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PubMed2003

Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet.

BACKGROUND: This prospective study evaluated the effect of weight reduction on anthropometric indices and ovarian morphology in anovulatory overweight patients with polycystic ovary syndrome (PCOS). METHODS: Thirty-three anovulatory overweight patients with PCOS were enrolled in the study. All had patent Fallopian tubes and chronic anovulation: 27 of them were oligo-amenorrhoeic. The partners were normospermic. Patients were prescribed a 1200 kcal/day diet, and physical exercise was recommended. Anthropometric indices and ovarian imaging parameters were assessed at baseline and after weight loss of 5 and 10%. RESULTS: Twenty-five patients (76%) lost at least 5% of their body weight. Eleven of these patients (33%) reached a 10% decrease in weight. Waist circumference at the umbilical level, hip circumference, four skin folds, body mass index and fatty mass ratio were significantly reduced after 5 and 10% weight loss. Ovarian morphology changed during the diet: we observed a significant reduction in ovarian volume and in the number of microfollicles per ovary. Among the 27 patients with oligo-amenorrhoea, 18 had a resumption of regular cycles and 15 experienced spontaneous ovulation; 10 spontaneous pregnancies occurred in patients who lost at least 5% of their weight. CONCLUSIONS: Weight loss through a controlled low-calorie diet improves anthropometric indices in obese PCOS patients, reduces ovarian volume and microfollicle number and can restore ovulatory cycles, allowing spontaneous pregnancy.

Adipose Tissue↗
PubMed2004

Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility.

BACKGROUND: Anti-Müllerian hormone (AMH), produced by growing pre-antral and early antral ovarian follicles, has been shown to be a useful marker for ovarian ageing. Serum AMH concentrations are elevated during reproductive life in anovulatory women, especially in those patients exhibiting polycystic ovaries (PCO). The current study was designed to investigate whether the decrease in AMH serum concentrations over time is different comparing women with normogonadotrophic anovulation [World Health Organization (WHO) group 2 (including polycystic ovary syndrome (PCOS)] and normo-ovulatory controls. METHODS AND RESULTS: AMH serum levels were assessed on two occasions in 98 patients suffering from WHO 2 anovulatory infertility as well as in 41 normo-ovulatory premenopausal women. Median time interval between both visits was 2.6 years (range 0.3-9.0) for WHO 2 patients compared with 1.6 years (range 1.0-7.3) in controls. Serum AMH concentrations were significantly (P < 0.0001) elevated on both occasions in WHO 2 patients (AMH1, median = 7.5 microg/l, range 0.1-35.8; and AMH2, median = 6.7 microg/l, range 0.0-30.6) compared with controls (AMH1, median = 2.1 microg/l, range 0.1-7.4; and AMH2, median = 1.3 microg/l, range 0.0-5.0). Regression analysis, corrected for age, indicated a significant relative decrease in serum AMH concentrations over time for both groups (P < 0.001). However, the decline in serum AMH in WHO 2 patients was significantly less compared with controls (P = 0.03). CONCLUSION: The present longitudinal study shows that serum AMH concentrations decrease over time both in women presenting with WHO 2 anovulatory infertility and in normo-ovulatory controls. The decrease in WHO 2 patients is less pronounced despite distinctly elevated concentrations. This observation may suggest retarded ovarian ageing and hence a sustained reproductive life span in these patients.

Adolescent↗
PubMed2004

Does the addition of recombinant LH in WHO group II anovulatory women over-responding to FSH treatment reduce the number of developing follicles? A dose-finding study.

BACKGROUND: In anovulatory women undergoing ovulation induction, addition of recombinant human LH (rLH) to FSH treatment may promote the dominance of a leading follicle when administered in the late follicular phase. The objective of this study was to find the optimal dose of rLH that can maintain the growth of a dominant follicle, whilst causing atresia of secondary follicles. METHODS: Women with infertility due to anovulation and over-responding to FSH treatment were randomized to receive, in addition to 37.5 IU recombinant human FSH (rFSH), either placebo or different doses of rLH (6.8, 13.6, 30 or 60 microg) daily for a maximum of 7 days. The primary efficacy endpoint was the proportion of patients who had exactly one follicle > or = 16 mm on hCG day. RESULTS: Among 153 enrolled patients, the five treatment groups were similar in terms of baseline characteristics. The proportion of patients with exactly one follicle > or = 16 mm ranged from 13.3% in the placebo group to 32.1% in the 30 microg rLH group (P = 0.048). The pregnancy rate ranged from 10.3% in the 60 microg group to 28.6% in the 30 microg rLH group. Adverse events were similar between groups. CONCLUSIONS: In patients over-responding to FSH during ovulation induction, doses of up to 30 microg rLH/day appear to increase the proportion of patients developing a single dominant follicle (> or = 16 mm). Our data support the 'LH ceiling' concept whereby addition of rLH is able to control development of the follicular cohort.

