed consent in hospitals. PATIENT(S): Women undergoing laparotomy or oophorectomy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Follicular size, E2, histology. RESULT(S): Human FSH (at a dose of 1.5 U/mL) induced antral growth of follicles, and the addition of human LH (2.5 ng/mL) to human FSH stimulated growth and antral development. Histologic studies showed that most of the early antral follicles did not contain an oocyte and already had begun to undergo atresia before culturing. Levels of E2 increased in the incubation medium as the follicles increased in size, but those levels were significantly greater when the follicles contained oocytes. CONCLUSION(S): It is possible to grow small human follicles after they have been isolated manually. To develop successfully, they require a low concentration of human LH in addition to human FSH. The rate of atresia between the preantral and early antral stages in vivo is very high; therefore, it is worthwhile to develop techniques for isolating and culturing the follicles before the antral stages.

Adult↗
PubMed1997

Local control of ovarian steroidogenesis.

A number of putative paracrine factors are now thought to interact with FSH in the control of ovarian steroidogenesis. The relative importance of these factors remains to be determined, but the presence of the insulin-like growth factors and their binding proteins and the mechanism of control of the latter through the local production of proteases suggests a role for this system in folliculogenesis. We have demonstrated over-production of steroid hormones in tissue from women with polycystic ovaries. Theca cells in monolayer culture produced excessive amounts of progesterone and androstenedione and granulosa cell oestradiol production was considerably enhanced in response to FSH. Recent evidence points to a genetic defect in the expression or translation of steroidogenic hormones as a cause of excess androgen production, but the gene or genes involved has not been established. Data from our group suggest that granulosa cells from anovulatory polycystic ovaries are prematurely matured and we hypothesize that this is due to the interaction of the raised circulating insulin levels with LH in these follicles, an interaction that results in arrested follicular growth.

Androgens↗