Polycystic Ovary Syndrome - part 4 docx

40 Balen Table 1 Clinical Symptoms and Signs in Women with polycystic ovary syndrome (PCOS) Percentage frequency of symptom or sign Balen et al. (5) (n = 1741) (%) Franks (9) (n = 300) (%) Goldzieher (10) (n = 1079) [n (%)] % Number of cases a Menstrual cycle disturbance Oligomenorrhea 47 52 29 b n = 547 Amenorrhea 19.2 28 51 n = 640 Hirsutism 66.2 64 69 n = 819 Obesity 38.4 35 41 n = 600 Acne 34.7 27 – – Alopecia 6 3 – – Acanthosis nigricans 2.5 <1 – – Infertility (primary/secondary) 20 42 74 n = 596 a In the Goldzieher study, clinical details were not available for the entire 1079 women, thus the number of cases that were used to determine the frequency of each symptom is stated. b In this series, any abnormal pattern of uterine bleeding was included. –, Denotes feature not recorded. Table 2 Biochemical Features of Women with polycystic ovary syndrome (PCOS) Percentage frequency Balen et al. (5) (n = 1741) (%) Franks (9) (n = 300) (%) Elevated serum LH 39.8 51 Elevated serum testosterone 28.9 50 Elevated serum prolactin 11.8 7 3. POLYCYSTIC OVARIES IN THE ABSENCE OF MENSTRUAL DYSFUNCTION In the series reported by Balen et al. (5), approximately 20% were amenorrheic, 50% oligomenorrheic, and 30% had a regular menstrual cycle, whereas the series of Franks and Goldzieher each reported 20% with a regular menstrual cycle (9,10). Several studies have been performed to attempt to determine the prevalence of polycystic ovaries as detected by ultrasound alone in the general population and have found prevalence rates in the order of 17–33% (4,11–16) The study designs and results are summarized in Table 3. All of the studies used transabdominal ultrasound for the diagnosis of polycystic ovaries except for Cresswell et al. (16), who converted to a transvaginal scan if the transabdominal picture was unclear. Table 3 The Prevalence of Polycystic Ovaries in the General Population Authors Polson et al. (11) Tayob et al. (12) Clayton et al. (13) Farquhar et al (14) Botis et al. (15) Cresswell et al. (16) Michelmore et al. (4) Study population Volunteers recruited from clinical and secretarial staff at St. Mary’s Hospital, London (n = 257) Volunteers using a low dose combined OCP, recruited from routine clinics at the Margaret Pyke centre and the Royal Free Hospital, London (n = 120) Volunteers born between 1952 and 1969 recruited from a list of a Group Practice in Harrow, London, by random postal invitation (n = 190) Volunteers recruited from two electoral roles in Auckland, NZ, by random postal invitation (n = 183) Volunteers recruited from women presenting to an outpatient clinic for routine Pap smear (n = 1078) Volunteers born between 1952 and 1953 recruited from records of the Jessop Hospital, Sheffield, by invitation and personal interview (n = 235) Volunteers from a University population and general practice in Oxford (n = 230) Response rate Unknown Unknown 18% 16% Unknown 68% 21–27% Age range 18–36 years 18–30 years (mean = 24 years) 18–36 years 18–45 years (mean = 33 years) 17–40 years 40–42 years 17–25 years Prevalence 22% 22% 22% 21% 17% 21% 33% 95% CI 17–27% 14–30% 16–28% 14–27% 14–19% 16–26% 27–39% 42 Balen The study populations recruited by Polson et al. (11), Tayob et al. (12), and Botis et al. (15) were all subject to a degree of selection bias because of the fact that they recruited women from hospital-associated populations (both hospital workers and patients) and not from the general population. The low response rates achieved in the community-based studies by Clayton et al. (13) and Farquhar et al. (14) might reduce confidence in the validity of their estimates of prevalence, but reassuringly Cresswell et al. (16) who achieved a much higher response rate in their sample determined a very similar prevalence. However, in the absence of a large, cross-sectional population- based study, the prevalence rates detected above provide the best estimates of the occurrence of polycystic ovaries in the “normal” population. The pooled prevalence is 26.6%, indicating that polycystic ovaries (as defined by their ultrasound appearance) are extremely common. In all of the studies, hirsutism was identified more commonly in women with polycystic ovaries. Menstrual cycle abnormalities were also found to be more common in the PCO groups, except in the study by Clayton et