The etiology of polycystic ovary syndrome (PCO)

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The Etiology of Polycystic Ovary Syndrome

(PCO)

R. KAZER Northwestern

University

Medical School, 333 E. Superior Street, Chicago, IL 60614, USA

Abstract - Consideration of existing data leads to the.hypothesis that polycystic ovary syndrome results from a primary abnormality in the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis characterized by increased IGF-1 activity at multiple sites. The effect of elevated IGF-1 activity upon the ovary, the adrenal, and on peripheral tissues may lead to the clinical and biochemical features of PCO, including hyperandrogenemic chronic anovulation, insulin resistance, and elevated adrenal androgen secretion. The fundamental defect may be a consequence of feeding behavior early in life.

Introduction

PC0 is a heterogeneous disorder which reflects a chronic anovulation state associated with a luteinizing hormone (LH) dependent overproduction of androgens by the ovary. The elucidation of the pathophysiologic mechanisms underlying PC0 has long been a popular area of research for endocrinologists. While many interrelationships have been established among the clinical and biochemical findings which typify PCO, a fundamental understanding of the etiology of the disorder is still lacking. Recently published data indicate that women with PC0 exhibit two persistent abnormalities following extended suppression of ovarian steroidogenesis with analogs of gonadotropin-releasing hormone (GnRH): mild insulin resistance (IR) independent of the presence of obesity (1) and elevated production of the adrenal androgen dehydroepiandrosterone sulfate (DYIEA-S) (2). Following a review of prmcipal endrocrinologic features of PCO, this article

focuses on these two observations and develops a specific hypothesis which explains in an economical way the constellation of findings which comprises this enigmatic disorder. Possible experimental approaches to testing the hypothesis are discussed. Endocrinologic Abnormalities cyclic@

abnormalities in PC0 of ovarian steroidogenesis and

Women with PC0 characteristically have elevated circulating levels of testosterone (T) and androstenedione (A) resulting from excessive ovarian secretion. The peripheral conversion of A to estrone (El), particularly in obese women, leads to elevated circulating El levels. Estradiol (EJ levels are generally in the early follicular range. Levels of sex hormone-binding globulin (SHBG) are reduced, resulting in an increased fraction of free sex steroids which may be more biologically available to target tissues. In151

152

MEDICAL HYPOTHESES

creased androgen production by the ovarian stroma and theta is thought to disrupt the and inhibit folovarian “microenvironment” loculogenesis, resulting in chronic anovulation and ultimately, oligomenorrhea and infertility. This sequence of pathological events appears to be dependent at least partly upon an abnormal pattern of gonadotropin secretion. Abnormalities

of pulsatile gonadotropin

secretion

It has been known for some time that women with PC0 frequently have elevated circulating levels of LH in the face of relatively normal levels of follicle-stimulating hormone (FSH). The discovery that LH, and to a lesser extent FSH, is released in response to the similarly pulsatile release of GnRH from the arcuate nucleus of the hypothalamus led to efforts to pinpoint the nature of the abnormal LH secretion in PCO. Current data indicate that the enhanced LH secretion in PC0 can be attributed to increased LH pulse amplitude in the face of a normal pulse frequency (3). This abnormality may result from the induction of enhanced anterior pituitary sensitivity to GnRH by chronic elevations in non-SHBG bound E2 (4). Elevated levels of Ei and T appear less likely to play a direct role, although an indirect role via conversion to E2 cannot be ruled out. The possibility remains that the abnormal sex steroid milieu can similarly increase the size of GnRH pulses. While, taken together, these data obviate the need for the invocation of a primary hypothalamic defect to explain the observed patterns of gonadotropin secretion in PCO, considerable effort has been directed towards the identification of such an abnormality. Hypothalamic function in PC0