Adult↗
PubMed1995

Human follicle-stimulating hormone produced by recombinant DNA technology: a review for clinicians.

Human follicle-stimulating hormone (FSH) is now produced in vitro by recombinant DNA technology. FSH being a complex heterodimeric protein, a eukaryotic cell line has been selected for expression work (Chinese hamster ovary cells). The pharmaceutical preparation of recombinant human FSH (r-FSH) differs from that of human menopausal gonadotrophin (HMG) and the first generation of urinary human FSH (u-FSH) in terms of (i) source of bulk materials, (ii) purity and specific activity, (iii) batch to batch consistency, and (iv) complete absence of luteinizing hormone (LH) activity. Pharmacokinetic characterization of r-FSH has shown an absolute bioavailability of approximately 75% after both s.c. and i.m. administration and an apparent terminal half-life of 37 +/- 25 h. These characteristics are very similar to those of u-FSH. Clinical efficacy and safety are currently demonstrated through several randomized, well controlled studies, comparing r-FSH administered s.c. with u-FSH administered i.m. for stimulating follicular development prior to assisted reproduction treatment and in World Health Organization (WHO) group II anovulation. To date, approximately 1000 patients have been treated with r-FSH. Moreover, r-FSH has recently been used successfully in association with recombinant human LH for inducing ovulation and pregnancy in WHO group I anovulatory patients. At this stage of r-FSH preparation assessment, it is likely that r-FSH will replace all urinary-derived FSH preparations for stimulating ovarian follicular development. For clinicians, current experience with r-FSH indicates that it should be used with the regimes and doses applied to u-FSH.

Animals↗
PubMedDate not supplied

The link between female infertility and cancer: epidemiology and possible aetiologies.

Infertility has been suggested as a risk factor for various gynaecological cancers. Data analyses show that among infertile women, those with anovulation or polycystic ovarian syndrome (PCOS) have an increased risk of cancer. Clinical and laboratory data such as anthropometric measurements, endogenous hormones and growth factors may explain mechanisms which link tumorogenesis or tumour promotion to infertility. The possible association between ovulation induction and cancer is discussed both on theoretical grounds and based on epidemiological data. We conclude that according to epidemiological studies, laboratory data and on theoretical grounds, infertile patients have an increased lifetime risk of gynaecological cancer. The risk of cancer should be evaluated further for each subpopulation of infertile patients. Thus, more adequate means of monitoring these patients will become available. These data are necessary for a further evaluation of the possible cancer risks of infertility treatments.

Anovulation↗
PubMedDate not supplied

Current and future status of ovulation induction in polycystic ovary syndrome.

Great progress had been achieved during the last 20 years in the field of ovulation induction in patients with polycystic ovary syndrome (PCOS). Clomiphene citrate remains the first line of treatment for all anovulatory women with PCOS, since in properly selected patients the cumulative pregnancy rate approaches that in normal women. Human urinary gonadotrophins have been used extensively for ovulation induction, but the development of low-dose regimens has opened a new era in the management of anovulation related to PCOS. This article discusses the main advantages and disadvantages of the principal methods and regimens currently used for ovulation induction in patients with PCOS including clomiphene citrate, gonadotrophins, pulsatile gonadotrophin-releasing hormone (GnRH) and GnRH agonists. It also discusses new drugs discovered recently, particularly recombinant gonadotrophins and GnRH antagonists, and provides some thoughts regarding their use in future protocols. Finally, based on the discovery of new ovarian substances which specifically control luteinizing hormone (LH) secretion, this article develops assumptions on possible implications of these substances in the pathophysiology of PCOS and their potential use in the management of the syndrome.