al. (13), which detected no significant difference in menstrual patterns when comparing women with polycystic versus those with normal ovaries. Botis et al. (15) noted a greater tendency toward obesity in their group of women with polycystic ovaries, but significant differences in obesity were not identified in the other reports. All of these studies determined higher mean ovarian volumes in women with polycystic ovaries when compared with women with normal ovaries. The frequency of symptoms and signs identified in women with and without polycystic ovaries is summarized in Table 4. The inconsistencies between these studies may be due in part to differences in the definitions used for each symptom or sign that was recorded. However, the method of recruitment may also be relevant as the community-based studies (13,14,16) show frequencies of menstrual cycle disturbances and of hirsutism that are much lower than those recorded in the larger studies of women with PCOS recruited from repro- ductive/endocrine clinics (Table 1). The studies by Botis and by Polson (11,15) record frequencies that resemble more closely those previously determined in the hospital- based studies, suggesting that their populations were subject to greater selection bias. In a study of 224 normal female volunteers between the ages of 18 and 25 years, polycystic ovaries were identified using transabdominal ultrasound in 33% of participants (4). Fifty percent of the participants were using some form of hormonal contraception, which is a common experience when studying young women, but the prevalence of polycystic ovaries in users and non-users of hormonal contraception was identical. Polycystic ovaries in the non-users of hormonal contraception were associated with irregular menstrual cycles and significantly higher serum testosterone concentrations when compared with women with normal ovaries; however, only a small proportion of women with polycystic ovaries (15%) had “elevated” serum testos- terone concentrations outside the normal range. Interestingly, there were no significant differences in acne, hirsutism, body mass index (BMI), or body fat percentage between women with polycystic and normal ovaries, and hyperinsulinism and reduced insulin sensitivity were not associated with polycystic ovaries in this group. Also, no signif- icant differences were identified for -cell function between the groups, unlike other studies that have shown pancreatic -cell dysfunction in women with PCOS when compared with controls (17). Table 4 Frequency of Clinical Symptoms and Signs in Women with and Without Polycystic Ovaries Polson et al. (11) (%) Clayton et al. (13) (%) Farquhar et al. (14) (%) Botis et al. (15) (%) Cresswell et al. (16) (%) Michelmore et al. (4) (%) PCO (n =33 a ) Norm (n = 116 a ) PCO (n = 43) Norm (n = 165) PCO (n = 39) Norm (n = 144) PCO (n = 183) Norm (n = 823) PCO (n = 49) Norm (n = 186) PCO (n = 74) Norm (n = 150) Menstrual cycle disturbance 76 1 29 a 27 46 20 80 – 41 27 65 45 Hirsutism – – 14 2 23 4 40 10 14 2 12 10 Obesity – – 33 29 23 19 41 10 35 48 26 22 a Value includes only non-OCP users with PCO. 44 Balen In this study by Michelmore et al. (4), the prevalence of PCOS was as low as 8% using the NIH consensus definition for PCOS (17) or as high as 26% if the broader “European criteria” (1) were applied. However, features included in the European criteria (menstrual irregularity, acne, hirsutism, BMI > 25 kgm 2 , raised serum testos- terone, or raised LH) were found to occur frequently in women without polycystic ovaries, and 75% of women with normal ovaries had one or more of these attributes. Sub-group analyses of women, according to the presence of normal ovaries, polycystic ovaries alone, or polycystic ovaries and features of PCOS, revealed greater mean BMI in women with PCOS but also indicated lower fasting insulin concentrations and greater insulin sensitivity in PCO and PCOS groups when compared with women with normal ovaries, which is in contrast to studies of older women (18,19). These inter- esting findings were difficult to interpret in light of current understanding of PCOS but forced us to consider the possibility that this young, mainly non-overweight population might reflect women early in the natural history of the development of PCOS and that abnormalities of insulin metabolism might evolve following weight