Investigations designed to document defects at the hypothalamic level in PC0 fall into two main groups: baseline LH pulse frequency studies and studies which employ pharmacologic hypothalamic probes to detect abnormalities of the neuroendocrine control of GnRH release in PCO. Determinations of LH pulse frequency are frequently employed as indices of GnRH pulse frequency given the elegant animal data revealing a striking one-to-one relationship between the two respective trains of pulses. As described above, LH pulse frequency appears to be normal in women with PC0 although they do not display

the sleep induced decline in LH pulse frequency observed in cycling women during the early follicular phase. It is possible that this transient phenomenon is related to the immediately preceding exposure of the hypothalamic pulse generator to luteal phase concentrations of progesterone, which is known to modulate LH pulse frequency via opioidergic mechanisms during this phase of the cycle. It is unlikely that this finding represents a fundamental abnormality of the GnRH pulse generator. The finding that circulating prolactin levels were frequently elevated in PC0 in the light of early evidence suggesting that dopamine was an endogenous inhibitor of GnRH release led to speculation that an intrinsic defect in dopaminergic activity might play a key role in the development of PCO. A recent study in which dopamine and metoclopramide, a dopamine antagonist, were administered to women with PC0 failed to provide data in support of this view (5). Furthermore, recent in vitro studies have cast doubt on the early view of dopamine as an inhibitor of GnRH release. mild The hyperprolactinemia frequently observed in PC0 may simply reflect a chronic exposure of lactotropes to an estrogen rich milieu. Following the discovery that GnRH release is modulated by opioidergic inputs as well, several investigators employed naloxone, an opioidergic antagonist, as a probe to study hypothalamic function in PCO. To date none of these studies have yielded consistently positive findings. The concept of a self-perpetuating

cycle

Yen and his colleagues have suggested that the endocrinologic abnormalities observed in PC0 might be viewed as a set of self-perpetuating defects which could be arranged in a kind of “vicious circle”. In essence, the abnormalities of ovarian steroidogenesis would result from increased pulsatile LH release, which in turn stemmed from abnormal sex steroid feedback at the level of the anterior pituitary and/or hypothalamus. Once the abnormal pattern was set into motion, by a transient increase in adrenal androgen secretion at the time of puberty, for example, it could maintain itself indefinitely. An element of self-reinforcement may well play a role in the pathogenesis of PCO. Nevertheless, the fact that long term suppression of ovarian steroidogenesis by progestins, oral contraceptives, or GnRH analogs is rapidly followed by a return to the hyperandrogenemic, chronical-

THE ETIOLOGY OF POLYCYSTICOVARY SYNDROME (PCO)

153

ly anovulatory state strongly suggests that a persistent organic defect exists at some level. In the absence of convincing evidence for such a defect in the hypothalamic-pituitary-ovarian axis, attention is turned now to the possibility that it resides elsewhere.

might result in a similarly abnormal picture, a possibility which is discussed in more detail below, In short, while an occasional patient with a true variant of congenital adrenal hyperplasia might be diagnosed as having PCO, the observation of elevated adrenal androgen production in some women with PC0 should be viewed in the light of substantial data indicating the absence of primary adrenal disease in this disorder.

