Polycystic ovary syndrome

C u r r e n t

OBSTETRICS & GYNAECOLOGY aetics in obstel

Polycystic ovary syndrome

M . R a j k h o w a a n d R . N. C l a y t o n

Definition

Polycystic ovary syndrome is a commonly diagnosed female endocrinopathy affecting between 3 to 6% of women in the reproductive age group. The major criteria for diagnosis are presence of hyperandrogenism and chronic anovulation in the presence of polycystic ovaries on ultrasound scan. The presence of polycystic ovaries on scan in the absence of clinical features is not sufficient to make the diagnosis. The most consistent biochemical abnormality is hyperandrogenism which may be the key to suppressing ovarian folliculogenesis. The source of the raised serum androgens may be either of ovarian or adrenal origin. Primary dysregulation of cytochrome P450-17a is cited as a possible factor in the development of the disorder. The regulation of abnormal androgen metabolism may be related to raised serum luteinizing hormone (LH) or to hyperinsulinaemia, and the latter has been suggested to act as a co-gonadotrophin on the ovary, leading to hyperandrogenism. The common clinical presentation is menstrual disturbances, hirsutism, acne/alopecia and infertility. Obesity is a feature in between 35 to 60% of women with polycystic ovary syndrome (PCOS) and associated with a greater severity of clinical manifestations than non-obese women with the syndrome, inspite of similar degree of biochemical abnormality. Weight reduction is of greatest importance in the initiation of clinical management, though practically often hard to achieve. Management is essentially symptomatic, with the desire for achieving fertility an important consideration. Assessment of long-term risk of developing impaired glucose tolerance and non-insulin dpendent diabetes, as well as increased cardiovascular risk in obese women with PCOS, may be an added consideration.

Polycystic ovary syndrome (PCOS) is a commonly diagnosed female endocrinopathy and it is the commonest cause of anovulatory infertility. 1 The major criteria for the diagnosis of PCOS, which are in general agreement, are: hyperandrogenism, chronic anovulation, presence of polycystic ovaries on ultrasound and absence of secondary causes of polycystic ovaries like late onset congenital adrenal hyperplasia or androgen producing neoplasms? The presence of polycystic ovaries on ultrasound scan, without clinical features or serum androgen elevation is not sufficient to make the diagnosis of the syndrome.

History In 1935, Stein and Leventhal drew attention to women with amenorrhoea, hirsutism and enlarged polycystic ovaries. They included women who were at the more severe end of the spectrum and were primarily interested in the therapeutic effect of wedge resection on restoration of menstruation and fertility. It was not their intention to define limits to the disorder. The Stein Leventhal syndrome, as such, is a rare disorder. Goldzieher and Axelrod 3 analysed 1097 reported cases in the literature in 1963, showed a wide variability of signs and symptoms associated with sclerocystic ovaries. There is undoubtedly a broad spectrum of clinical features in women with the polycystic ovary syndrome, which extends from women with no complaints to the extreme degree of masculinization. The rigid criteria of Stein and Leventhal severely underestimates the breadth of phenotypic expression. With the availability of non invasive technique of transabdominal and later transvaginal ultrasound the morphological diagnosis of polycystic ovaries is more easily made and has been confirmed to match the histological diagnosis in several reports. This technique,

M. Rajkhowa, Registrar, Obstetrics and Gynaecology, 7 New Health Close, New Cross Hospital, Wolverhampton WV10 0QP, UK, R. N. Clayton*, Department of Medicine, School of Post Graduate Medicine, Keale University, North Staffordshire Hospital, Thornburrow Drive, HartshiU, Stoke-on-Trent, UK *Address correspondence to: R. N. C

Current Obstetrics & Gynaeeology (1995) 5, 191-200 © 1995 Pearson Professional Ltd

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192 CURRENT OBSTETRICS AND GYNAECOLOGY which in combination with biochemical evaluation, has added a new perspective to the range of disorders in women with polycystic ovary syndrome. It has confirmed that PCOS covers a wide range of disorders with minimal findings of hyperandrogenism (acne/hirsutism) in lean women with regular menstrual cycles to obese women with oligo/amenorrhoea and severe hirsutism as described by Stein and Leventhal.

Epidemiology PCOS is a common disorder and estimated to occur in between 3 to 6% of women in the reproductive age. 4 The ultrasonographic features of polycystic ovaries was reported to occur in 22% of normal female volunteers, s of whom 75% had irregular cycles. In a similar survey by clayton et al in 1992, 6 the prevalence of polycystic ovaries in the community in women of reproductive age was 21%, but only 25% of these women had irregular cycles, and 58% were of proven fertility. This data suggests that the isolated ultrasound finding of polycystic ovaries in women is of yet unknown biological significance. A distinction should therefore be made between the morphological finding of polycystic ovaries and the polycystic ovary syndrome. Whether these women will develop the clinical features of polycystic ovary syndrome in the event of a precipitating factor such as a gain in weight is not known and may be a possibility.