gain in later life. Despite the problems of small sample populations and inconsistent methodology, the epidemiological studies indicate a high prevalence (27%) of polycystic ovaries in the “general” population. They have also shown that many of these women have symptoms and signs that may be attributable to PCOS but reinforce the observation that in some women with polycystic ovaries, no clinical or biochemical abnormalities are detected. The question of whether polycystic ovaries alone are pathological or a normal variant of ovarian morphology is still debated. The consensus statement on defining the morphology of the PCO states that “A woman having PCO in the absence of an ovulation disorder or hyperandrogenism (“asymptomatic PCO”) should not be considered as having PCOS, until more is known about this situation” (2). While the spectrum of “normality” might include the presence of polycystic ovaries in the absence of signs or symptoms of PCOS, there is evidence that women with polycystic morphology alone show typical responses to stresses such as gonadotropin stimulation during IVF treatment or to weight gain, whether spontaneous or as stimulated by sodium valproate therapy (5,20). The difficulty in answering this question lies in the fact that to date there are no large scale, longitudinal prospective studies of women with polycystic ovaries. 4. OVARIAN DYSFUNCTION IN PCOS The distinct ovarian morphology is pathognemonic for the syndrome, its major marker being hyperandrogenemia arising from the theca cells. Follicular development is disturbed with antral follicles arrested at a diameter of 2–9 mm. It is thought that the abnormal endocrine environment adversely affects follicular maturation although it is uncertain whether there is in addition an intrinsic abnormality within the follicle of polycystic ovaries. The whole process of follicle development from primordial to preovulatory takes about 6 months, with only the final 2 weeks being gonadotropin dependent. Preantral follicle development is dependent on local growth factors that determine growth and survival of those follicles that escape death by atresia. A study of follicle densities from normal and polycystic ovaries found that normal ovaries contained 11.4 small preantral follicles/m 3 (4–34) ovulatory polycystic ovaries PCO Versus PCOS 45 had a density of 27.4 follicles/m 3 (9–81), whereas anovulatory polycystic ovaries had a density of 73.0 follicles/m 3 (31–94). This significant difference was also demonstrated for primary follicles (21). Anovulatory polycystic ovaries had the highest overall density of follicles although there was no significant difference between those from anovulatory and ovulatory polycystic ovaries or between ovulatory polycystic ovaries and normal ovaries. Primordial follicle density was similar in all three groups although those from polycystic ovaries were less likely to be healthy. Thus, there appears to be a significantly higher density of small preantral follicles particularly in anovulatory polycystic ovaries. This is thought to be due to a higher rate of recruitment from the resting follicle pool in polycystic ovaries rather than a reduced rate of atresia (which if anything may be slightly increased). The observation that women with PCOS do not have an early menopause suggests that there may be a higher starting follicle pool although this is yet to be proven. The presence of enlarged polycystic ovaries suggests that the ovary is the primary site of endocrine abnormality, particularly the hyperandrogenism. A number of studies have shown that the primary cause of excess androgen production by the PCO is not solely due to hypersecretion of LH, and the intrinsic defect was due to an ovarian theca-interstitial cell dysfunction or other stimulatory influences such as insulin or insulin-like growth factor (IGF)-1 (2–25). Inhibin is an FSH-inducible factor that is capable of interfering with the downregu- lation of steroidogenesis. Plasma inhibin and androstenedione concentrations correlate, and women with PCOS have elevated serum inhibin-B (26). This helps to explain the relatively low serum concentrations of FSH compared with LH in anovulatory women with PCOS. As inhibin stimulates androgen production and androgens in turn stimulate inhibin secretion, there is a potential for the development of a vicious cycle