Insulin resistance and elevated adrenal androgen levels

As alluded to in the introduction, women with Circulating insulin-like growth factor (ZGF-1) PC0 display mild IR as well as elevated DHEAS levels even after prolonged ovarian sup- activity pression with GnRH analogs. These findings A degree of IR in conjunction with elevated adrenal androgen secretion has been documented render unlikely the view that these abnormalities result from abnormal ovarian sex steroid secre- in at least two other groups: patients with tion. On the contrary, they would seem to acromegaly and normal pubertal children (9). constitute potential clues to an underlying disor- These also constitute the two most obvious examples .of clinical states in which the circulating der at a deeper level. (GH) and the Basal insulin levels and stimulated levels fol- levels of growth hormone lowing a glucose load are both elevated in peripheral mediator of many of its metabolic effects, IGF-1, are elevated. If one considers other women with PCO. More sophisticated testing utilizing the euglycemic clamp technique has con- endocrine disorders characterized by abnormal levels of DHEA-S, a striking pattern emerges firmed this finding. The IR can be partitioned into one component attributable to obesity per se with respect to concomitant abnormalities of the and a second component associated only with the GH-IGF-1 axis as well as of insulin action (Table diagnosis of PC0 (6). The defect seems to reflect 1). Women with anorexia nervosa (AN) have a defect of insulin action at the post-receptor level in the absence of circulating antibodies or decreased IGF-1 levels in the face of decreased abnormal receptor binding. The IR is subtle, and DHEA-S production and enhanced sensitivity to women with PC0 do not generally appear to be insulin. GH levels are elevated in AN, suggesting at risk for the subsequent development of adult . that nutritional deprivation decreases the produconset diabetes mellitus. The finding of IR in tion of IGF-1, primarily in the liver, in response PC0 has generated considerable interest in light to GH stimulation. Interestingly, the normalizaof data indicating that insulin can stimulate tion of IGF-1 levels precedes that of DHEA-S ovarian androgen production (7). production following weight recovery (10). Elevated basal DHEA-S levels and exagThe simplest explanation for this collection of gerated dehydroepiandrosterone (DHEA) res- findings is that increasing circulating IGF-1 acponses to ACTH administration have been repeatedly demonstrated in women with PCO, Table Insulin resistance and circulating levels of but are by no means seen in all subjects (6). It DHEA-S, GH, IGF-1 in various conditions. (I: has been proposed that some of these women increased, D: decreased) have an adrenal defect in 3P-hydroxysteroid IR DHEA-S GH IGF-I dehydrogenase (3P-HSD) activity which results in larger increases in the A5 steroids (DHEA and Acromegaly I 1 I I 17-OH-pregnenolone) in comparison to those of Puberty 1 I I I the A4 steroids (17-OH progesterone and androsAnorexia Nervosa D D I D tenedione) in response to ACTH. There is Uremia I D D currently no evidence of the kind provided by Diabetes I D D pedigree analysis that indicates the existence of PC0 I I D an autosomal recessive defect of 3P-HSD activity Decreased adrenal androgen production, high GH levels, analagous to that of 21-hydroxylase. Furtherand decreased IGF-1 activity have also been documented more, the induction of an increase in the activity in young diabetics and in uremic children (11). In these of adrenal 17-hydroxylase and 17,20 desmolase groups, elevated GH levels may reflect decreased negative relative to that of 3P-HSD, for whatever reason, feedback by IGF-1.

154 tivity leads to both IR and enhanced adrenal androgen production while decreased activity results in parallel declines in the same two parameters. The proposition that increased IGF-1 activity might lead to IR seems superficially paradoxical. While short term studies in humans confirm the ability of IGF-1 to acutely decrease circulating glucose levels, longer term studies in rats reveal that chronic IGF-1 administration results in the development of hyperglycemia (12). It is known that IGF-1, which is structurally very similar t.o insulin, can bind to insulin receptors. At this point, however, the mechanism by which IR might be induced can only be specmated upon. It should be born in mind that it has never been conclusively demonstrated that the diabetogenic effect of GH is entirely direct, as opposed to being at least partly mediated by other peptides. With respect to induced alterations in adrenal androgen production, it has been proposed that a circulating factor called corticoadrenal-stimulating hormone (CASH) induces an increase in the production of adrenal androgens relative to cortisol during puberty. A corollary to the proposal outlined above is the identification of IGF-1 with CASH. In vitro determinations of adrenal microsomal enzyme activity in humans reveal an increase in the activity of 17-hydroxylase and 17,20 desmolase during puberty. (13). To the extent that the pubertal increase in IGF-1 activity is responsible for the increased activity of these enzymes, a relative deficiency in 3@HSD could be observed even if 3l3-HSD activity per se were normal. Furthermore, a number of sex steroids, including DHEA, have been shown to inhibit 3fiHSD activity in vitro. Thus even if absolute 3P-HSD activity were diminished, it might be simply due to substrate inhibition. In summary, currently available data derived from widely divergent contexts supports the hypothesis that increased IGF-1 activity can both induce IR and increase adrenal androgen secretion.