Is PCOSfamilial? The most consistent biochemical abnormality in all groups of women with PCOS is hyperandrogenaemia. This supports a hypothesis that PCOS is caused by an underlying disorder of androgen biosynthesis or metabolism, though there are several other genes likely to modify the expression of PCOS, for example genetic tendency for obesity. Familial aggregation/clustering of PCOS is generally observed, however there are few family studies and the mode of inheritance is not clear. In a recent review, Simpson concluded that the mode of inheritance is unclear and is unlikely to be a single gene defect, 7 A male phenotype with premature balding (male pattern balding (MPB)) has been described. 8 Hague et al, identified affected relatives by ovarian ultrasonography and found the prevalence of PCO too high to be explained by simple mendelian dominant inheritance. 9 Carey et al, conducting a segregation analyis in affected family members to determine mode of inheritance, concluded that it is an autosomal dominant disorder with virtual full penetrance and suggested a single gene defect caused polycystic ovaries and male pattern baldness] ° though this is possibly modified by other genes such as those for obesity and insulin resistance.

Pathophysiology of PCOS Polycystic ovary syndrome is characterised by chronic anovulation. Raised serum androgens (testosterone or androstenedione) is the most consistent biochemical abnormality in PCOS. This supports the hypothesis that, despite the multifactorial and multiorgan nature of the disease, it appears that an underlying disorder in androgen biosynthesis of metabolism may be the central event suppressing ovarian folliculogenesis and giving rise to the disorder. The exact nature of this abnormality in androgen secretion/metabolism is however still unknown. In vitro studies have shown that testosterone is a key regulator of follicular development. Hillier et al have shown that testosterone suppresses hCG stimulated estrogen/progesteromne production by the follicle. 11 Inappropriate exposure of small antral follicles to excessive concentrations of androgens would result in inappropriate inhibition of FSH action and follicular atresia. Long-term administration of androgens can produce polycystic changes to the ovaries. ~2 The primary source of the increased androgens may be intraovarian or extraovarian (adrenal sources).

Adrenal source of hyperandrogenaemia The secretion of dehydroepiandrosterone sulphate, an exclusive adrenal steroid, is increased in up to 50% of subjects with PCOS, both baseline and in response to ACTH. Hyperandrogenaemia may be corrected following partial dexamethasone suppression in some women with PCOS. As adrenal androgen production is corticotrophin dependent, it will occur in situations where cortisol production is limited as in patients with congenital adrenal hyperplasia, cortisol resistance, or enhanced metabolism/clearance of cortisol. Cortisol clearance is enhanced in situations characterised by changes in the activity of various metabolising enzymes. Stewart et al reported increased activity of 5~ reductase in women with PCOS which converts cortisol to inactive 5a dihydrocortisol, while at the same time increasing the peripheral conversion of testosterone to dihydrotestosterone. 13 Rodin et al demonstrated dysregulation of 1113 hydroxysteroid dehydrogenase, either primary or secondary, leading to increased metabolic clearance of cortisol, with increased ACTH stimulated androgen production in some women with PCOS.14

Ovarian sources of hyperandrogenaemia Other evidence suggests that the ovaries are the principal source of excess androgens in PCOS. This includes that the principal androgens raised in PCOS are plasma testosterone, androstenedione, and their production has been shown to be increased in polycystic ovarian tissue in vitro studies. 15 The elevated androgens are not completely suppressed by dexamethasone, indicating that they are of ovarian origin. Selective administration of G n R H agonists for

POLYCYSTICOVARYSYNDROME 193 1 month suppresses the androgens to castrate levels which demonstrates the ovarian source of these androgens. 16 Further evidence indicating an ovarian source of the androgens include ovarian catheterization studies. Further ablation of androgen producing interstitial tissue following ovarian diathermy or laser coagulation temporarily decreases serum testosterone and androstenedione concentrations, as well as LH with restoration of ovarian cyclicity. The raised androgens in the presence of normal oestradiol raises the possibility of incomplete conversion of androgens to oestrogen in this syndrome. Primary dysregulation of the enzyme cytochrome P450c17a, which catalyses the conversion of progesterone to 17~ hydroxyprogesterone and thence to androstenedione, has been suggested as the central abnormality in PCOS. Barnes et al reported an exaggerated response of 17a hydroxyprogesterone, androstenedione, and estrone to gonadotrophin stimulation, indicating a 'masculinization' of the androstenedione forming enzyme cytochrome P450c17c~ in the theca interstitial cells. 16,17This could occur secondary to elevated LH, intrinsic defect in the theca-interstitial cells, or from 'adrenal rest' cells within the ovaries. This forms the basis of the GnRH analogue stimulation tests where the same authors 17 demonstrated a 58% increase in 17 OHP due to increase in the activity of 17 alpha hydroxylase with partial down regulation of the 17-20 lyase activity, i.e. dysregulation of cytochrome P 450c17o~. The other enzyme dysregulation suggested by in vitro studies include a defect in 3[~ hydroxysteroid dehydrogenase or aromatase deficiency. The aromatase deficency can be easily reversed by the addition of exogenous FSH, implying that it is secondary to the dysregulation of gonadotrophins. Aromatase deficiency may also be secondary to atresia from any cause. The atretic follicle has very little capacity to convert androstenedione to oestrdiol and therefore androgens are predominant in atretic follicles. Androgen biosynthesis in the ovary is regulated by luteinizing hormone, and possibly by insulin. Thus, two groups of women with PCOS have been identified: those with a high LH but normoinsulinaemic, and the other with normal LH but hyperinsulinaemic. Abnormalities in secretion of L H