within the ovary that would inhibit follicle development. Alternatively, a defect in the IGF system could cause an alteration of the set point for the response of the granulosa cell to FSH. It has been suggested that LH acts on granulosa cells in the presence of insulin, thereby leading to premature luteinization, maturational arrest, and excess androgen production (25). In summary, as a consequence of dysregulation of androgen synthesis within the ovary, women with PCOS have ovarian hyper-responsiveness to gonadotropins: that of thecal cells to LH explaining the excess androgens and that of granulosa cells to FSH leading to increased estrogens. A PCO functioning relatively “normally” may therefore behave in a more typically “polycystic” fashion when the balance is tipped by a change in either the gonadotropin or insulin/growth factor milieu. 5. EXPRESSION OF PCOS IN WOMEN WITH PCO It has been found that some women with hypogonadotropic hypogonadism (HH) also have polycystic ovaries detected by pelvic ultrasound, and when these women were treated with pulsatile GnRH to induce ovulation, they had significantly higher serum LH concentrations than women with HH and normal ovaries (27). Furthermore, the elevation in LH concentration was observed before serum estradiol concentrations rose. Thus, hypersecretion of LH occurred in these women when the hypothalamus was replaced by an artificial GnRH pulse generator (i.e., the GnRH pump), with a fixed GnRH pulse interval of 90 min (equivalent to the pulse interval in the early 46 Balen follicular phase). These results suggest that the cause of hypersecretion of LH involves a perturbation of ovarian–pituitary feedback rather than a primary disturbance of hypothalamic pulse regulation. Polycystic ovaries with or without clinical symptoms are also a common finding in patients referred for IVF. For example, two studies have identified between 33 and 43.5% of patients presenting with previously undetected polycystic ovaries (6,28). It must be stressed that the first-line treatment for PCOS is not IVF. Occasionally, the IVF specialist will be presented with a patient with PCOS or polycystic ovaries alone, who either has never had induction of ovulation or assisted conception. Provided there is no other cause for their infertility, for example tubal damage, it then behooves the clinician to try induction of ovulation first. Infertility in patients with polycystic ovaries is caused either by PCOS (i.e., failure to ovulate at a normal rate and/or hypersecretion of LH) or by all the other causes of infertility or a combination of the two. Ovulation induction is appropriate for the first group (PCOS). IVF may be necessary in the second group (other causes) and in patients with PCOS who have failed to conceive despite at least six ovulatory cycles (i.e., those who have coexisting “unexplained” infertility). The response of the PCO to stimulation in the context of ovulation induction aimed at the development of unifollicular ovulation is well documented and differs significantly from that of normal ovaries. The response tends to be slow initially but then with a danger of exceeding the threshold thereby presenting a significant risk of multiple follicle formation, multiple pregnancy, and ovarian hyperstimulation (4,29–31). Conventional IVF currently depends on inducing multifollicular recruitment. It is thus to be expected that the response of the PCO within the context of an IVF program should also differ from the normal, with an ‘explosive’ nature of the ovarian response. There are several possible explanations for this ‘explosive’ response, which are beyond the scope of this chapter. Ovarian follicles, of which there are too many in polycystic ovaries, are increasingly sensitive to FSH (receptors for which are stimulated by high local concentrations of estrogen), and as a result, there is multiple follicular development associated with very high levels of circulating estrogen. In some cases, this may result in the ovarian hyperstimulation syndrome (OHSS), to which patients with polycystic ovaries are particularly prone (32). It is interesting also to note that the presence of polycystic ovaries is a marker for increased ovarian reserve and a reduced rate of ovarian aging (33,34). 