Polycystic ovary syndrome (PCOS) is a true syndrome, being a heterogeneous collection of signs an... more Polycystic ovary syndrome (PCOS) is a true syndrome, being a heterogeneous collection of signs and symptoms that gathered together form a spectrum of a disorder with a mild presentation in some, whilst in others there is a severe disturbance of reproductive, endocrine and metabolic function. There has been much debate about phenotype and, more recently, genotype. There has also been scepticism in some quarters, with a feeling that we may be looking at one end of a spectrum that is in reality 'normal', or perhaps a consequence of the modern disease of obesity. Whilst the polycystic ovary is at the centre of the syndrome, it is external effects such as hyperinsulinism, that influence its expression. There is no consensus on the definition of PCOS and so studies that compare epidemiology and treatments often have very different starting points, and so cannot be compared. In this debate we wish to re-explore our current thinking on PCOS, with a particular emphasis on the British and European perspective and invite others to contribute to the discussion which could form the basis for an international consensus.
Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common... more Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common, affecting up to one in five women of reproductive age. It has significant and diverse clinical implications including reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles) and psychological features (increased anxiety, depression and worsened quality of life). Polycystic ovary syndrome is a heterogeneous condition and, as such, clinical and research agendas are broad and involve many disciplines. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and bodyweight. Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS. Furthermore, it has clinical implications across the lifespan and is relevant to related family members with an increased risk for metabolic conditions reported in first-degree relatives. Therapy should focus on both the short and long-term reproductive, metabolic and psychological features. Given the aetiological role of insulin resistance and the impact of obesity on both hyperinsulinaemia and hyperandrogenism, multidisciplinary lifestyle improvement aimed at normalising insulin resistance, improving androgen status and aiding weight management is recognised as a crucial initial treatment strategy. Modest weight loss of 5% to 10% of initial body weight has been demonstrated to improve many of the features of PCOS. Management should focus on support, education, addressing psychological factors and strongly emphasising healthy lifestyle with targeted medical therapy as required. Monitoring and management of long-term metabolic complications is also an important part of routine clinical care. Comprehensive evidence-based guidelines are needed to aid early diagnosis, appropriate investigation, regular screening and treatment of this common condition. Whilst reproductive features of PCOS are well recognised and are covered here, this review focuses primarily on the less appreciated cardiometabolic and psychological features of PCOS.
I searched for original articles focusing on PCOS in MEDLINE published between 2002 and present. ... more I searched for original articles focusing on PCOS in MEDLINE published between 2002 and present. The search term I used was "PCOS". I then selected all papers that characterized genetic variation in PCOS. Data predating 2002 were obtained from a similar literature search that was carried out in the summer of 2002. The vast majority of papers were English-language full-text papers. Manuscripts examining related phenotypes such as hyperandrogenism were also examined, although in a much less rigorous manner.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. The clinical man... more Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. The clinical manifestation of PCOS varies from a mild menstrual disorder to severe disturbance of reproductive and metabolic functions. Management of women with PCOS depends on the symptoms. These could be ovulatory dysfunction-related infertility, menstrual disorders, or androgen-related symptoms. Weight loss improves the endocrine profile and increases the likelihood of ovulation and pregnancy. Normalization of menstrual cycles and ovulation could occur with modest weight loss as little as 5% of the initial weight. The treatment of obesity includes modifications in lifestyle (diet and exercise) and medical and surgical treatment. In PCOS, anovulation relates to low follicle-stimulating hormone concentrations and the arrest of antral follicle growth in the final stages of maturation. This can be treated with medications such as clomiphene citrate, tamoxifen, aromatase inhibitors, metformin, glucocorticoids, or gonadotropins or surgically by laparoscopic ovarian drilling. In vitro fertilization will remain the last option to achieve pregnancy when others fail. Chronic anovulation over a long period of time is also associated with an increased risk of endometrial hyperplasia and carcinoma, which should be seriously investigated and treated. There are androgenic symptoms that will vary from patient to patient, such as hirsutism, acne, and/or alopecia. These are troublesome presentations to the patients and require adequate treatment. Alternative medicine has been emerging as one of the commonly practiced medicines for different health problems, including PCOS. This review underlines the contribution to the treatment of different symptoms.