The most commonly described abnormality of PCOS is an elevated serum LH or an elevated LH/FSH ratio, an increased LH pulse frequency, increased LH pulse amplitude, an exaggerated response of LH to GnRH, and altered diurnal LH pulse frequency. However, serum LH levels may be normal in up to 40% of women with PCOS. 18-2° So what is the cause of LH hypersecretion in PCOS, though all women with the disorder do not have a raised LH? Both oestrogens and progesterone influence LH secretion by abnormal steroid feedback, there being no evidence that

androgens directly influence the LH secretion from the pituitary. The increased amplitude of the LH pulses is probably explained by increased sensitivity of the gonadotrophs to GnRH due to prolonged exposure to unopposed oestrogen. The source of this oestrogen is thought to be oestrone from the peripheral conversion of androstenedione. Lobo et al reported that the bioactive/immunoreactive LH ratio is elevated in women with PCOS. 21This could enhance androgen production in the ovary. It was suggested that the bioactive LH may be elevated even in the absence of raised immunoactive LH, implying a more bioactive form of LH in this disorder. Puberty and PCOS

PCOS is said to be perimenarcheal in onset. A primary pituitary abnormality has been suggested on the ground that there may be abnormal diurnal pattern of gonadotrophin release in adolescent girls who have the clinical features of polycystic ovary syndrome. 22Irregular menstrual cycles are common in adolescence. Evaluation of these girls often reveals hyperandrogenism and multicystic ovaries. The nocturnal slowing of the LH pulse amplitude in the early follicular phase has been said to not occur in this syndrome. Abnormalities of the diurnal pattern of LH have also been described with a reversal of the normal diurnal pattern of LH secretion in postmenarcheal teenagers with classic PCOS. These girls have an early morning rise in LH as compared to the nocturnal rise seen in normal premenarcheal pubertal girls. These abnormalities in the pulsitility of LH suggest that there may be a primary abnormality in GnRH secretion, though what central dysregulation is responsible for this abnormality remains unclear. FSH secretion in PCOS

FSH plays a crucial role in the normal ovulatory process. The FSH concentration in PCOS is either normal or low. The reason behind the disparity in the secretion of FSH and LH is still unclear. It has been suggested that there is preferential suppression of FSH, selective inhibition of FSH by inhibin or related growth factors in PCOS, or diminished bioactivity. An intercycle rise in FSH activity is critical for normal folliculogenesis to take place and this is absent in anovulatory cycles, hence failure to initiate the normal process of folliculogenesis. Precisely how this arises is not clear, though failure of a progesterone rise in the preceding luteal phase can lead to failure of the normal luteal slowing of GnRH secretion which favours FSH synthesis. Role of insulin as co-gonadotrophin in PCOS

The observation of insulin resistance and hyperinsulinaemia in a subset of women with PCOS has

194 CURRENTOBSTETRICSAND GYNAECOLOGY added a new dimension to the understanding of the pathogenesis of PCOS, as well as recognition that the syndrome has substantial metabolic as well as reproductive complications. Burghen et al, first reported the presence of hyperinsulinaemia in a group of obese PCOS subjects and showed significant correlation with the raised serum testosterone, androstenedione and insulin. 23 Since then, there have been many reports confirming the presence of insulin resistance and consequent hyperinsulinaemia in obese and non-obese subjects with PCOS. Studies have demonstrated insulin resistance in PCOS unrelated to body weight and composition, though obese PCOS women have consistently been shown to have a greater degree of insulin resistance compared to weight matched controls. 24 Insulin resistance in non-obese PCOS subjects, however, has been controversial. While Dunaif et al and Burghen et al have described insulin resistance of similar degree in non-obese PCOS, 24'25others have failed to demonstrate insulin resistance and hyperinsulinaemia in non-obese PCOS subjects when compared to weight matched controls. 25,26Robinson et al described insulin resistance in non-obese PCOS with menstrual irregularities but not in those with regular cycles. 18It has been suggested that about 30% of non-obese PCOS subjects may be insulin resistant with subsequent hyperinsulinaemia. 19

