Endocrine and metabolic changes in women with polycystic ovaries and with polycystic ovary syndrome
Chapter 1. Introduction
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of fertile age. The prevalence of PCOS varies between 2.5 and 7.5% (Futterweit & Mechanick 1988, Knochenhauer et al. 1998, Taylor 2000a). Its clinical manifestations include menstrual dysfunction and hyperandrogenic symptoms, and it can be associated with metabolic dysfunction in which hyperinsulinemia and peripheral insulin resistance are central features. A significant proportion of women with PCOS have insulin resistance greater than that of their weight-matched controls. Furthermore PCOS is thought to present an early manifestation of the metabolic syndrome (or syndrome X), which is a cluster of abnormalities where the combination of insulin resistance and compensatory hyperinsulinemia predisposes individuals to develop a high plasma triglyseride (Trigly) and a low high-density lipoprotein (HDL) cholesterol concentration, high blood pressure and coronary heart disease (Reaven 1994). Women with PCOS may represent one of the largest unique groups of women at high risk for the development of early onset coronary heart disease (Franks 1995, Talbott et al. 2000). It has been proposed that there is a mild form of PCOS which includes women who have mild hyperandrogenism and an isolated ultrasonic finding of polycystic ovaries but whose ovulatory function is maintained (PCO). These women may be susceptible to developing the syndrome as well. Thus, they may also be subject to increased morbidity (Carmina & Lobo 1999).
The etiology of PCOS is still obscure. It has been well documented that inappropriate gonadotrophin secretion, especially high luteinizing hormone (LH) secretion, is associated with the classic form of PCOS (MacArthur et al. 1958, Yen et al. 1970). The frequency of the recently discovered genetic variant form of LH (v-LH) is high in the Finnish population (Haavisto et al. 1995). In the United Kingdom, women heterozygous for the v-LH allele have higher levels of serum testosterone (T), estradiol (E2) and sex-hormone-binding globulin (SHBG), which may indicate differences in ovarian LH action between normal (or wild type, wt) LH and v-LH (Rajkhow et al. 1995).
Several studies have indicated that polycystic ovaries usually produce excess androgen (Kirschner et al. 1976, Chang et al. 1983, Rosenfield 1999). The mechanisms leading to increased androgen production in PCOS are not completely understood. Chronic LH stimulation in PCOS induces sustained hypersecretion of androgens by theca compartment, probably augmented by insulin and insulin-like growth factors (IGFs) (Yen et al. 1970, Poretsky et al. 1999). Most data suggests that the primary dysfunction may be at the ovarian level (Rosenfield et al. 1990, Franks 1995) or all manifestations of the syndrome may occur secondary to hyperinsulinemia (Barbieri et al. 1986, Dunaif 1999).
PCOS women have been shown to have an exaggerated 17-hydroxyprogesterone (17-OHP) and androstenedione (A) response to gonadotrophin releasing hormone agonist (GnRHa) and human chorionic gonadotrophin (hCG). Based on the results of these studies it has been suggested that women with PCOS have a primary dysregulation of ovarian P450c17, leading to enhanced activities of both 17¦Á-hydroxylase and 17,20-lyase in the ovarian theca cells (Barnes et al. 1989b, Ibanez et al. 1996, Gilling-Smith et al. 1997, Levrant et al. 1997).
In the present study, we investigated the prevalence of PCO in the Finnish population. We also studied the frequency of v-LH in the Finnish population and compared it to patient cohorts from the Netherlands, the United Kingdom and the United States. Special attention was paid to occurrence of v-LH in women with PCOS, since LH is considered to play a central role in this syndrome. Due to the well-known association between insulin resistance and PCOS, the prevalence of PCO in women with a history of gestational diabetes mellitus (GDM) and the present-day carbohydrate metabolism among these women were also examined. In addition, the ovarian steroidogenic response to exogenously administered gonadotrophins, i.e. hCG, human menopausal gonadotrophin (hMG) and follicle stimulating hormone (FSH) were
2.1. General background of polycystic ovary syndrome (PCOS)
As early as 1844, Chereau described sclerocystic changes in the human ovary (Chereau 1844). Although occasional reports on this condition continued to appear over the years, more interest was aroused in 1935 when bilateral polycystic ovaries were related by Stein and Leventhal in a clinical syndrome consisting of ¡°menstrual irregularity featuring amenorrhea, a history of infertility, masculine type hirsutism and, less consistently, obesity (Stein & Leventhal 1935). The condition was for a long time called the Stein-Leventhal syndrome.
