Polycystic Ovary Syndrome - part 4 docx

Table 1 Clinical Symptoms and Signs in Women with polycystic ovary syndrome PCOS Percentage frequency of symptom or sign Balen et al.. Table 2 Biochemical Features of Women with polycyst

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

Menstrual cycle disturbance

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

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

Clayton et al.

Cresswell et

Michelmore et

Study population

Volunteers recruited from clinical and secretarial staff

Hospital, London (n

Hospital, London (n

Volunteers recruited from

Volunteers recruited from

personal interview (n

Volunteers from

University population and

Oxford (n

Response rate

18–36 years

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).

Menstrual cycle disturbance

a Value

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 kgm2, 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/m3(4–34) ovulatory polycystic ovaries

PCO Versus PCOS 45

had a density of 27.4 follicles/m3 (9–81), whereas anovulatory polycystic ovaries had a density of 73.0 follicles/m3 (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

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

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