Role of insulin resistance in the pathogenesis of PCOS Barbieri et al first reported the effect of insulin and insulin-like growth factors on ovarian androgen production in ovarian tissue obtained from hyperandrogenic and normal cycling w o m e n . 27 They concluded that both LH and insulin independently, and in combination, significantly increased the production of testosterone and androstenedione from ovarian stroma/theca cells from women with PCOS compared to normal women. They suggested that insulin may be mediating its effect via IGF receptors in the theca cells or by reducing the availibility of IGF-BR Whether the hyperinsulinaemia noted in PCOS subjects is responsible for the development of hyperandrogenaemia or vice versa, or whether they are independent features is hotly debated. The physiological role of insulin may be indirect by regulating the action of IGF and IGFbinding proteins, both of which modulate the LH stimulated biosynthesis of androgen in the ovary in-vitro. It has been shown that insulin lowers SHBG levels thus increasing the circulating, biologically available, androgens (free T) 26 which by inhibiting follicular maturation, may initiate the sequence of events leading to PCOS. The evidence for hyperandro enaemia causing hyperinsulinaemia is not convincing. Dunaif et al demonstrated that suppression of hyperandrogenaemia did not alter the hyperinsulinaemia in women with PCOS. 28 Moreover, insulin resistance persists in women with hyperandrogenaemia after ovariectomy and the menopause, 29,3°and predates the development of hyperandrogenism in pubertal girls. 31

The hypothesis that hyperinsulinaemia, secondary to insulin resistance in PCOS, contributes to hyperandrogenaemia is more convincing. Suppression of serum insulin by oral diazoxide lowered serum androgens 32 in obese women with PCOS. Weight loss is associated with a reduction in serum insulin and increase in SHBG, resulting in a fall in the circulating free testosterone. This was associated with an improvement in menstrual pattern, and fertility. 33 Diverse disease states that, result in severe hyperinsulinaemia viz. type A and type B insulin resistance, leprechaunism and lipoatrophic diabetes are invariably associated with hyperandrogenism. However, studies have demonstrated that there is no direct causal relationship between the hyperinsulinaemia and hyperandrogenamia in women with PCOS 24,26with the suggestion that they may be independent features of this diverse syndrome, or the result of an as yet unknown third factor.

Mechanism of insulin resistance The mechanism of insulin resistance in women with PCOS and the possible role in the pathogenesis has been studied extensively. Barbieri expounds the 'insulin hypothesis', stating that marked hyperinsulinaemia synergises with LH to stimulate ovarian androgen production. 34 The example of a possible linkage between point mutations in the insulin receptor gene and PCOS is suggested by the HAIR-AN syndrome, i.e. hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The cellular mechanisms that account for target tissue insulin resistance in PCOS is still unknown. In order to examine the likelihood of subtle point mutations in the insulin receptor gene in women with PCOS, several studies have been performed. While some have shown normal receptor number, others have shown lower insulin binding. Based on the latter finding, it was suggested that insulin resistance may be secondary to lesions at the receptor level. However, most of those reports included patients with severe insulin resistance and AN, and may represent a less common variant group of women with PCOS. Thus, it is possible that only a subgroup of women with PCOS have primary abnormality of insulin receptor number and auto phosphorylation. The other possibility is that of post receptor abnormalities in glucose transport? 4

Clinical features of P C O S

The major clinical features in 166 (107 obese and 59 non-obese) women with diagnosis of PCOS on biochemical and ultrasound features is shown in Figure 1, compared to 225 (75 obese and 150 non-obese) age and weight matched referents with regular ovulatory cycles and normal ovaries on transvaginal ultrasound. Menstrual abnormalities occur in about 85% of patients, with oligomenorrhoea

POLYCYSTIC OVARY SYNDROME

in 65% and amenorrhoea in 20%. The menstrual irregularities often start from the time of menarche, which may be late, and recur after stopping the oral contraceptive pill which is often taken to regularise the cycle. The incidence of oligomenorrhea was 66% in non-obese subjects (BMI < 25) compared to 88% in obese subjects (BMI > 25). Oligomenorrhoea is a common symptom of PCOS with 5 out of 6 women with oligomenorrhoea shown to have polycystic ovaries. 35,36 Infertility is probably related to the anovulatory cycles and is the presenting complaint in about 40% of women with PCOS. Dysfunctional uterine bleeding is another common presenting feature37 and is secondary to the failure of ovulation. The unopposed action of oestrogen leads to thickened endometrium which can be demonstrated on ultrasonography and has been shown to match the degree of hyperplasia on histology,z°,37In a retrospective follow-up of women with PCOS, Dahlgren et al found that 21% of the women with PCOS had undergone hysterectomy, compared to 2% in the referent population (P < 0.01).38 The major indication for the hysterectomy was menorrhagia. Hirsutism is the presenting complaint in 60% of the subjects. When graded by Ferriman Gallwey score > 7, 60% of non-obese women and 80% of obese PCOS were hirsute in our study group. The other manifestations of hyperandrogenism which have been described include male pattern baldness with temporal recession and occipital baldness, and diffuse hair loss. There is racial difference in the degree of hirsutism in the presence of similar degree of hyperandrogenaemia. Carmina et al studied the ethnic diversity in three groups of women of North American, Italian and Japanese origin. 39 Though the degree of hyperandrogenism, insulin resistance was similar in the three groups, the Japanese women were not hirsute and less obese. Seborrhoea and acne are other manifestations of raised androgens.

