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PubMed2006

Vascular endothelial growth factor and basic fibroblast growth factor in polycystic ovary syndrome during controlled ovarian hyperstimulation.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that causes anovulation and consequent subfertility. It is well established that increased ovarian mass, supported by new blood vessel proliferation in stroma and theca, is a key feature of PCOS. Recent studies suggest a role for angiogenetic factors in this phenomenon. AIM: To evaluate of levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in serum and follicular fluid of PCOS patients during a controlled ovarian hyperstimulation. METHODS: In 52 patients undergoing in vitro fertilization treatments, 26 PCOS patients and 26 controls, serum VEGF and bFGF levels were assessed before starting administration of follicle-stimulating hormone (FSH) (day 0), on the day of administration of human chorionic gonadotropin (hCG) and on the day of oocyte retrieval. Follicular fluid levels of the two growth factors were detected on the day of oocyte retrieval. RESULTS: PCOS patients showed higher serum VEGF levels than controls before starting FSH administration, on the day of hCG administration and on the day of oocyte retrieval. Serum VEGF levels showed a rise after hCG administration only in the PCOS patients. In addition, serum bFGF levels were higher in PCOS patients than in controls on the day of hCG administration and the day of oocyte retrieval. Furthermore, on the day of hCG administration, serum bFGF levels were directly correlated to the amount of FSH previously administered (p < 0.0001). In follicular fluid, higher VEGF and bFGF levels were found in PCOS patients than in controls. Furthermore, follicular-fluid bFGF concentrations were inversely correlated with the percentage of mature oocytes collected (p < 0.05). CONCLUSIONS: The present study revealed elevated levels of VEGF and bFGF in serum and follicular fluid in PCOS patients compared with controls. bFGF seems to be an FSH-dependent growth factor and its levels in follicular fluid are inversely correlated with the percentage of mature oocytes collected.

Case-Control Studies↗
PubMed2006

Mutation analysis of the WNT-4 gene in patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of childbearing age and is characterized by chronic anovulation with either oligomenorrhea or amenorrhea and hyperandrogenism. The etiology of this entity remains unknown. It has been suggested that genomic variants in genes related to the regulation of androgen biosynthesis and function could be involved in genetic predisposition to PCOS. WNT-4 is a member of the WNT family of secreted molecules. Studies on female Wnt-4 knockout mice have suggested that this gene suppresses gonadal androgen synthesis in normal females. We investigated if 25 women with PCOS presented mutations in WNT-4 as the cause of their disorder. Direct sequencing of all five exons demonstrated no mutant alleles in any patient. This study demonstrates that, at least in the population studied, mutations of the open reading frame of WNT-4 gene or its intron/exon junctions are not the cause of PCOS. However, the present data do not rule out the possible existence of causative mutations in the WNT-4 gene promoter region.

Adolescent↗
PubMed2006

Early severe pre-eclamptic findings in a patient with Cushing's syndrome.

Cushing's syndrome occurs rarely in pregnancy because of ovulatory disturbances including anovulation which is caused by hypercortisolism, but it can cause maternal complications such as hypertension, gestational diabetes, spontaneous abortion, premature birth, pre-eclampsia and stillbirth. Herein we present the case of a 22-year-old patient in the 11th week of pregnancy who was admitted to our hospital with Cushing's syndrome complicated by early pre-eclampsia. Severe pre-eclampsia has high maternal and perinatal morbidities, and therefore the possibility of this complication requires that Cushing's syndrome, although rare in pregnancy, be given a high clinical suspicion. Medical therapy and/or surgical therapy should be considered promptly to influence outcome favorably.

Adrenal Cortex Neoplasms↗
PubMed1999

Diagnosis of subtle ovulation disorders in subfertile women with regular menstrual cycles: cost-effective clinical practice?

Serial monitoring by plasma progesterone measurement is advised in the literature for fertility work-up, to detect ovulation disturbances in women presenting with regular menstrual cycles. Three strategies to diagnose such 'subtle ovulation disorders' (SOD, defined as anovulation, inadequately timed ovulation or ovulation of a follicle of reduced size in regularly cycling women) were evaluated, in order to investigate costs of such a diagnosis. On the basis of a 'maximal', an 'ultrasound-only', and a 'preselection' strategy, total medical costs and costs including non-medical costs were calculated for each SOD diagnosis. A 'maximal' diagnostic strategy resulted in a total medical cost of ECU 9057 per diagnosis (including non-medical costs ECU 12,787); an 'ultrasound-only' strategy in ECU 4520 (ECU 6791) per diagnosis. By use of a 'preselection' strategy, 4.25% of the women were found to have an SOD, at a cost of ECU 3036 (ECU 6868) for each diagnosis. As the real significance of SOD diagnosis for the prognosis of the patient to become pregnant without treatment remains unclear, and as no randomized trials on treatment effectiveness have as yet been undertaken, it is questionable whether this approach is worthwhile.