Anovulation↗
PubMed1996

Transvaginal interstitial laser treatment of the ovary: a feasibility study in cows.

In 12 cows, transvaginal interstitial laser treatment (TILT) of the ovaries was performed using a neodynium:yttrium aluminium-garnet laser to investigate the feasibility of a new treatment approach for clomiphene-resistant patients with chronic hyperandrogenic anovulation. Powers of 1 and 2 W during 5 min of exposure were used. Sonographic changes of thermal damage during TILT, the extent and healing of the lesions by light microscopy and ultrasound during 3 month follow-up and adhesion formation were studied. During laser irradiation, a hyperechogenic zone developed around the fibre tip, with a mean +/- SD diameter of 4.4 +/- 2.0 mm at 1 W and 6.9 +/- 1.5 mm at 2. W. The mean diameters of the histological lesions 2 days after treatment were 7.3 +/- 2.5 mm at 1 W and 13.0 +/- 2.1 mm at 2 W. During follow-up, the mean diameter of both the histologically and the sonographically assessed lesions decreased, although transvaginal sonography (TVS) systematically and significantly underestimated the thermal damage. Lesions healed by fibrosis and no adhesions were present. TILT of the ovaries in cows is easy to perform and produces central or subcapsular necrosis without adhesions. TVS gives an indication of thermal damage but underestimates the extent of tissue damage in cow ovaries. Obviously, this study does not allow conclusions to be drawn concerning its safety and efficacy in man.

Animals↗
PubMed1988

Mechanism and management of ovulatory failure in women with polycystic ovary syndrome.

Polycystic ovary syndrome is the most important cause of chronic anovulation. In women who fail to respond to clomiphene, low-dose FSH given in a step-wise fashion can induce normal follicular growth and ovulation. The failure of the action of endogenous FSH in these women may be related to reduced biological activity of circulating FSH, but may also involve inhibition of its action at follicular level by polypeptide growth factors such as EGF.

Androgens↗
PubMed1991

Quintuplet pregnancy and third degree ovarian hyperstimulation despite withholding human chorionic gonadotrophin.

A patient who suffered from polycystic ovarian disease and anovulation, was treated with pure follicle stimulating hormone for induction of ovulation. The treatment was stopped and human chorionic gonadotrophin was not administered because of high serum oestradiol levels and multiple follicular development. Ovulation occurred 11 days after pure follicle stimulating hormone was discontinued, the patient developed third-degree ovarian hyperstimulation syndrome and conceived with a quintuplet pregnancy.

Adult↗
PubMed1991

Triggering ovulation with endogenous luteinizing hormone may prevent the ovarian hyperstimulation syndrome.

In a series of 126 therapeutic cycles in 48 patients with primary infertility and treated with HMG for anovulation or preparation to insemination, ovulation was triggered by endogenous LH instead of HCG when the patient was considered to be at high risk for ovarian hyperstimulation syndrome (OHS), (plasma oestradiol greater than 1200 pg/ml) and/or multiple pregnancy (greater than 3 follicles greater than 17 mm in diameter). The endogenous LH surge was provoked and maintained by intranasal buserelin 200 micrograms three times at 8-hourly intervals. In the 37 cycles with buserelin, no OHS occurred despite high preovulatory levels of oestradiol; a single twin pregnancy was recorded despite the presence of numerous mature preovulatory follicles. Conception results (21.6% pregnancy per therapeutic cycle) compared favourably with HCG administration (16.8%). It is concluded that, when ovulation must be triggered in a hazardous situation, the use of endogenous LH through the administration of a short-acting GnRH analogue prevents the complications of exaggerated follicular stimulation.

Administration, Intranasal↗
PubMed1992

The role of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) in the pathogenesis of polycystic ovary syndrome.