°/~Hhi~rf~

pcos (n=107)

pcos (n=59)

cont (n=75)

n-ob cont (n=150)

Fig. 1--The schematic representation of the clinical features of oligomenorrhoea, hirsutism, ache and acanthosis nigricans in the four groups.

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Obesity is present in between 35 to 60% of women with polycystic ovary syndrome. Commonly noted is the history of oligomenorrhoea or amenorrhoea being precipitated at the time of weight gain, such as after childbirth. As is evident from Figure 1, all the clinical manifestations of this disorder are more marked in obese PCOS women, inspite of biochemical abnormalities of the same extent as is seen in nonobese women. Acanthosis nigricans was noted to the same extent in women with obese PCOS and obese controls in our cohort.

PCOS and recurrent early miscarriage The role of PCO in recurrent miscarriage is currently receiving a great deal of interest. Sagle et al reported that 82% of women with recurrent miscarriage had ultrasonic features of PCO. 4° Ovulation induction in women with PCOS is associated with a 30% miscarriage rate. An association between raised serum LH and recurrent miscarriage has been reported by Regan et al. 41 A normal LH is associated with a miscarriage rate of 12% while a high LH had a miscarriage rate of 65%. The elevated LH in the follicular phase may lead to premature maturation of the oocyte, while high LH in the luteal phase may lead to functional abnormalities in the endometrium, either directly or indirectly, at the time of implantation.

Ultrasound diagnosis of PCOS The histological features of polycystic ovaries show an increase in the number of small (5-10 ram) follicles and in the amount of stroma as compared to normal ovaries. In addition, some subjects show features of thecal hyperplasia. These features are identifiable on high resolution pelvic ultrasound. Adams et al defined the ultrasonic criteria for the diagnosis of polycystic ovaries as one which contains in one plane at least 10 follicles (between 2-8 mm in diameter) distributed peripherally, and an increased echodense stroma) s,36 The follicles may also be distributed throughout the stroma. The ovarian volume is usually increased, though this may not always be so. The ultrasound appearance can be distinguished from normal, even in women on the oral contraceptive pill. z° The accuracy of pelvic ultrasound has been validated with the morphological appearance of the ovary in women undergoing wedge resection of ovary and with laparoscopy.42,43Adams et al and Franks et al identified polycystic ovaries in 32% of women with amenorrhoea, 87% of women with oligomenorrhoea and 60% with hirsutism,z°,36 The same group reported the presence of polycystic ovaries in 22% of a normal population, though 78% of the subjects with PCO on scan had irregular cycles with normal biochemical parameters. Therefore, the presence of polycystic ovaries on ultrasound

196

CURRENT OBSTETRICS AND GYNAECOLOGY

in the absence of clinical/biochemical abnormalities is of yet unknown significance. Ultrasonography has its limitations. It is often a subjective assessment and may have an operator bias. When the ovarian volume is normal, it is often difficult to differentiate polycystic from a 'multifollicular' ovary. This pattern is observed in patients with hypogonadotrophic amenorrhoea usually due to weight loss, characterised by increase in number of follicles distributed throughout the stroma, without any increase in stroma. The accuracy of presence of polycystic ovaries as a single diagnostic criterion for PCOS is again debatable. It is well recognized that the ultrasonic features of polycystic ovaries may be seen in other conditions of hyperandrogenic anovulation such as androgen producing adrenal tumours, Cushing's syndrome, congenital adrenal hyperplasia, hyperprolactinaemia.44 Using ultrasonographic diagnosis of PCO as sole diagnostic criterion, 21% of their subjects would have been erroneously diagnosed as having PCOS. 44Increased ovarian stoma may be a more sensitive marker of the disorder as has been suggested by Dewailly et al who have stressed that increased and hyperechogenic ovarian stroma may be diagnostically more important. 45 They assessed the efficacy of a computerised semi-quantitative objective assessment of stromal hypertrophy in patients with PCOS, and reported a significantly higher stromal area as well as total ovarian volume in their subjects which correlated with the androstendione and 17OH progesterone levels. The total microcyst area did not correlate with either.