Blood Chemical Analysis↗
PubMed2005

Contraception during perimenopause.

Perimenopause marks the transition from normal ovulation to anovulation and ultimately to permanent loss of ovarian function. Fecundity, the average monthly probability of conception, declines by half as early as the mid-forties, however women during the perimenopause still need effective contraception. Issues arising at this period such as menstrual cycle abnormalities, vasomotor instability, the need for osteoporosis and cardiovascular disease prevention, as well as the increased risk of gynecological cancer, should be taken into consideration before the initiation of a specific method of contraception. Various contraceptive options may be offered to perimenopausal women, including oral contraceptives, tubal ligation, intrauterine devices, barrier methods, hormonal injectables and implants. Recently, new methods of contraception have been introduced presenting high efficacy rates and minor side-effects, such as the monthly injectable system, the contraceptive vaginal ring and the transdermal contraceptive system. However, these new methods have to be further tested in perimenopausal women, and more definite data are required to confirm their advantages as effective contraceptive alternatives in this specific age group. The use of the various contraceptive methods during perimenopause holds special benefits and risks that should be carefully balanced, after a thorough consultation and according to each woman's contraceptive needs.

Contraception↗
PubMed2000

Insulin sensitivity and fertility.

This review sets in context significant recent advances in the understanding of the pathophysiology of polycystic ovary syndrome (PCOS). The occurrence of variable insulin sensitivity in individuals is discussed. Information is presented to demonstrate that prolonged anovulation decreases insulin sensitivity and, conversely, that improvement in insulin sensitivity normalizes ovarian function in PCOS. In addition, a meta-analysis of studies on metformin and troglitazone treatment in PCOS is presented.

Journal Article↗
PubMed2000

Function of the polycystic ovary.

The mechanism of the increase in the number of follicles in polycystic ovaries (PCO) is still not understood, but most data indicate that folliculogenesis is abnormal at all stages. This increase is probably due to prolonged follicle growth in both ovulatory (ov) and anovulatory PCO (anovPCO) rather than over-recruitment from the primordial stage. There appear to be fewer follicles in ovPCO than in anovPCO and this may be due to slow growth combined with arrested development in the anovPCO, preventing the normal process of atresia. This idea is supported by data indicating that the preponderance of structures in anovPCO are functional follicles rather than atretic cysts. In contrast, follicles in ovPCO are primarily atretic, analogous to the situation in the normal ovary. Closer analysis of the function of these follicles reveals an intrinsic defect in the theca cell layer in the expression of the genes encoding steroidogenic enzymes. Although androgen production is increased in all PCOs, the serum concentrations of androgen tended to be higher in anovulatory women indicating that there may be a link between the ovarian concentration and anovulation. Granulosa cells in small follicles from anovPCO behave in a similar fashion to those in preovulatory follicles from normal ovaries in terms of steroidogenic responses. This, in combination with the finding of LH-responsiveness in small follicles from anovPCO, has led to the suggestion that these follicles are prematurely luteinized. The recent finding that follistatin gene regulation may be abnormal in women with polycystic ovary syndrome (PCOS) provides a new insight into the possible defect in the function of these ovaries. Elucidation of the precise nature of the defect may provide the key to understanding the apparent contradiction of increased steroidogenesis in the presence of abnormal and arrested follicle growth.