5.1. Insulin Resistance and Expression of PCOS The cellular and molecular mechanisms of insulin resistance in PCOS have been extensively investigated, and it is evident that the major defect is a decrease in insulin sensitivity secondary to a post-binding abnormality in insulin receptor-mediated signal transduction, with a less substantial, but significant, decrease in insulin respon- siveness (35). It appears that decreased insulin sensitivity in PCOS is potentially an intrinsic defect in genetically susceptible women, as it is independent of obesity, metabolic abnormalities, body fat topography, and sex hormone levels. There may be genetic abnormalities in the regulation of insulin receptor phosphorylation, resulting in increased insulin-independent serine phosphorylation and decreased insulin-dependent tyrosine phosphorylation (35). PCO Versus PCOS 47 Although the insulin resistance may occur irrespective of BMI, the common association of PCOS and obesity has a synergistic deleterious impact on glucose homeostasis and can worsen both hyperandrogenism and anovulation. Insulin acts through multiple sites to increase endogenous androgen levels. Increased peripheral insulin resistance results in a higher serum insulin concentration. Excess insulin binds to the IGF-1 receptors which enhances the theca cells androgen production in response to LH stimulation (36). Hyperinsulinemia also decreases the synthesis of sex hormone- binding globulin (SHBG) by the liver. Therefore, there is an increase in serum-free testosterone (T) concentration and consequent peripheral androgen action. At the heart of the pathophysiology of PCOS for many is insulin resistance and hyperinsulinemia, and even if this is not the initiating cause in some, it is certainly an amplifier of hyperandrogenism in those that gain weight. 6. CONCLUSIONS The presence of polycystic ovaries presents the possibility for a hyperandrogenic state and the expression of the PCOS in a facilitative environment, for example when stimulated by endogenous or exogenous gonadotropins or insulin. A counter argument may propose that the PCO is a secondary effect, whereby it is the exposure of a normal ovary to androgens (stimulated through insulin or LH) that makes it polycystic— although against this proposition is the observation that normalization of endocrinology does not appear to correct ovarian morphology. There are likely to be many routes to the development of the PCOS, including a genetic predisposition, environmental factors, and disturbances of a number of endocrine pathways (e.g., the hypothalamic–pituitary–ovarian axis, feedback loops, hyperinsulinemia, and the metabolic syndrome). In some, the ovary may change as a secondary effect, whereas in others there may be an inherent defect originating in the ovary. Polycystic ovaries are detected in about 27% of the general population, of whom approximately 80% have symptoms of PCOS, albeit usually mild. Thus, approximately 20% of women with polycystic ovaries are symptom free. The presence of polycystic ovaries, however, may be a marker for increased reproductive and metabolic risk. The presence of polycystic ovaries also appears to be associated with an increased ovarian reserve and a reduced rate of ovarian aging. Ovarian dysfunction is expressed when the ovaries of women with polycystic ovaries alone are stressed, by either a gain in weight and rise in circulating insulin levels or stimulation with FSH for assisted conception treatments. Longitudinal studies are required to better explore the evolution of signs and symptoms of the syndrome over time in women with polycystic ovaries and by comparison with those with normal ovaries. REFERENCES 1. Fauser B, Tarlatzis B, Chang J, Azziz R, Legro R, Dewailly D, Franks S, Balen AH, Bouchard P, Dahlgren E, Devoto, Diamanti E, Dunaif A, Filicori M, Homburg R, Ibanez L, Laven J, Magoffin D, Nestler J, Norman R, Pasquali R, Pugeat M, Strauss J, Tan SL, Taylor A, Wild R, Wild S. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on 48 Balen diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reprod 2004; 19:41–47. 2. Balen AH, Laven JSE, Tan SL, Dewailly D. 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Fertil Steril 1993; 59:323–331. [...]... ASPsc 148 PCOS/93 controls (Continued) Negativeb 33 Not significantd 33 Negativeb 47 Positive 45 Positive 44 Positive 44 Positive 132 Positive SNP 44 only 75 76 Chromosome location 15q23 10q 24. 