Endocrine profile in PCOS Since the first description of elevated LH in women with Stein Leventhal syndrome, several different hormones have been used in the diagnosis of PCOS, including raised LH, LH/FSH ratio > 3, LH/FSH ratio > 2, and elevated total testosterone, free testosterone, androstenedione, or dehydroepiandrostenedione sulphate. To be of value, the normal range for all the hormones should be precisely defined in a group of regularly ovulating women in the early follicular phase of the menstrual cycle, for the assay used in each laboratory. In women with chronic anovulation, oligomenorrhoea or hirsutism and PCO on ovarian ultrasound, Adams et al and Robinson et al reported that raised serum androgens were the most commonly found abnormality?6,46 Franks, Robinson et al, found that elevated LH (above 2SD/95th confidence interval) in 51% and 35% of women with PCOS, while the LH/FSH ratio was elevated in only 44%. 20,46 Serum testosterone was elevated in 70% and androstenedione in 53% of the cohort. 46 It is apparent that no single biochemical marker is invariably abnormal, though serum testosterone may be the single most common abnormality. Robinson et al concluded that combination of testosterone, androstenedione and LH

n 14 12 10

I

~DIONE

(xl0) 'RONE pcos (n=107)

pcos (n=59)

cont (n=75)

n-ob cont (n=150)

* P < 0.05, PCO$ vs Controls (ob and non-ob) # p<0.05,ob PCOS vs non-ob PCOS

Fig. 2 - - T h e serum androgens and S H B G in the four groups. FTi = free testosterone index, A4dione = androstenedione. * P < 0.005 PCOS vs Controls (obese and nonobese), # P < 0.01 obese PCOS vs nonobese PCOS (only for S H B G a n d FTI).

increased diagnostic sensitivity to 86%.46 Fox et al found that a combination of LH, testosterone and free testosterone gave a diagnostic sensitivity of 89%.47 Most authors suggest that LH/FSH ratio should be abandoned as a criterion for the diagnosis of PCOS. 20,46 The endocrine profile of our recent cohort is shown in Figure 2. All estimations were carried out within 7 days of menstruation for controls and PCOS. Where the PCOS subjects had 3 or more months of amenorrhoea, samples were taken at random. The 95th centile of the control population was taken as the upper normal limit. Raised serum LH (> 9 iu/1) was found in 36.6% of PCOS subjects. Testosterone was elevated in 55% (> 3.0 nmol/1), androstenedione in 34% (> 12 nmol/1) and free testosterone index (FTI) in 60% (> 7.3). SHBG was significantly lower in obese PCOS compared to obese controls as well as nonobese PCOS, and consequently the FTI was significantly higher in this group. Conway et al reported a higher testosterone in hirsute compared to non hirsute women, 19 while Gilling-Smith and Franks reported a higher LH, FSH, testosterone and androstenedione in women with menstrual irregularity with anovulation than those with regular ovulatory cycles.48 Obhrai et al suggested that the hormonal abnormalities became more profound with greater severity of menstrual disorder.49 We did not find a difference in the hormone profile in hirsute and non hirsute women, or between those with regular menses compared to those with oligomenorrhoea.

Progesterone challenge test Fox and Hull demonstrated that 92% of patients with PCOS had a withdrawl bleed to progesterone

POLYCYSTIC OVARY SYNDROME

challenge indicating oestrogenisation, 5° the diagnostic accuracy by a positive progesterone challenge alone was 89%.

Metabolic abnormalities

Impaired glucose tolerance The studies examining insulin resistance in obese and non-obese women with PCOS have shown that nonobese women with PCOS may demonstrate insulin resistance in the presence of a completely normal glucose tolerance. Up to 66% of women with PCOS are obese, and obesity has a synergistic deleterious effect on glucose tolerance. Dunaif et al reported that 20% of obese women with PCOS develop non-insulin dependent diabetes (NIDDM) by their early 30's, making PCOS a common risk factor for NIDDM. 24It is further suggested that non-obese PCOS are likely to have a higher prevalence of N I D D M if followed beyond the fourth decade. 51 Dahlgren et al, in a retrospective study, reported that 39% of women with PCOS and 11% of the referent population were being treated for hypertension (P < 0.001) and 15% of PCOS were diabetic compared to 2.3% of the referents (P < 0.05). There was a strong heredity for metabolic disease with 85% of PCOS subjects having at least one parent with diabetes mdlitus or cardiovascular disease or both.

Lipid abnormalities and cardiovascular risk Cardiovascular disease is the most common cause of death in women, and those with polycystic ovary syndrome appear to be at a particularly high risk. The relative risk for myocardial infarction in women with PCOS was 7.4 when calculated by risk factor model analysis. 52 This is due to the compound effect of multiple risk factors including obesity, glucose intolerance, hypertension and dyslipidaemia. Insulin resistance, increased levels of male sex steroids and central obesity all increase the risk of developing cardiovascular disease although it is possible that this is mediated by associated dyslipidaemia. In PCOS the dyslipidaemia is characterised by an increase inserum triglycerides and a low H D L but attempts to elucidate the metabolic abnormality underlying the dyslipidaemia are confounded by effects of obesity and insulin resistance. Conway et al showed an influence of fasting insulin on H D L 2 cholesterol levels in lean and obese women with PCOS. s3 Graf et al, in a controlled study, demonstrated that obesity was associated with a significant decrease in H D L levels in both PCOS as well as controls and was the major factor affecting the lipid profile in PCOS. 54They concluded that obesity is the primary cause of most of the lipid abnormalities in PCOS. We examined the lipid profile in our cohort of obese and non-obese subjects with PCOS. The

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obese PCOS subjects had raised serum triglycerides similar to obese controls. In addition, there was significant reduction in the cholesterol and phospholipid content of H D L in obese PCOS, even when compared to obese controls, though this was not seen in the nonobese PCOS. These results suggest that the atherogenic lipid profile is largely dependent on the degree of obesity in PCOS subjects.