BACKGROUND: The extremes of BMI are associated with an increased risk of miscarriage both in spon... more BACKGROUND: The extremes of BMI are associated with an increased risk of miscarriage both in spontaneously conceived pregnancies and after fertility treatment. The aim of the present study was to study the effect of BMI on miscarriage rate (MR) in fresh IVF/ICSI, and in spontaneous and hormonally substituted frozen-thawed embryo (FET) cycles. METHODS: Analysis was carried out on 3330 first pregnancy cycles, performed during the years 1999-2004, of which 2198 were fresh, 666 were spontaneous and 466 were hormonally substituted FET cycles. A categorical, a linear and a quadratic models of the effect of BMI on miscarriage were studied by logistic regression. Factors related to patient characteristics, protocol and embryo parameters were also examined. RESULTS: MR was higher in hormonally substituted FET (23.0%), compared with the fresh cycles (13.8%) and spontaneous FET (11.4%, P < 0.0001). Multivariate logistic regression revealed that the relationship between BMI and the risk of miscarriage is not linear but quadratic (U-shaped) (P 5 0.01), indicating a higher risk of miscarriage in underweight and obese women. Hormonal substitution for FET was also associated with a 1.7-fold higher MR, compared with the fresh cycles (P 5 0.002, 95% confidence interval 1.2-2.3). CONCLUSIONS: Obese and underweight women have an increased risk of miscarriage, and hormonally substituted FET is associated with an even higher MR.
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by ova... more Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by ovarian hyperandrogenism. Theca interna cells isolated from the ovaries of women with PCOS are characterized by increased expression of cytochrome P450 17␣-hydroxylase (CYP17) [steroid 17␣-hydroxylase/17,20 lyase (P450c17)], a steroidogenic enzyme obligatory for the biosynthesis of androgens. Augmented expression of the gene encoding P450c17 (CYP17) in PCOS theca has been attributed, in part, to differential transcriptional regulation of the CYP17 promoter in normal and PCOS cells. The present studies examine whether CYP17 gene expression is also posttranscriptionally regulated at the level of mRNA stability in normal and PCOS theca cells maintained in longterm culture. Determination of endogenous CYP17 mRNA half-life by pharmacological inhibition of transcription demonstrated that the half-life of CYP17 mRNA increased 2-fold in PCOS theca cells, compared with normal theca cells. Forskolin treatment also prolonged CYP17 mRNA half-life in both normal and PCOS theca cells. In vitro mRNA degradation studies demonstrated that the 5-untranslated region confers increased stability to CYP17 mRNA in PCOS theca cells and showed that the 5-untranslated region of CYP17 also confers forskolin-stimulated stabilization of CYP17 mRNA. These studies indicate that a slower rate of CYP17 mRNA decay contributes to increased steady-state mRNA accumulation and augmented CYP17 gene expression in PCOS theca cells. (J Clin Endocrinol Metab 90: 1720 -1727, 2005)
Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies ... more Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.
Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 5-10% of women ... more Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 5-10% of women of reproductive age, and is characterized by infertility, hirsutism, abnormal follicular development, and increased ovarian androgen production. The phenotype of elevated androgen production persists in theca cells isolated from PCOS women and maintained in longterm culture. Increased androgen biosynthesis in PCOS theca cells is correlated with increased enzyme activity and gene expression of several steroidogenic enzymes responsible for androgen biosynthesis including cytochrome P450 17α-hydroxylase (CYP17) and cytochrome P450 cholesterol side chain cleavage (CYP11A).