MEDICAL HYPOTHESES

tal defect which is. The fact that the adrenal androgen abnormalities in particular are frequently not observed is compatible with this view. Most important is the possibility that IGF-1 might directly impact upon ovarian steroidogenesis. In the rat, IGF-1, like insulin, is capable of potentiating LH induced androgen secretion by theta-interstitial cells (14). This raises the possibility that IGF-1 can directly, as well as indirectly via the induction of increased insulin levels, increase ovarian androgen production and so initiate the sequence of abnormalities described earlier. IGF-1 is produced in many peripheral sites, and the extent to which it acts as a paracrine rather than an endocrine hormone is not clear. In the context of the hypothesis presented here it is assumed that an endocrine mode predominates, but a systemic increase in paracrine activity might potentially play an analagous role as well. One possibility regarding how such a primary defect (involving one or both of these mechanisms) might develop concerns feeding behaviors early in life. It has been shown that maternal protein deprivation during the period before weaning can induce permanent alterations in the GH-IGF-1 axis in young rats. (15). It was proposed that the “set point” for IGF-1 production as a function of nutritional status can be changed by such a maneuver. One might speculate that in the case of women with PCO, a period of “protein loading” during infancy might effect a change in the other direction, towards increased circulating levels of IGF-1. Early in this century, following the steady urbanization and feminization of the work force, many women chose to feed their infants either formula or cow’s milk rather than breast feeding. Both of these contain substantially more protein than human breast milk. It is speculated here that this early exposure to high protein diets placed certain infants at risk for subsequent long term.increases in IGF-1 activity.

IGF-1 and PC0

It is proposed here that PC0 is a manifestation of a primary elevation of systemic IGF-1 activity. To the extent that IGF-1 is capable of inducing IR and enhanced adrenal androgen secretion, the two findings described in the Introduction can be explained. It is suggested that in both cases the abnormalities are not critical to the pathogenesis of PCO, but instead reflect the more fundamen-

Current evidence and future research No direct evidence for the hypothesis

proposed in this manuscript has yet been described. Nevertheless it is of interest that GH levels in women with PC0 are less than that of weight-matched controls (16). Unpublished data from this unit indicates that circulating levels of IGF-1 are normal in both obese women and in women with PCO.

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THE ETIOLOGY OF POLYCYSTIC OVARY SYNDROME (PCO)

6. Pasquali R, Casimirri F, Venturoli S, et al. Insulin resisIt should be kept in mind, however, that several tance in patients with polycystic ovaries: its relationship factors modulate target organ responses to cirto body weight and androgen levels. Acta Endocrinol culating IGF-1, including the concentration of (Copenh): 104: 110, 1983. specific IGF-1 binding proteins, the presence of 7. Barbieri R L, Makris A, Ryan K J. Effects of insulin on circulating inhibitors of IGF-1, and potential difsteroidogenesis in cultured porcine theta. Fertil Steril: 40: 237, 1983. ferences in recentor number and activitv., ~~~ As 8. Hoffman D I, Klove K, Lobo R A. The prevalence and alluded to abode, hypothetical variations in significance of elevated dehydroepiandrosterone sulfate paracrine (local) IGF-1 activity would probably levels in anovulatory women. Fertil Steril: 42: 76, 1984. not be reflected in altered circulating concentra9. Amiel S A, Sherwin R S, Simonson D C, et al. Impaired insulin action in oubertv: a contributine factor to Door tions . glycemic control in adolescents with dia?betes. N E&l J Both direct and indirect approaches can be Med: 315: 215, 1986. utilized to test this hypothesis. It would be of in- 10. Winterer J, Gwirtsman H E, George D T, et al. terest, for example, to determine if circulating Adrenocorticotrophin-stimulated adrenal androgen sebioassayable IGF-1 activity is elevated in women cretion in anorexia nervosa: impaired secretion at low weight with normalization after long-term weight with PCO. Indirect approaches include the comrecovery. J Clin Endocrinol Metab: 61: 693, 1985. parison of 24 hour GH profiles and GH 11. Zumoff B, Walter L, Rosenfeld R S, et al. Subnormal responses to growth hormone-releasing hormone adrenal androgen levels in men with uremia. J Clin En(GHRH) administration in women with PC0 docrinol Metab: 51: 801, 1980. with those of cycling women matched for age and 12. Timely F C, Smith M C, Dimarchi, R D, Shar C J. The effect of continuous subcutaneous infusion of IGF-1 Or weight. This unit is currently carrying out such IGF-II on plasma growth hormone and glucose constudies. centration in normal male rats lAbstract 991. In:

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