3 10q 24. 3 10q 24. 3 10q 24. 3 10q 24. 3 10q 24. 3 10q 24. 3 15q21 Gene CYP11A CYP17 CYP17 CYP17 CYP17 CYP17 CYP17 CYP17 CYP19 CYP19 – 34 promoter D10S192 D10S192 – 34 promoter – 34 promoter – 34 promoter – 34 promoter D15S520 P4... CAPN10 CAPN10 SNP -4 3 SNP-19 SNP-63 SNP -4 4 SNP -4 3 SNP-19 SNP-63 SNP -4 4 (CAG)n (CAG)n (CAG)n (CAG)n Polymorphism/ Allele US Hispanic Chinese,Asian Indian Australian Cauc Finnish Cauc African American US Cauc Cauc cce cce cce cce TDTa cce Ethnicity cce Study Design Table 1 (Continued) 146 trios 331 PCOS/525 controls 205 PCOS/831 controls 106 cases/112 controls 57 African American PCOS 1 24 Caucasian PCOS... Words: PCOS; genetic association; linkage; CYP11A; insulin gene VNTR; androgen receptor; calpain-10; SHBG; D19S8 84 From: Contemporary Endocrinology: Polycystic Ovary Syndrome Edited by: A Dunaif, R J Chang, S Franks, and R S Legro © Humana Press, Totowa, NJ 51 52 Urbanek 1 POLYCYSTIC OVARY SYNDROME Polycystic ovary syndrome (PCOS) is a genetically complex disorder that is characterized by hyperandrogenemia...5 Genetic Analyses of Polycystic Ovary Syndrome Margrit Urbanek, PHD CONTENTS 1 2 3 4 5 Polycystic Ovary Syndrome Familial Basis of PCOS Current Status of PCOS Genetic Studies PCOS Candidate Genes Future Directions Summary Polycystic ovary syndrome (PCOS) is a very common endocrine disorder with a strong genetic component that is... rs4 646 Haplotype CYP19 rs12907866 rs 241 4096 150 families 39 ASPsc US Cauc US Cauc US Hispanic cce cce 152 PCOS/96 controls 180 women 109 PCOS/95 controls 2 24 women cohort 25 PCOS/50 controls 30 HAi girls/ 14 controls Spanish Cauc UK (97% Cauc.) MexicanMestizo 186 PPh /71 controls >90% US Cauc >90% US Cauc cce cce Mutation screen cce TDTa Linkage (Continued) Positive association w/irregular menses 144 ... population cohort 440 PCOS/1062 controls 255 trios 69 PCOS/63 CAHg /1 24 controls Sample size Negativeb 137 Not significantd 33 Negativeb 33 Negativeb 138 Possible increased risk with C/C genotype 136 Negativeb 137 Negativeb 1 34 Negativeb 135 Negativeb 133 Not significantd 48 Findings 15q21 15q21 15q21 6p21.1 6p21.1 3q13.31 3q13.31 CYP19 CYP19 CYP19 CYP21 CYP21 DRD3 DRD3 MscI Y113H V281L Q318X R354W P453S MscI... in OGTT in African American women 73 Negativeb 74 No association with measures hyperandrogenism 88 Shorter repeats associated with lower androgen levels 89 Longer repeats associated with PCOS 86 Negativeb 87 Findings 2q37.3 15q 24. 1 15q23 15q23 15q23 15q23 CAPN10 CYP1A CYP11A CYP11A CYP11A CYP11A D19S519 D15S520 D19S519 D19S519 D19S519 SNP -4 3 SNP-19 SNP-63 T6235C European and Asian European Greek Cauc... signaling (33, 34) As the connection between PCOS and the metabolic syndrome becomes more clearly established, genes implicated in the development of diabetes and obesity have also become ideal candidates Chromosome location 12q13.12 2q22.2 3p22 3q27.3 3q27.3 8p12 1q 24. 2 19q13.32 Xq11.2 Gene ACTR1 ACTR2A ACTR2B ADIPOQ ADIPOQ ADRB3 AGT APOE AR G45T T276G Y64R M235T Epsilon2 Epsilon3 Epsilon4 (CAG)n D3S1298... >90% US Cauc cce cce Mutation screen cce TDTa Linkage (Continued) Positive association w/irregular menses 144 Negativeb 143 Increased heterozygosity in symptomatic hyperandrogenism 141 Negativeb 142 Positive for rs 241 096 139 Negativeb 140 Not significantd 33 Negativeb 33 Positive for rs 241 096 and haplotype 139 ... intensively The six genes are CYP11A, insulin gene variable number of tandem repeats (VNTR), calpain-10, sex hormone-binding globulin (SHBG), androgen receptor (AR) and X-chromosome inactivation, and the chromosome 19p13.2 susceptibility locus, D19S 844 While past genetic studies of PCOS have yielded only modest results, the resources and techniques to remedy the major deficits of these early studies have now . 60:858–863. 33. Mulders-Annemarie-G-M-G-J, Laven-Joop-S-E, Eijkemans-Marinus-J-C, de-Jong-Frank-H, Themmen-Axel-P-N, Fauser-Bart-C-J-M. Changes in anti-Müllerian hormone serum cocentrations over. 2q37.3 SNP -4 3 SNP-19 SNP-63 SNP -4 4 TDT a cc e Cauc. 146 trios 331 PCOS/525 controls Negative b  74 CAPN10 2q37.3 SNP -4 3 SNP-19 SNP-63 cc e Spanish Cauc. 148 PCOS/93 controls Positive SNP 44 only. 41 27 65 45 Hirsutism – – 14 2 23 4 40 10 14 2 12 10 Obesity – – 33 29 23 19 41 10 35 48 26 22 a Value includes only non-OCP users with PCO. 44 Balen In this study by Michelmore et al. (4) , the