Journal Article↗
PubMed2000

The role of inhibin in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder which, in its severest manifestations, is associated with anovulation, hyperandrogenism and metabolic imbalance. The biochemical markers for the condition can include a significantly raised LH:FSH ratio and a raised testosterone concentration, indicating a derangement of the hypothalamo--pituitary--ovarian axis which may be primary or secondary to a primary ovarian pathology. The bioactive inhibins are heterodimeric glycoproteins consisting of alpha-betaA (inhibin A) and alpha-betaB (inhibin B) subunits. They play an endocrine role in co-regulating (with oestradiol) the suppression of FSH during the late follicular and luteal phases of the ovarian cycle and they are implicated in intraovarian paracrine signalling. Inhibin B, which is the predominant form in small pre-ovulatory follicles, increases in concentration from early in the follicular phase to reach a peak coincident with the onset of the decrease in FSH which forms the basis of the pattern of mono-ovulation seen in normo-ovulatory women. Several unique features of the dysovulation of women with PCOS, namely their failure to recruit and develop a dominant follicle despite having 'normal' concentrations of endogenous FHS, the raised LH:FSH ratio and their exquisite sensitivity to exogenous FSH injections, may be explained by their significantly higher inhibin B concentrations. Studies into inhibin B parameters in women with PCOS demonstrate that women with anovular PCOS have significantly higher concentrations of circulating inhibin B and that they lack the pulsatile pattern of secretion that can be detected in normo-ovulatory women during the mid-follicular phase. The inhibin B response to ovulation induction with clomiphene citrate in women with PCOS differs from that in normo-ovulatory women taking the antioestrogen. Women with PCOS who over-respond to ovulation induction with injected FSH in a 'low-dose' step-up protocol' and recruit multiple follicles have significantly higher concentrations of pre-treatment inhibin B than PCOS subjects who do not.

Journal Article↗
PubMed1996

Unraveling bleeding problems in midlife women.

Menopause often is accompanied by abnormal uterine bleeding-mostly due to anovulation and correctable with hormone therapy. However, all patients should be fully evaluated for gynecologic and nongynecologic causes of bleeding.

Acute Disease↗
PubMed2001

Polycystic ovary syndrome: relationship between insulin sensitivity, sex hormone levels and ovarian stromal blood flow.

Polycystic ovary syndrome (PCOS) is the most common cause of menstrual disorders, and is characterized by chronic anovulation, hyperandrogenism and infertility. In recent years, it has become apparent that PCOS is also associated with hyperinsulinemia that is probably central to the pathogenesis of PCOS. As a peculiar vascular pattern has been reported to be present in PCOS, the aim of this study was to investigate intraovarian stromal vascularization in PCOS patients and its possible correlation with sex hormones, gonadotropins and insulin levels. Twenty-eight oligomenorrheic or amenorrheic patients with PCOS and 14 eumenorrheic women with a PCOS-like ovarian pattern undergoing endocrine screening and ultrasound color Doppler intraovarian blood flow were recruited to the study. Ten healthy women with regular menses represented the control group. Hormonal assays (follicle-stimulating hormone (FSH), luteinizing hormone (LH), androstenedione, testosterone, sex hormone-binding globulin (SHBG) and estradiol), oral glucose tolerance test (OGTT), baseline and glucose-induced insulin levels, and transvaginal ultrasonographic and color Doppler analysis (pulsatility index (PI), resistance index (RI) and velocity (Vmax) of ovarian stromal flow) were performed in all participants in the early proliferative phase. Endocrine values showed significant differences in PCOS patients compared with PCOS-like women and controls, while PI and RI indices were significantly higher in controls. PCOS patients were divided into hyperinsulinemic (n = 16) and normoinsulinemic (n = 12). Androstenedione was significantly higher (p < 0.01) in the hyperinsulinemic than in the normoinsulinemic patients and controls, while SHBG was significantly (p < 0.01) lower in the hyperinsulinemic group. Analysis of color Doppler intraovarian vascularization showed a significantly lower RI and a higher Vmax in the hyperinsulinemic subjects than in the normoinsulinemic PCOS patients and controls. An increased stromal blood flow was observed in the PCOS and PCOS-like patients by transvaginal color Doppler evaluation, but this technique is not able to differentiate these two similar ovarian patterns. However, hyperinsulinemic PCOS patients had an increased vascularity of the ovarian stroma. A strong correlation between hyperinsulinemia, hyperandrogenism and low SHBG levels was evidenced, and a hyperinsulinemia-induced mechanism for ovarian stromal angiogenesis is discussed.

Adult↗
PubMedDate not supplied

A survey of gynecologists concerning menorrhagia: perceptions of bleeding disorders as a possible cause.

We sought to determine perceptions and practices of American gynecologists when treating with a woman complaining of menorrhagia, specifically with regard to an underlying bleeding disorder as a potential cause. A mail survey of Georgia members of the American College of Obstetricians and Gynecologists was conducted. The survey response was 52%, and the analysis includes 376 physicians who reported seeing at least one gynecological patient per week. On average, respondents were in practice 20 years and reported that 8% of their patient population complain of menorrhagia. Virtually all physicians reported employing a menstrual history as a starting point for the workup for menorrhagia, and 95% order a hemoglobin/hematocrit determination. About 50% of physicians considered saturating three tampons/pads per 4 hours as excessive, although the criterion varied widely (range 0-24 per 4 hours, SD = 3). The diagnoses considered most likely among reproductive age women were anovulatory bleeding or benign lesions or that the heavy bleeding was within normal limits. Only 4% of physicians would consider von Willebrand disease (VWD) for this age group (women of reproductive age). Among girls near menarche, physicians overwhelmingly consider anovulatory bleeding or bleeding within normal limits the likely diagnoses, and 16% would consider VWD in this age group. Only rarely (3%) do surveyed physicians refer menorrhagia patients to other specialists. Most respondents believe that most menorrhagia is caused by anovulation or is within normal limits. Bleeding disorders are believed to be a rare cause of menorrhagia.