The objective of this study was to elucidate the relationship and role of insulin-like growth factor-1 (IGF-1), IGF binding protein-1 (IGFBP-1), insulin and luteinizing hormone (LH) in the pathogenesis of polycystic ovary syndrome (PCOS). In a pilot study, serum concentrations of IGF-1 were determined in women with PCOS (n = 10), hypopituitarism (n = 12) and normal controls (n = 10). In the main study, serum concentrations of IGF-1, IGFBP-1, insulin and LH in women with anovulation associated (n = 23) and not associated (n = 47) with PCOS were determined. Serum concentrations of IGF-1 were not different in women with PCOS, anovulatory non-PCOS and healthy women but were low in those with hypopituitarism. Mean serum IGFBP-1 in PCOS (33.8 +/- 21.2 micrograms/l) was decreased compared with anovulatory non-PCOS (60.0 +/- 22 micrograms/l) (P = 0.0001), and correlated negatively with insulin concentrations (r = -0.67, P = 0.0006). Patients with PCOS could be separated into those with high LH and those with high insulin levels. It was concluded that women with PCOS have normal serum IGF-1 concentrations but IGFBP-1 levels, regulated by insulin, are low. Hyperinsulinaemia and raised LH are independently capable of stimulating ovarian androgen production. Growth factors may have an important role in the pathogenesis of PCOS.

Adult↗
PubMed1996

Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs.

The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.

Adult↗
PubMed1975

Hormonal profiles in anovulatory patients treated with gonadotropins and synthetic luteinizing hormone releasing hormone.

Ten patients with hypothalamic anovulation weretreated with a "retard" preparation of synthetic luteinizing hormone releasing hormone (LHRH) after an HMG stimulation in order to induce ovulation and pregnancy. Four of the patient ovulated after intramuscular administration of the LHRH preparation. This study suggests that is is possible to induce ovulation with LHRH in patients pretreated with HMG, and that LHRH has advantages over HCG since it does not induce hyperstimulation even in the presence of exagerated follicular growth. Nevertheless, the optimal conditions for the use and monitoring of LHRH treatment have yet to be clarified.

Adult↗
PubMed2002

Treatment of the infertile patient with polycystic ovarian syndrome.

UNLABELLED: Polycystic ovarian syndrome is associated with infertility due to anovulation caused by this disorder. Many treatments can increase both ovulation and fertility rates in these women. This is a comprehensive review of the literature, with an emphasis on randomized controlled trials of the medical and surgical treatment options for women with polycystic ovarian syndrome and infertility. Both standard and novel treatments are addressed. In the past, clomiphene citrate was the first-line medical treatment for subfertility in these women, followed by gonadotropins with or without gonadotropin releasing-hormone agonists for those women with clomiphene-resistance. Surgical treatments such as ovarian drilling were occasionally added to these regimens. The introduction of the insulin-sensitizing agents as adjuvants to clomiphene citrate and gonadotropins has changed the treatment strategy. The evidence in support of this change will be discussed. Data on the use of glucocorticoids, opioid receptor antagonists, and antiandrogens as adjuvants to standard therapies, as well as surgical treatments such as wedge resection and ovarian drilling will also be discussed. Based upon the evidence, medical treatment remains the primary therapy for women with this syndrome, especially in light of the recent introduction of insulin-sensitizing agents to the treatment armamentarium. These drugs have allowed us to develop less aggressive therapies that are safer and easier for women to utilize, and may in the future become the primary treatment for women with this syndrome. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to explain the pathophysiology of PCOS, to list the factors that predispose women to develop PCOS, and to outline the treatment regiments for PCOS-associated infertility.

Anovulation↗
PubMed2004

Metformin in obstetric and gynecologic practice: a review.

Metformin is a common treatment for women who have insulin resistance manifesting as type 2 diabetes or polycystic ovarian syndrome (PCOS). With an increasing number of these patients conceiving, it is expected that the use of metformin in and around the time of pregnancy will increase. This article reassesses the mechanisms, safety, and clinical experience of metformin use in obstetrics and gynecology. Metformin is an attractive therapeutic option because administration is simple, hypoglycemia rare, and weight loss promoted. There is a large volume of research supporting the use of metformin treatment in diabetes mellitus, androgenization, anovulation, infertility, and recurrent miscarriage. Although metformin is known to cross the placenta, there is, as yet, no evidence of teratogenicity. Metformin has an array of complex actions, accounting for the varied clinical roles, many of which are still to be fully evaluated. Much research is still needed.

Abortion, Spontaneous↗
PubMed2006

Ovarian biopsy in infertile patients with ovarian dysfunction.