Management

Diagnosis and investigations The diagnosis of PCOS should be based on the clinical features of menstrual irregularity and/or chronic anovulation, with some evidence of hyperandrogenism (hirsutislrdacne) together with the demonstration of polycystic ovaries on ultrasound scan, and biochemical evidence of hyperandrogenaemia. A hormone profile within 7 days of menstruation should include LH, FSH, testosterone, androstenedione and prolactin. It is important to exclude other causes of menstrual disturbances viz. hyperprolactinaemia, premature ovarian failure, hypothalamic amenorrhoea. Serum prolactin levels of > 1000 mU/1, on more than one occasion, require further investigations to exclude the possibility of prolactinoma. This should be performed irrespective of the presence of PCOS on pelvic ultrasound. Patients with serum testosterone levels > 5 nmol/1, or androstenedione of > 20 nmol/1, should undergo further investigations to exclude late onset congenital adrenal hyperplasia, Cushing's syndrome, adrenal and ovarian androgen producing tumours. A useful clinical test is the progesterone challenge test, especially in those with amenorrhoea. In view of the recent evidence of higher incidence of glucose intolerance and increased cardiovascular risk in obese women with PCOS, there may be a place for performing an oral glucose tolerance test and estimation of fasting serum triglycerides and H D L cholesterol, especially in those with a BMI > 25.

Treatment Management is essentially symptomatic, for menstrual irregularities associated subfertility is an important consideration, The aim of treatment is to restore ovarian cyclicity, or reversing the effects of hyperandrogenism, that is hirsutism, alopecia and/or acne.

Weight reduction Obesity is associated with greater severity in the menstrual disturbances and hirsutism than in lean women with PCOS. Kiddy et al reported an improvement in menstrual pattern, endocrine profile and fertility in obese women (body mass index > 25) with PCOS if they lost more than 5% of the body weight by

198 CURRENTOBSTETRICSAND GYNAECOLOGY long-term calorie restriction. 33 This is supported by the observation of improvement in response to clomiphene following weight loss in obese PCOS women. Therefore, weight reduction needs to be emphasised to all obese women with PCOS at the outset of treatment. Though it is often difficult to achieve, it ensures a better outcome in the management of both hirsutism and infertility.

Infertility-ovulation induction PCOS is the commonest cause (73%) of anovulatory infertility 1Before initiating ovulation induction, seminal fluid analysis should be noted to be satisfactory. Tubal status examination can be deferred for 3 to 6 cycles unless indicated clinically. The first line of treatment in ovulation induction is anti-oestrogens. Clomiphene citrate is used for the chemical initiation of ovulation and has been in use now for more than 25 years. The main site of action is the hypothalamus, releasing it from the negative feedback of endogenous oestrogen, increasing activity of the L H R H pulse generator, increased release of FSH and stimulation of folliculogenesis. The other sites of action include the pituitary, ovary and cervical mucous, having a deleterious effect on the latter. The minimum effective dose should be utilised, and there is no evidence to indicate that a dose of more than 100 mg/day for 5 days has any additional beneficial effect. Monitoring of therapy to determine the minimum effective dose can be determined by midluteal progesterone or monitoring the initial cycle by serial ultrasound follicle tracking. The discrepancy between ovulation and conception rates may not be as large as previously reported if patient selection is appropriate. 55 There is increased risk of multiple pregnancies (8% of all pregnancies) with the majority constituting twins. Rossing et al, in a retrospective analysis, reported a higher incidence of borderline ovarian tumours in women exposed to clomiphene over prolonged periods of time (> 12 months) with a relative risk of 7.7. 56 A patient is termed clomiphene resistant when she does not respond to the maximum ovulatory dose over a period of at least 6 months. The second line of therapy is usually gonadotrophins - either low dose gonadotrophins, or G n R H analogue down regulation followed by gonadotrophin therapy. Gonadotrophin therapy requires close monitoring by serial ultrasound scans with or without serial oestradiol measurements to avoid complications. It should be carried out in centres equipped with monitoring facilities and capable of dealing with any complications that may arise. The traditional human menopausal gonadotrophins (HMG) contain both FSH and LH, with the active constituent representing only 3% of the total product. The recently developed purer products, both urinary derived and recombinant, are > 95% pure, and with > 9000 IU/mg protein. The theoritical advantage of a product devoid of LH have not been proven in clinical