Notwithstanding the potential public health impact of the polycystic ovary syndrome (PCOS), estim... more Notwithstanding the potential public health impact of the polycystic ovary syndrome (PCOS), estimates regarding its prevalence are limited and unclear. Between July 1998 and October 1999, 400 unselected consecutive premenopausal women (18 -45 yr of age) seeking a preemployment physical at the University of Alabama at Birmingham were studied (223 Black, 166 White, and 11 of other races). Evaluation included a history and physical examination, a modified Ferriman-Gallwey hirsutism score, and serum screening for hyperandrogenemia, hyperprolactinemia, and 21-hydroxylase-deficient nonclassical adrenal hyperplasia. PCOS was diagnosed by the presence of the following: 1) oligoovulation, 2) hyperandrogenemia and/or hirsutism (modified Ferriman-Gallwey score > 6), and 3) the exclusion of related disorders. Confirmed PCOS was established in those individuals whose evaluation was complete and indicative of PCOS, and possible PCOS was established when the hormonal evaluation was not complete or was unavailable, but the clinical phenotype was otherwise suggestive of the disorder. The individual probability of PCOS in women with possible PCOS was assigned a weight based on the findings in similar subjects whose evaluation was complete, and the total number of PCOS cases arising from these individuals was calculated (i.e. individual probability of PCOS ؋ total number of subjects in the group). The cumulative prevalence of PCOS in our population was 6.6% (26.5 of 400), including 15 subjects among the 347 women completing their evaluation and a calculated prevalence of 11.5 subjects among the remainder. The prevalence rates of PCOS for Black and White women were 8.0 and 4.8%, respectively, not significantly different. These data from a large representative unselected population support the concept that PCOS is the most common endocrine abnormality of reproductive-aged women in the United States. (J Clin Endocrinol
Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mech... more Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mechanisms that result in the expression of chronic anovulation and hyperandrogenism. This syndrome has been for many years one of the most controversial entities in gynecological endocrinology. Polycystic ovary syndrome has been proven to be a familial condition. Although the role of genetic factors in PCOS is strongly supported, the genes that are involved in the etiology of the syndrome have not been fully investigated until now, as well as the environmental contribution in their expression. The heterogeneity of the syndrome entertains the mystery around this condition which concerns thousands of infertile women worldwide. Some genes have shown altered expression suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling steroidogenesis, steroid hormones action, gonadotrophin action and regulation, insulin action and secretion, energy homeostasis, chronic inflammation and others. The present review of the contemporary literature constitutes an effort to present all the trends in the current research for the etiology of polycystic ovary syndrome. Hippokratia 2009; 13 (4): 216-223
Malnutrition is a major problem in developing countries, and obesity and eating disorders are inc... more Malnutrition is a major problem in developing countries, and obesity and eating disorders are increasingly common in developing as well as developed countries. The reproductive axis is closely linked to nutritional status, especially undernutrition in the female, and inhibitory pathways involving detectors in the hind brain suppress ovulation in subjects with weight loss. Recovery may occur after minimal reacquisition of weight because energy balance is more important than body fat mass. Anorexia nervosa and bulimia nervosa affect up to 5% of women of reproductive age causing amenorrhoea, infertility and, in those who do conceive, an increased likelihood of miscarriage. Obesity can affect reproduction through fat cell metabolism, steroids and secretion of proteins such as leptin and adiponectin and through changes induced at the level of important homeostatic factors such as pancreatic secretion of insulin, androgen synthesis by the ovary and sex hormone-binding globulin (SHBG) production by the liver. WHO estimates that 9 to 25% of women in developed countries are severely obese, and obese mothers are much more likely to have obese children, especially if they have gestational diabetes. Obesity-associated anovulation may lead to infertility and to a higher risk of miscarriage. Management of anovulation with obesity involves diet and exercise as well as standard approaches to ovulation induction. Many obese women conceive without assistance, but pregnancies in obese women have increased rates of pregnancy-associated hypertension, gestational diabetes, large babies, Cesarean section and perinatal mortality and morbidity. Among contraceptors, the fear of weight gain affects uptake and continuation of hormonal contraceptives, although existing trials indicate that any such effects are small. For all methods of hormonal contraception, weight above 70 kg is associated with increased failure rates.