Adolescent↗
PubMed1999

Vegetarianism and menstrual cycle disturbances: is there an association?

The question of whether menstrual disturbances are more common in vegetarian than in nonvegetarian women is complex. Disturbances of the cycle may be clinical (ie, amenorrhea or oligomenorrhea) or subclinical (i.e., normal-length cycles with anovulation or a short or defective luteal phase). Detection of the latter requires that the menstrual cycle be monitored, but may help prevent recruitment bias in studies comparing vegetarians with nonvegetarians because vegetarians with menstrual disturbances may be more likely to volunteer for a study on menstrual disturbances and vegetarianism. Three general mechanisms that could contribute to menstrual disturbances that may differ between vegetarians and nonvegetarians include energy imbalances associated with body-weight disturbances or exercise, psychosocial and cognitive factors, and dietary components. Evidence for each of these mechanisms is reviewed and studies comparing menstrual function between vegetarians and nonvegetarians are described in this article. Although results from several cross-sectional studies suggest that clinical menstrual disturbances may be more common in vegetarians, a prospective study that controlled for many potential confounders found that subclinical disturbances were less common in weight-stable, healthy vegetarian women. Because the sample studied may not be representative of all vegetarian women, however, these results cannot be generalized. Population studies are needed to draw definitive conclusions.

Body Weight↗
PubMed1997

The use of laparoscopic ovarian electrocautery in preventing cancellation of in-vitro fertilization treatment cycles due to risk of ovarian hyperstimulation syndrome in women with polycystic ovaries.

Fifty women with polycystic ovaries took part in a prospective randomized study. All women required treatment by in-vitro fertilization (IVF) for reasons other than anovulation. They had all previously undergone ovarian stimulation with gonadotrophin therapy which had failed to result in pregnancy or had been abandoned due to high risk of developing ovarian hyperstimulation syndrome (OHSS). Twenty-five women were treated by long-term pituitary desensitization followed by gonadotrophin therapy, oocyte retrieval and embryo transfer (group 1). Twenty-five women underwent laparoscopic ovarian electrocautery after pituitary desensitization followed by gonadotrophin therapy, oocyte retrieval and embryo transfer (group 2). A significantly higher number of women in group 1 had to have the treatment cycle abandoned due to impending or actual OHSS, determined by endocrine and clinical findings. In addition, the development of moderate or severe OHSS in completed cycles was higher in group 1. The pregnancy rate and miscarriage rates in the two treatment groups were similar. The authors propose that laparoscopic ovarian electrocautery is a potentially useful treatment for women who have previously had an IVF treatment cycle cancelled due to risk of OHSS or who have suffered OHSS in a previous treatment cycle.

Abortion, Spontaneous↗
PubMed1997

Influences of weight, body fat patterning and nutrition on the management of PCOS.

Polycystic ovary syndrome (PCOS) is a heterogeneous clinical entity that is defined as the association of hyperandrogenism with chronic anovulation in women without specific underlying diseases of the adrenal or pituitary glands. PCOS is also associated with a metabolic disturbance (insulin resistance). The nature of the complex interrelation of obesity, insulin resistance and endocrine abnormalities in PCOS remains unresolved. However, several studies link obesity, body fat distribution and nutritional habitus with the hormonal and metabolic profiles of PCOS. Moreover, intervention studies have suggested that reducing weight and/or hyperinsulinaemia either by diet alone or by a combination of diet and drugs improves hirsutism, fertility and the hormonal and metabolic profiles of PCOS. In fact, the evaluation of nutritional factors in PCOS is helpful for the screening of metabolic abnormalities and the management of women with PCOS. A point of particular interest in the management of PCOS is that the choice of contraception remains difficult in these high cardiovascular risk women. The impact of pills with ethinyl oestradiol on weight, body fat distribution and carbohydrate metabolism in women with PCOS has not been thoroughly evaluated. The lack of prospective studies to evaluate long-term metabolic and cardiovascular tolerance necessitates care and the assessment of other hormonal possibilities.