studies, and the purified product confers no advantage on that level. However, simplified subcutaneous self administration offers some convinience. Conventional gonadotrophin regimes are associated with multifollicular development and increased rate of multiple pregnancy (reported rates varying from 10-50% ), ovarian hyperstimulation syndrome (OHSS) (mild to moderate ranging from 8-20%) and severe hyperstimulation requiring hospitalisation in up to 2% of cases. 57 Low dose gonadotrophin therapy has been advocated to overcome some of these problems. Gilling-Smith and Franks reported 72% ovulatory cycles on the low dose regime, of which 73% were ovulatory, and cumulative pregnancy rate of 55%. The use of G n R H analogue down regulation with gonadotrophin therapy is being advocated to avoid premature pre hCG luteinization. In patients where gonadotrophin treatment is unsuccessful, assisted conception techniques such as IVF and ET may be required. Though the pregnancy rate and 'take home' baby rate are similar to a normal population, there is greater incidence of complications like OHSS, higher miscarriage and cancellation rates. Besides these, some of the other problems particularly associated with PCOS in assisted conception programmes include raised tonic LH with poor outcome, premature luteinization, greater number of oocytes (but of poor quality), cyst formation, variable follicle growth and luteal phase defects.

Hyperandrogenism The management of hirsutism, acne and alopecia, again includes emphasis on weight reduction in obese patients. A clear explanation of the cause of the hirsutism and reassurance of its benign nature, coupled with advice regarding cosmetic measures such as depilatory aids and electrolysis, is often sufficient. Anti androgens are second line therapy, those most commonly employed being the reverse sequential regime with cyproterone acetate 50o100 mg and ethinyl oestradiol 35-50 ~tg. Acne is reported to improve in 500100% of subjects in 3q5 months, while hirsutism is reduced in 50% in 6-9 months. This can be maintained with Dianette, i.e. low dose CPA 2 mg with 35 ~tg of ethinyl oestradiol. This may be adequate by itself in women with mild to moderate hirsutism. Other available anti androgens include spironolactone and flutemide. Adrenal suppression with glucocrticoids has also been used for those with predominantly adrenal hyperandrogenism. Ovarian suppression with combined oral contraceptive pill, GnRH agonist (for short duration only) and GnRH agonist with HRT has been used. Newer 5a reductase inhibitors like fmasteride are currently being evaluated.

Surgical management of PCOS Historically wedge resection of the ovary was known to be an effective method of restoring ovarian cyclicity

POLYCYSTIC OVARY SYNDROME

a n d i m p r o v i n g the degree o f h y p e r a n d r o g e n i s m in w o m e n w i t h P C O S . L a p a r o s c o p i c techniques o f ovarian diathermy, b i o p s y a n d laser c o a g u l a t i o n are n o w available for the m a n a g e m e n t o f c l o m i p h e n e or g o n a d o t r o p h i n resistant a n o v u l a t o r y infertility. I t has the a d v a n t a g e o f simplicity, c a n be c a r r i e d o u t as a d a y case a n d m a y be c o m b i n e d with d i a g n o s t i c laparoscopy. Several studies have shown t h a t the e n d o c r i n e changes, with r e d u c t i o n in s e r u m a n d r o gens a n d L H following o v a r i a n d i a t h e r m y o r laser c o a g u l a t i o n are similar to those following wedge resection. 58 O f the patients w h o r e m a i n oligoo v u l a t o r y after these procedures, m o s t will have been r e n d e r e d sensitive to c l o m i p h e n e citrate. O v u l a t i o n rates o f 7 0 - 9 0 % a n d c o n c e p t i o n rates o f 60% are r e p o r t e d in p u b l i s h e d literature. 58,59 K n o w l e d g e o f l o n g - t e r m effects o f these techniques is still limited a n d the c o n c e r n s are r e g a r d i n g p o s t operative a d h e s i o n s a n d the d u r a t i o n o f the beneficial effect.

Menstrual disorders M e n s t r u a l i r r e g u l a r i t y in w o m e n varies f r o m o l i g o m e n o r r h o e a to p o l y m e n o r r h a g i a . I f they d o n o t require fertility t r e a t m e n t , in o r d e r to avoid the risk o f d e v e l o p i n g e n d o m e t r i a l h y p e r p l a s i a cyclical withdrawl bleed with c o m b i n e d pill, or cyclical low dose n o n a n d r o g e n i c p r o g e s t o g e n s is advocated. G n R H agonist c a n be used as s h o r t - t e r m treatment. Obese w o m e n s h o u l d be e n c o u r a g e d to lose weight as obesity exacerbates the situation. T h e incidence o f h y s t e r e c t o m y for m e n o r r h a g i a is h i g h e r in w o m e n with P C O S c o m p a r e d to age m a t c h e d referents. 38

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