To determine whether overexpression of CYP17 or CYP11A messenger (m)RNA in theca cells from polyc... more To determine whether overexpression of CYP17 or CYP11A messenger (m)RNA in theca cells from polycystic ovaries is related to polymorphic regions in the gene promoters that may increase transcription. Design: Case-control study. Setting: Research institute. Patient(s): Fifty-one women with PCOS and 280 regularly cycling controls underwent genotyping. Thecal cells were obtained from 23 women with PCOS and 51 controls. Main Outcome Measure(s): Ovarian tissue was obtained from women with PCOS undergoing wedge resection for treatment of their infertility and from controls undergoing ovariectomy for indications unrelated to the study. Expression of mRNA in theca cells was measured by using competitive reverse transcriptase polymerase chain reaction. Genotype analysis for polymorphisms in the CYP11A and CYP17 promoters was performed by using polymerase chain reaction. Result(s): Although expression of CYP11A and CYP17 mRNA was higher in women with PCOS, no significant dose effects of CYP11A or CYP17 alleles were observed with respect to serum testosterone; follicular fluid androstenedione, estradiol, and androstenedione-to-estradiol ratio; or CYP11A or CYP17 mRNA expression. Conclusion(s): Overexpression of CYP17 and CYP11A mRNA in theca cells from polycystic ovaries is explained by polymorphic differences in the gene promoters. (Fertil Steril 2002;77:274 -80.
results: The search showed that alteration of many factors may directly or indirectly impair the ... more results: The search showed that alteration of many factors may directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions, resulting in a lower pregnancy rate in patients with PCOS. The extra-ovarian factors identified included gonadotrophins, hyperandrogenemia and hyperinsulinemia, although intra-ovarian factors included members of the epidermal, fibroblast, insulin-like and neurotrophin families of growth factors, as well as the cytokines. † Two equal first authors.
The developmental pathophysiology of polycystic ovary syndrome (PCOS) is unknown. However, prenat... more The developmental pathophysiology of polycystic ovary syndrome (PCOS) is unknown. However, prenatally androgenized female rhesus monkeys exhibit ovarian and endocrinological features that mimic those found in women with PCOS. Thus, prenatal androgen excess may provide an etiology for hyperandrogenism and anovulation in adulthood.
BACKGROUND: We sought to determine whether metformin, which had facilitated conception in 72 olig... more BACKGROUND: We sought to determine whether metformin, which had facilitated conception in 72 oligoamenorrhoeic women with polycystic ovary syndrome (PCOS), would safely reduce the rate of first trimester spontaneous abortion (SAB) and increase the number of live births without teratogenicity. METHODS: Seventytwo oligoamenorrheic women with PCOS conceived on metformin (2.55 g/day). They were prospectively assessed in an outpatient clinical research centre. Outcome measures included number of first trimester SAB, live births, normal ongoing pregnancies ≥13 weeks, gestational diabetes (GD), congenital defects (CD), birthweight and height, as well as weight, height, and motor and social development during the first 6 months of life. RESULTS: Of the 84 fetuses, to date there have been 63 normal live births without CD (75%), 14 first trimester SAB (17%), and seven ongoing pregnancies ≥13 weeks with normal sonograms without CD (8%). Previously, without metformin, 40 of the 72 women had 100 pregnancies (100 fetuses) with 34 (34%) live births and 62 (62%) first trimester SAB. In current pregnancies on metformin in these 40 women (46 pregnancies, 47 fetuses), there have been 33 live births (70%), two pregnancies ongoing ≥13 weeks (4%), and 12 SAB (26%) (P < 0.0001). There was no maternal lactic acidosis, and no maternal or neonatal hypoglycaemia. Fasting entry serum insulin was a significant explanatory variable for total (previous and current) first trimester SAB, odds ratio 1.32 (for each 5 µU/ml rise in insulin), 95% CI 1.09-1.60 (P ⍧ 0.005). On metformin, GD developed in 4% of pregnancies versus 26% of previous pregnancies without metformin, P ⍧ 0.025. There have been no major CD in the 63 live births or CD by sonography in the seven fetuses ≤13 weeks. In the 63 live births, neither weight nor height differed from the normal neonatal population. At 6 month follow-up, height was greater (P ⍧ 0.008) and weight did not differ from the normal paediatric population; motor and social development were normal. CONCLUSIONS: Metformin therapy during pregnancy in women with PCOS was safely associated with reduction in SAB and in GD, was not teratogenic, and did not adversely affect birthweight or height, or height, weight, and motor and social development at 3 and 6 months of life.
Objective: To investigate insulin sensitivity and secretion in young adolescent girls with childh... more Objective: To investigate insulin sensitivity and secretion in young adolescent girls with childhood onset polycystic ovarian syndrome (PCOS) and to identify the early metabolic derangement(s).