In 1958 McArthur and coworkers observed elevated LH levels in women with polycystic ovaries (MacArthur et al. 1958) and the introduction of radioimmunoassays (RIAs) in 1971 stimulated reliance on a biochemical diagnosis. Although it was suspected as early as 1962 that there was a wide variety of clinical presentation of PCOS, the concept of PCOS with normal LH concentrations was not conceived until 1976 (Rebar et al. 1976). The next milestone was the discovery of the association of PCOS and insulin resistance by Kahn and coworkers (Kahn et al. 1976) and Burghen et al. (Burghen et al. 1980). The ultrasonographic finding of polycystic ovaries was described for the first time in 1981 (Swanson et al. 1981). Adams and coworkers introduced a definition for the ultrasonographic appearance of PCO in 1985 as one diagnostic criterion of PCOS (Adams et al. 1985). This has been widely used thereafter, especially in Europe.
2.2. Epidemiology of PCOS
Data on the prevalence of PCOS are variable due, in part, to the lack of well accepted criteria for diagnosis. If PCOS is defined histopathologically (i.e. by the presence of polycystic ovaries upon oophorectomy or wedge resection), between 1.4-3.5 of unselected women (Vara & Niemineva 1951) and 0.6-4.3% of infertile women (Breteche 1952) suffer from this syndrome.
If PCOS is defined by the ultrasonographic appearance of PCO, the prevalence varies depending on the study settings used. Polycystic ovaries are seen in 92% of women with idiopathic hirsutism, 87% of women with oligomenorrhea (Adams et al. 1986), 21-23% of randomly selected women (Clayton et al. 1992, Farquhar et al. 1994), 23 % of women who consider themselves normal and who report regular menstrual cycles (Polson et al. 1988) and in 17% of women participating in routine PAP smear (Botsis et al. 1995). Up to 25% of patients with this sonographic picture may be entirely asymptomatic (Swanson et al. 1981), however, nor do all patients with hyperandrogenism demonstrate PCO (Orsini et al. 1985, el Tabbakh et al. 1986, Carmina & Lobo 1999).
When biochemical parameters have been used as diagnostic criteria, the prevalence of PCOS varies from 2.5-7.5% (Futterweit & Mechanick 1988). It has recently been observed in an unselected, minimally-biased population of consecutive women, that the overall prevalence of PCOS appears to be approximately 4.6%, although it could be as low as 3.5% and as high as 11.2% (Knochenhauer et al. 1998). It is accepted, however, that PCOS is one of the most common reproductive endocrinological disorders in women.
2.3. Clinical features of PCOS
Polycystic ovary syndrome is a syndrome, not a disease, and reflects multiple potential etiologies and variable clinical presentations. The heterogeneity of the disorder makes the pathogenesis as well as the definition of PCOS difficult. The National Institutes of Health - National Institute of Child Health and Human Development (NIH-NICHD) Conference on PCOS was held in April 1990. In that conference a clear-cut definition was not reached, but the majority of participants believed that PCOS should be defined by 1) ovulatory dysfunction, 2) clinical evidence of hyperandrogenism and/or hyperandrogenemia, and 3) exclusion of related disorders, such as hyperprolactinemia, thyroid dysfunction and nonclassical adrenal hyperplasia (Zawadzki & Dunaif 1992). A peripubertal onset of the symptoms has been used as a diagnostic citeria (Yen 1999). There is strong evidence of a peripubertal onset of the PCOS (see 2.4.1.1).
Oligomenorrhea or dysfunctional bleeding are frequently early and dominant symptoms of the anovulatory component of PCOS. The menstrual irregularity of the PCOS is chronic and can be manifested in several different ways. Probably the most common is erratic menstruation owing to anovulation. Some women with PCOS have prolonged amenorrhea associated with endometrial atrophy. Some women have regular cycles at first and experience menstrual irregularity in association with weight gain (Taylor 1998). The occurrence of oligomenorrhea may be explained by PCOS in approximately 85-90% of women, whereas 30-40% of amenorrheic patients have been reported to have the disorder (Goldzieher & Green 1962).
Hyperandrogenism is the second defining characteristic of PCOS. Clinically, the most common sign of hyperandrogenism in PCOS women is hirsutism. The range of the prevalence of hirsutism in PCOS women varies between 17 and 83% (Goldzieher & Green 1963, Guzick 1998). Hirsutism may develop peripubertally or during adolescence (Yen 1980) or it may be absent until the third decade of life (McKenna et al. 1983). The Ferriman and Gallwey scale is most commonly used for the assessment of hirsutism (Ferriman & Gallwey 1961). Another common sign of hyperandrogenism is acne. Overt signs of virilization, i.e. male pattern balding, alopecia, increased muscle mass, a deepening voice or clitoromegaly usually reflect the presence of an androgen-producing tumor or ovarian hyperthecosis (Yen 1999).