Evaluation of ovarian histology is feasible by obtaining ovarian tissue through laparoscopy; however, the role of an ovarian biopsy in an infertility workup is not widely accepted. To gain insight into the role of ovarian biopsy in reproductive medicine, we conducted a cross-sectional study in infertile patients with ovarian dysfunction and correlated follicle stimulating hormone (FSH) and estradiol serum concentrations with ovarian follicular counts. Fifty women were recruited and classified into four groups: premature ovarian failure (POF), chronic anovulation, diminished ovarian reserve, and ovulatory patients (control group). Ovarian endocrine function was assessed by the determination of FSH, luteinizing hormone, and estradiol serum concentrations and correlated with the number of follicles present in the ovarian biopsies obtained by laparoscopy. The number of ovarian follicles observed for each individual biopsy varied extensively. Patients with POF presented significantly lower counts of primordial, primary, and secondary follicles. No significant differences were found in the other groups. In the total sample, primordial follicle counts correlated inversely with serum FSH levels (r = -0.4, p = 0.003) and directly with serum estradiol levels (r = 0.5, p = 0.001) however, such associations no longer remained after adjusting by group. We conclude that ovarian biopsies do not provide additional information to the clinical-hormonal criteria previously established in the workup of infertile patients. Therefore, its use cannot be generalized in the study of infertile patients with ovarian dysfunction. In contrast, ovarian biopsies may be useful to identify patients with POF when the ovarian reserve is likely altered.

Adult↗
PubMed2001

Reproductive suppression in female Damaraland mole-rats Cryptomys damarensis: dominant control or self-restraint?

Colonies of Damaraland mole-rats Cryptomys damarensis exhibit a high reproductive skew. Typically one female breeds and the others are anovulatory. Two models, the dominant control model (DCM) and the self-restraint model (SRM), have been proposed to account for this reproductive suppression. The DCM proposes that suppression is under the control of the dominant breeder and is imposed by mechanisms such as aggression, pheromones and interference with copulation, whereas the SRM does not involve aggression directed towards non-breeders and may function in order to minimize inbreeding. We investigated potential proximate mechanisms involved in the suppression of females in a series of experiments. Socially induced stress through aggression did not appear to be responsible for anovulation. Nor did breeders actively interfere with subordinate copulation. Females were physiologically suppressed when housed in intact colonies. However, as predicted by the DCM, they did not become reproductively active when removed from the presence of breeders. We found no evidence that pheromonal cues block ovulation. We suggest that the SRM is the basic model found in the Damaraland mole-rat and that self-restraint functions in order to minimize inbreeding by restricting reproduction until an unrelated male is present. This would explain the rapid onset of reproductive activation in females when paired with an unrelated male, as demonstrated in this study.

Analysis of Variance↗
PubMed2004

Review of nonsurgical and surgical treatment and the role of insulin-sensitizing agents in the management of infertile women with polycystic ovary syndrome.

OBJECTIVES: To review the nonsurgical and surgical treatment and the role of insulin-sensitizing agents in the management of anovulatory infertile women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: The search term of subfertile women with anovulation and PCOS was used for identification of randomized controlled trials. Nonrandomized controlled studies were identified through computer MEDLINE and EMBASE searches for the years 1980-2002. RESULTS: For obese PCOS women weight loss of > 5% of pretreatment weight restores menstrual regularity in 89%, of whom 30% achieved spontaneous pregnancy. It was estimated that 75-80% of anovulatory PCOS women will respond to clomiphene citrate (CC) and 35-50% will achieve pregnancy. For CC-resistant PCOS women (20-25%), CC + metformin (1.5 g/day) for 3-6 months has a 70% chance of restoration of regular menses and ovulation, and a 23% chance of pregnancy. Laparoscopic ovarian drilling (LOD) can be offered to CC-resistant PCOS women. There was no statistically significant difference in the ovulation rate following LOD with electrocoagulation and laser [83% vs. 77.5%; odds ratio (OR) 1.4; 95% CI 0.9-2.1], while there was a significantly higher cumulative pregnancy rate at 12 months after surgery (65% vs. 54.5%; OR 1.5; 95% CI 1.1-2.1). CONCLUSION: Diet and exercise followed by CC should be used for nonsurgical ovulation induction. For CC-resistant PCOS women, metformin may be included in a stepwise approach before a surgical approach. LOD with electrocautery is superior to laser drilling and gonadotropin therapy.

Adult↗