Polycystic ovary syndrome (PCOS) is a true syndrome, being a heterogeneous collection of signs an... more Polycystic ovary syndrome (PCOS) is a true syndrome, being a heterogeneous collection of signs and symptoms that gathered together form a spectrum of a disorder with a mild presentation in some, whilst in others there is a severe disturbance of reproductive, endocrine and metabolic function. There has been much debate about phenotype and, more recently, genotype. There has also been scepticism in some quarters, with a feeling that we may be looking at one end of a spectrum that is in reality 'normal', or perhaps a consequence of the modern disease of obesity. Whilst the polycystic ovary is at the centre of the syndrome, it is external effects such as hyperinsulinism, that influence its expression. There is no consensus on the definition of PCOS and so studies that compare epidemiology and treatments often have very different starting points, and so cannot be compared. In this debate we wish to re-explore our current thinking on PCOS, with a particular emphasis on the British and European perspective and invite others to contribute to the discussion which could form the basis for an international consensus.
Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common... more Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common, affecting up to one in five women of reproductive age. It has significant and diverse clinical implications including reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles) and psychological features (increased anxiety, depression and worsened quality of life). Polycystic ovary syndrome is a heterogeneous condition and, as such, clinical and research agendas are broad and involve many disciplines. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and bodyweight. Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS. Furthermore, it has clinical implications across the lifespan and is relevant to related family members with an increased risk for metabolic conditions reported in first-degree relatives. Therapy should focus on both the short and long-term reproductive, metabolic and psychological features. Given the aetiological role of insulin resistance and the impact of obesity on both hyperinsulinaemia and hyperandrogenism, multidisciplinary lifestyle improvement aimed at normalising insulin resistance, improving androgen status and aiding weight management is recognised as a crucial initial treatment strategy. Modest weight loss of 5% to 10% of initial body weight has been demonstrated to improve many of the features of PCOS. Management should focus on support, education, addressing psychological factors and strongly emphasising healthy lifestyle with targeted medical therapy as required. Monitoring and management of long-term metabolic complications is also an important part of routine clinical care. Comprehensive evidence-based guidelines are needed to aid early diagnosis, appropriate investigation, regular screening and treatment of this common condition. Whilst reproductive features of PCOS are well recognised and are covered here, this review focuses primarily on the less appreciated cardiometabolic and psychological features of PCOS.
I searched for original articles focusing on PCOS in MEDLINE published between 2002 and present. ... more I searched for original articles focusing on PCOS in MEDLINE published between 2002 and present. The search term I used was "PCOS". I then selected all papers that characterized genetic variation in PCOS. Data predating 2002 were obtained from a similar literature search that was carried out in the summer of 2002. The vast majority of papers were English-language full-text papers. Manuscripts examining related phenotypes such as hyperandrogenism were also examined, although in a much less rigorous manner.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. The clinical man... more Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. The clinical manifestation of PCOS varies from a mild menstrual disorder to severe disturbance of reproductive and metabolic functions. Management of women with PCOS depends on the symptoms. These could be ovulatory dysfunction-related infertility, menstrual disorders, or androgen-related symptoms. Weight loss improves the endocrine profile and increases the likelihood of ovulation and pregnancy. Normalization of menstrual cycles and ovulation could occur with modest weight loss as little as 5% of the initial weight. The treatment of obesity includes modifications in lifestyle (diet and exercise) and medical and surgical treatment. In PCOS, anovulation relates to low follicle-stimulating hormone concentrations and the arrest of antral follicle growth in the final stages of maturation. This can be treated with medications such as clomiphene citrate, tamoxifen, aromatase inhibitors, metformin, glucocorticoids, or gonadotropins or surgically by laparoscopic ovarian drilling. In vitro fertilization will remain the last option to achieve pregnancy when others fail. Chronic anovulation over a long period of time is also associated with an increased risk of endometrial hyperplasia and carcinoma, which should be seriously investigated and treated. There are androgenic symptoms that will vary from patient to patient, such as hirsutism, acne, and/or alopecia. These are troublesome presentations to the patients and require adequate treatment. Alternative medicine has been emerging as one of the commonly practiced medicines for different health problems, including PCOS. This review underlines the contribution to the treatment of different symptoms.