Infertility was included in the original description of PCOS by Stein and Leventhal (Stein & Leventhal 1935). The prevalence of infertility, caused mainly by anovulation, in PCOS women varies between 35 and 94% (Goldzieher & Green 1963, Franks 1995, Guzick 1998). According to one retrospective study, however, women with PCOS are as likely to have children as healthy women, although often after infertility treatment (Dahlgren et al. 1992). Some studies have also described an increased miscarriage rate in PCOS, the mechanism of which is poorly understood. It has been suggested that high follicular phase concentrations of LH have a deleterious effect on rates of conception and miscarriage (Homburg et al. 1988, Balen 1993).
Although there are no controlled systematic studies to determine the exact prevalence of obesity, most investigators have found that 30-50% of PCOS women are obese (Franks 1995). PCOS women tend to have an increased waist-hip ratio, (WHR) i.e. abdominal (visceral) obesity (Rebuffe-Scrive et al. 1989, Bringer et al. 1993).
According to a study of G¨¹lekli et al. including subjects between 14-36 years old, PCOS is a disorder with perimenarchal onset and the clinical, endocrine and ultrasound features were not changed by the age of 36 years, although patients were prone to gain weight (G¨¹lekli et al. 1993). However, it has also been shown that hyperandrogenism partly resolves before menopause in women with PCOS and they tend to gain more regular menstrual cycles with increasing age (40 years and more) (Elting et al. 2000, Winters et al. 2000). A decline in follicle cohort has been reported to occur while aging (Faddy et al. 1992). Several findings have suggested, however, that the common denominator in women with hyperandrogenic anovulation, whether or not they have typical PCOS, could be functional ovarian hyperandrogenism (FOH) (Barnes & Rosenfield 1989a, Ehrmann et al. 1995).
2.3.1. Women with an isolated finding of polycystic ovaries
The isolated finding of polycystic ovaries (PCO, also called polycystic appearance ovaries, PAO), which meets the calssic ultrasonographic criteria, occurs in 10-33% of the normal population (Table 1). Normal ovulatory women with PCO (referring only to the ovarian morphology) are not considered to have PCOS. A subgroup of these women may, however, have subtle abnormalities resembling PCOS (Takahashi et al. 1992, Norman et al. 1995, Carmina et al. 1997). Women with PCO have exaggerated ovarian responses to gonadotrophins and GnRHa (Suikkari et al. 1995, Chang et al. 2000) and disturbances of glucose metabolism (see 2.4.3.8) as in women with PCOS (Lobo et al. 2000). Women with PCO may be susceptible to develop the syndrome and may also have increased morbidity associated with PCOS (see 2.5) (Carmina & Lobo 1999).
The presence of an isolated ultrasonographic finding of PCO may be associated with different endocrine dysfunctions. Therefore, the ultrasonic diagnosis of PCO should be supplemented with an endocrinologic biochemical evaluation to exclude other endocrine dysfunctions (Abdel Gadir et al. 1992).
Figure 1. An ultrasonograph picture of a polycystic ovary.
The ultrasound definition of PCO which has enjoyed the most widespread credibility is that of Adams and collagues: the presence of either multiple cysts (ten or more) from 2-8 mm in diameter distributed evenly around the ovarian periphery with an increased amount of stroma, or (less commonly) multiple small cysts 2-4 mm in diameter distributed throughout abundant stroma (Fig.1, Adams et al. 1985). The combination of multiple follicles and an increased amount of stroma contribute to the overall increase in the ovarian size, on the other hand, ovarian volume may be within the normal range in a significant proportion of women with all other morphological criteria for PCOS (Yeh et al. 1987, Pache et al. 1992).
It has been proposed that an increased ovarian stroma is the most valuable diagnostic criteria for PCO to distinguish it from multifollicular ovaries (MFO) (Polson et al. 1988, Conway et al. 1989). MFO are usually detected in women with hypogonadotrophic amenorrhoea, without increased stroma and filled by six or more follicles 4-10 mm in diameter. The observation of a stromal hypertrophy is considered visual and subjective and therefore the reliability of the diagnosis of PCO is totally dependent on the experience of the ultrasonographist. It has been reported that a visual analysis of the ovarian stroma by ultrasound is more sensitive (not more specific), but also more subjective than a computerized selective measurement (Robert et al. 1995). Increased total ovarian area (total area, TA > 5.5 cm2), which can be easily detected by carefully shaping a strict longitudinal ovarian cut) has been shown to have the same diagnostic value as an increased stromal area by computerized measurement (Robert et al. 1995). A recent study has indicated that the number of peripherally distributed follicles ¡Ý 10 was considered the most sensitive feature of PCO, while stromal brightness had the best specificity to detect PCO (Atiomo et al. 2000).
Ovarian stroma and volume determinations can be obtained more accurately through three-dimensional images than through traditional ultrasonography (Wu et al. 1998).
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Endocrine and metabolic changes in women with PCOS 