Body Constitution↗
PubMed1998

Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity.

Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low-dose regimen of the potent new antiprogestin ZK 137 316, which permits continued menstrual cyclicity but alters gonadal-reproductive tract activity, was established. Rhesus monkeys received vehicle (n = 6) or 0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01 mg/kg ZK 136317 permitted normal menstrual cyclicity in macaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation was disrupted in some animals. Increasing the dose to 0.1 mg/kg antagonized pituitary function and resulted in anovulation and amenorrhoea. A chronic low-dose regimen of the antiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity, has potential as a contraceptive in women.

Animals↗
PubMed1999

Clinical outcome after unilateral oophorectomy in patients with polycystic ovary syndrome.

The objective of this study is to report retrospectively on the clinical outcome of unilateral oophorectomy in 14 women with polycystic ovary syndrome who had undergone this treatment 14-18 years ago in our hospital for clomiphene citrate-resistant anovulation and long standing infertility or for severe hirsutism. The main outcome measures were menstrual cycle, pregnancy, hirsutism, testosterone concentrations, and premature ovarian failure. Unilateral oophorectomy restored regular menstrual cycles in 12 of the 14 patients. Thirteen years later, nine out of 12 patients still had regular menstrual cycles. Ten patients wished to become pregnant. Seven of them conceived spontaneously. Eleven patients complained of severe hirsutism. After unilateral oophorectomy, hirsutism regressed subjectively in six. Testosterone blood concentrations decreased significantly within the first year after unilateral oophorectomy in 11 patients. None of the women entered menopause within 14-18 years after surgery. Our results indicate that unilateral oophorectomy restores ovulatory function for many years in the majority of patients and does not result in premature ovarian failure. However, unilateral oophorectomy should not be recommended as a standard treatment for clomiphene citrate-resistant patients with polycystic ovary syndrome.

Adult↗
PubMed2001

Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells.

BACKGROUND: The present study was conducted to investigate the effect of androstenedione, insulin and LH on human granulosa cell oestrogen and progesterone production. We postulated that elevated concentrations of androstenedione, insulin and LH may be important modulators of granulosa cell steroidogenesis. METHODS: Granulosa cells obtained in connection with IVF procedures were cultured for a total of 4 days in serum-free medium containing androstenedione (10(-6) mol/l). We tested the effect of androstenedione (10(-5) mol/l) on insulin (0-800 microIU/ml), LH (1-10 ng/ml) as well as on insulin + LH-stimulated oestrogen and progesterone production. RESULTS: Insulin increased the basal secretion of steroid hormones, and furthermore augmented LH-stimulated oestrogen and progesterone accumulation in granulosa cell cultures. Androstenedione (10(-5) mol/l) stimulated basal oestrogen production, but significantly reduced (32-58%) insulin + LH-stimulated oestrogen and progesterone secretion (P < 0.05). CONCLUSION: These results suggest that high androstenedione concentrations may act directly to impair insulin augmentation of LH-stimulated oestradiol and progesterone production in cultured human granulosa luteal cells. This is compatible with the hypothesis that high androgen levels may inhibit oestrogen production in polycystic ovary follicles, and as such may contribute to anovulation and infertility in women with polycystic ovary syndrome.

Androstenedione↗
PubMed2002

Structure of the corpus luteum in the ovulatory polycystic ovary.

BACKGROUND: Women with polycystic ovaries (PCO) have a wide spectrum of presentation from anovulation and amenorrhoea to apparently regular, ovulatory menstrual cycles. We have recently reported a subtle defect in steroidogenic function in the luteal phase in the latter and an increase in the number of degenerating corpora lutea (CL) were observed in ovulatory PCO (ovPCO) during dissection. The possibility was therefore investigated of differences in structure or degeneration in CL formed during ovulatory cycles in women with PCO. METHODS: This study compared the histology of the CL in ovPCO with that in the normal ovary. Corpora lutea were collected from nine normal ovaries (days 1-27 of the cycle) and from 13 women with ovPCO (days 5-38). RESULTS: Variations in the degree of regression, both in relation to onset of menses and between different areas within individual CL, were recorded in both groups. During development and regression no obvious differences were observed between either group apart from an apparent increase in luteal haemorrhage, which was more common and more extensive in CL from PCO. CONCLUSIONS: The findings suggest that possible luteal phase abnormalities of steroid secretion in women with ovulatory PCO are not associated with obvious morphological defects in the CL, however it is possible that the persistence of luteal structures seen in PCO was a consequence of increased luteal haemorrhage.

Corpus Luteum↗