BACKGROUND: The extremes of BMI are associated with an increased risk of miscarriage both in spon... more BACKGROUND: The extremes of BMI are associated with an increased risk of miscarriage both in spontaneously conceived pregnancies and after fertility treatment. The aim of the present study was to study the effect of BMI on miscarriage rate (MR) in fresh IVF/ICSI, and in spontaneous and hormonally substituted frozen-thawed embryo (FET) cycles. METHODS: Analysis was carried out on 3330 first pregnancy cycles, performed during the years 1999-2004, of which 2198 were fresh, 666 were spontaneous and 466 were hormonally substituted FET cycles. A categorical, a linear and a quadratic models of the effect of BMI on miscarriage were studied by logistic regression. Factors related to patient characteristics, protocol and embryo parameters were also examined. RESULTS: MR was higher in hormonally substituted FET (23.0%), compared with the fresh cycles (13.8%) and spontaneous FET (11.4%, P < 0.0001). Multivariate logistic regression revealed that the relationship between BMI and the risk of miscarriage is not linear but quadratic (U-shaped) (P 5 0.01), indicating a higher risk of miscarriage in underweight and obese women. Hormonal substitution for FET was also associated with a 1.7-fold higher MR, compared with the fresh cycles (P 5 0.002, 95% confidence interval 1.2-2.3). CONCLUSIONS: Obese and underweight women have an increased risk of miscarriage, and hormonally substituted FET is associated with an even higher MR.
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by ova... more Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by ovarian hyperandrogenism. Theca interna cells isolated from the ovaries of women with PCOS are characterized by increased expression of cytochrome P450 17␣-hydroxylase (CYP17) [steroid 17␣-hydroxylase/17,20 lyase (P450c17)], a steroidogenic enzyme obligatory for the biosynthesis of androgens. Augmented expression of the gene encoding P450c17 (CYP17) in PCOS theca has been attributed, in part, to differential transcriptional regulation of the CYP17 promoter in normal and PCOS cells. The present studies examine whether CYP17 gene expression is also posttranscriptionally regulated at the level of mRNA stability in normal and PCOS theca cells maintained in longterm culture. Determination of endogenous CYP17 mRNA half-life by pharmacological inhibition of transcription demonstrated that the half-life of CYP17 mRNA increased 2-fold in PCOS theca cells, compared with normal theca cells. Forskolin treatment also prolonged CYP17 mRNA half-life in both normal and PCOS theca cells. In vitro mRNA degradation studies demonstrated that the 5-untranslated region confers increased stability to CYP17 mRNA in PCOS theca cells and showed that the 5-untranslated region of CYP17 also confers forskolin-stimulated stabilization of CYP17 mRNA. These studies indicate that a slower rate of CYP17 mRNA decay contributes to increased steady-state mRNA accumulation and augmented CYP17 gene expression in PCOS theca cells. (J Clin Endocrinol Metab 90: 1720 -1727, 2005)
Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies ... more Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.
Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 5-10% of women ... more Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 5-10% of women of reproductive age, and is characterized by infertility, hirsutism, abnormal follicular development, and increased ovarian androgen production. The phenotype of elevated androgen production persists in theca cells isolated from PCOS women and maintained in longterm culture. Increased androgen biosynthesis in PCOS theca cells is correlated with increased enzyme activity and gene expression of several steroidogenic enzymes responsible for androgen biosynthesis including cytochrome P450 17α-hydroxylase (CYP17) and cytochrome P450 cholesterol side chain cleavage (CYP11A).
Notwithstanding the potential public health impact of the polycystic ovary syndrome (PCOS), estim... more Notwithstanding the potential public health impact of the polycystic ovary syndrome (PCOS), estimates regarding its prevalence are limited and unclear. Between July 1998 and October 1999, 400 unselected consecutive premenopausal women (18 -45 yr of age) seeking a preemployment physical at the University of Alabama at Birmingham were studied (223 Black, 166 White, and 11 of other races). Evaluation included a history and physical examination, a modified Ferriman-Gallwey hirsutism score, and serum screening for hyperandrogenemia, hyperprolactinemia, and 21-hydroxylase-deficient nonclassical adrenal hyperplasia. PCOS was diagnosed by the presence of the following: 1) oligoovulation, 2) hyperandrogenemia and/or hirsutism (modified Ferriman-Gallwey score > 6), and 3) the exclusion of related disorders. Confirmed PCOS was established in those individuals whose evaluation was complete and indicative of PCOS, and possible PCOS was established when the hormonal evaluation was not complete or was unavailable, but the clinical phenotype was otherwise suggestive of the disorder. The individual probability of PCOS in women with possible PCOS was assigned a weight based on the findings in similar subjects whose evaluation was complete, and the total number of PCOS cases arising from these individuals was calculated (i.e. individual probability of PCOS ؋ total number of subjects in the group). The cumulative prevalence of PCOS in our population was 6.6% (26.5 of 400), including 15 subjects among the 347 women completing their evaluation and a calculated prevalence of 11.5 subjects among the remainder. The prevalence rates of PCOS for Black and White women were 8.0 and 4.8%, respectively, not significantly different. These data from a large representative unselected population support the concept that PCOS is the most common endocrine abnormality of reproductive-aged women in the United States. (J Clin Endocrinol
Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mech... more Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mechanisms that result in the expression of chronic anovulation and hyperandrogenism. This syndrome has been for many years one of the most controversial entities in gynecological endocrinology. Polycystic ovary syndrome has been proven to be a familial condition. Although the role of genetic factors in PCOS is strongly supported, the genes that are involved in the etiology of the syndrome have not been fully investigated until now, as well as the environmental contribution in their expression. The heterogeneity of the syndrome entertains the mystery around this condition which concerns thousands of infertile women worldwide. Some genes have shown altered expression suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling steroidogenesis, steroid hormones action, gonadotrophin action and regulation, insulin action and secretion, energy homeostasis, chronic inflammation and others. The present review of the contemporary literature constitutes an effort to present all the trends in the current research for the etiology of polycystic ovary syndrome. Hippokratia 2009; 13 (4): 216-223
Malnutrition is a major problem in developing countries, and obesity and eating disorders are inc... more Malnutrition is a major problem in developing countries, and obesity and eating disorders are increasingly common in developing as well as developed countries. The reproductive axis is closely linked to nutritional status, especially undernutrition in the female, and inhibitory pathways involving detectors in the hind brain suppress ovulation in subjects with weight loss. Recovery may occur after minimal reacquisition of weight because energy balance is more important than body fat mass. Anorexia nervosa and bulimia nervosa affect up to 5% of women of reproductive age causing amenorrhoea, infertility and, in those who do conceive, an increased likelihood of miscarriage. Obesity can affect reproduction through fat cell metabolism, steroids and secretion of proteins such as leptin and adiponectin and through changes induced at the level of important homeostatic factors such as pancreatic secretion of insulin, androgen synthesis by the ovary and sex hormone-binding globulin (SHBG) production by the liver. WHO estimates that 9 to 25% of women in developed countries are severely obese, and obese mothers are much more likely to have obese children, especially if they have gestational diabetes. Obesity-associated anovulation may lead to infertility and to a higher risk of miscarriage. Management of anovulation with obesity involves diet and exercise as well as standard approaches to ovulation induction. Many obese women conceive without assistance, but pregnancies in obese women have increased rates of pregnancy-associated hypertension, gestational diabetes, large babies, Cesarean section and perinatal mortality and morbidity. Among contraceptors, the fear of weight gain affects uptake and continuation of hormonal contraceptives, although existing trials indicate that any such effects are small. For all methods of hormonal contraception, weight above 70 kg is associated with increased failure rates.
To determine whether overexpression of CYP17 or CYP11A messenger (m)RNA in theca cells from polyc... more To determine whether overexpression of CYP17 or CYP11A messenger (m)RNA in theca cells from polycystic ovaries is related to polymorphic regions in the gene promoters that may increase transcription. Design: Case-control study. Setting: Research institute. Patient(s): Fifty-one women with PCOS and 280 regularly cycling controls underwent genotyping. Thecal cells were obtained from 23 women with PCOS and 51 controls. Main Outcome Measure(s): Ovarian tissue was obtained from women with PCOS undergoing wedge resection for treatment of their infertility and from controls undergoing ovariectomy for indications unrelated to the study. Expression of mRNA in theca cells was measured by using competitive reverse transcriptase polymerase chain reaction. Genotype analysis for polymorphisms in the CYP11A and CYP17 promoters was performed by using polymerase chain reaction. Result(s): Although expression of CYP11A and CYP17 mRNA was higher in women with PCOS, no significant dose effects of CYP11A or CYP17 alleles were observed with respect to serum testosterone; follicular fluid androstenedione, estradiol, and androstenedione-to-estradiol ratio; or CYP11A or CYP17 mRNA expression. Conclusion(s): Overexpression of CYP17 and CYP11A mRNA in theca cells from polycystic ovaries is explained by polymorphic differences in the gene promoters. (Fertil Steril 2002;77:274 -80.
results: The search showed that alteration of many factors may directly or indirectly impair the ... more results: The search showed that alteration of many factors may directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions, resulting in a lower pregnancy rate in patients with PCOS. The extra-ovarian factors identified included gonadotrophins, hyperandrogenemia and hyperinsulinemia, although intra-ovarian factors included members of the epidermal, fibroblast, insulin-like and neurotrophin families of growth factors, as well as the cytokines. † Two equal first authors.
The developmental pathophysiology of polycystic ovary syndrome (PCOS) is unknown. However, prenat... more The developmental pathophysiology of polycystic ovary syndrome (PCOS) is unknown. However, prenatally androgenized female rhesus monkeys exhibit ovarian and endocrinological features that mimic those found in women with PCOS. Thus, prenatal androgen excess may provide an etiology for hyperandrogenism and anovulation in adulthood.
BACKGROUND: We sought to determine whether metformin, which had facilitated conception in 72 olig... more BACKGROUND: We sought to determine whether metformin, which had facilitated conception in 72 oligoamenorrhoeic women with polycystic ovary syndrome (PCOS), would safely reduce the rate of first trimester spontaneous abortion (SAB) and increase the number of live births without teratogenicity. METHODS: Seventytwo oligoamenorrheic women with PCOS conceived on metformin (2.55 g/day). They were prospectively assessed in an outpatient clinical research centre. Outcome measures included number of first trimester SAB, live births, normal ongoing pregnancies ≥13 weeks, gestational diabetes (GD), congenital defects (CD), birthweight and height, as well as weight, height, and motor and social development during the first 6 months of life. RESULTS: Of the 84 fetuses, to date there have been 63 normal live births without CD (75%), 14 first trimester SAB (17%), and seven ongoing pregnancies ≥13 weeks with normal sonograms without CD (8%). Previously, without metformin, 40 of the 72 women had 100 pregnancies (100 fetuses) with 34 (34%) live births and 62 (62%) first trimester SAB. In current pregnancies on metformin in these 40 women (46 pregnancies, 47 fetuses), there have been 33 live births (70%), two pregnancies ongoing ≥13 weeks (4%), and 12 SAB (26%) (P < 0.0001). There was no maternal lactic acidosis, and no maternal or neonatal hypoglycaemia. Fasting entry serum insulin was a significant explanatory variable for total (previous and current) first trimester SAB, odds ratio 1.32 (for each 5 µU/ml rise in insulin), 95% CI 1.09-1.60 (P ⍧ 0.005). On metformin, GD developed in 4% of pregnancies versus 26% of previous pregnancies without metformin, P ⍧ 0.025. There have been no major CD in the 63 live births or CD by sonography in the seven fetuses ≤13 weeks. In the 63 live births, neither weight nor height differed from the normal neonatal population. At 6 month follow-up, height was greater (P ⍧ 0.008) and weight did not differ from the normal paediatric population; motor and social development were normal. CONCLUSIONS: Metformin therapy during pregnancy in women with PCOS was safely associated with reduction in SAB and in GD, was not teratogenic, and did not adversely affect birthweight or height, or height, weight, and motor and social development at 3 and 6 months of life.
Objective: To investigate insulin sensitivity and secretion in young adolescent girls with childh... more Objective: To investigate insulin sensitivity and secretion in young adolescent girls with childhood onset polycystic ovarian syndrome (PCOS) and to identify the early metabolic derangement(s).
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