1099

EDITORIALS Polycystic ovaries—disorder or sign?

feature. Consequently, the hypothesis that increased LH secretion is the lesion responsible for raised androgens in this condition4 has led the field until

(PCO) are thought to be the commonest cause of anovulatory infertility and menstrual irregularity and are often associated with other disturbances such as obesity, hirsuties, and endometrial carcinoma. Early miscarriage, especially after ovulation induction, is also common. However, neither the site nor the nature of the primary lesion in women with PCO is known, and there is no agreement

lately. Heightened pituitary sensitivity to circulating gonadotropin releasing hormone (GnRH) has also been suggested. Excess LH, as Prof Howard Jacobs had proposed,s might have a deleterious effect on

Polycystic

as to how

ovaries

infertile or hirsute women with PCO should be treated. Similarly, because of the clinical heterogeneity of patients presenting with PCO and the variation in ovarian size and morphology, diagnostic criteria have not been agreed. Some even question whether there is a specific entity, the polycystic ovary syndrome (PCO S), let alone a disease state as implied by those who refer to polycystic ovary disease (PCOD). A symposium at King’s College, Cambridge, UK, in September, organised by Prof R. W. Shaw (Royal Free Hospital, London) and sponsored by ICI as part of a series on reproductive endocrine disorders, brought together a multidisciplinary group of obstetricians, gynaecologists, and endocrinologists, who debated the issue and reviewed recent developments but failed to achieve unanimity. How should we diagnose the condition? After the original report by Stein and Leventhal,l large cystic ovaries were taken to be the characteristic ovarian change and hirsuties, oligomenorrhoea, infertility, and obesity the presenting clinical features. Nevertheless, whilst all seven patients in Stein and Leventhal’s series’1 were oligomenorrhoeic or amenorrhoeic, only two were obese and three were not hirsute. The lack of clinical uniformity is now well documented, as emphasised at the meeting. Despite the common impression that hirsuties and/or menstrual irregularity are frequent, these features are not invariable. Some slim fertile women with regular menses and no hirsuties have the characteristic macroscopic appearance of polycystic ovaries and, conversely, the typical clinical features can be associated with small "microcystic" ovaries or even with apparently normal gonads. Attempts have been made to find a biochemical marker for PCO. The raised luteinising hormone (LH) concentration, initially in urinez and then in blood,3 was originally believed to be the diagnostic

maturation and be associated with an increased miscarriage rate in women with PCOS. Professor Jacobs claimed at the meeting that a single measurement of LH on day 8 of the cycle might be predictive of an increased tendency to miscarriage. On the other hand, a raised LH or LH/FSH (follicle stimulating hormone) ratio is not invariable; many women with unequivocal clinical and morphological evidence of PCO have normal LH concentrations. LH secretion is pulsatile, so reliance on a single sample as a predictor would seem unwise. Moreover, since no LH receptor has been detected on the follicle itself (although such receptors are present on granulosa cells) it is not clear how LH could be deleterious to the follicle after ovulation. There is no doubt that the excess androgens in women with PCO are produced largely by the ovary and that LH is an important factor in ovarian androgen production, but is it necessarily the primary lesion? Could a lack of FSH be responsible, as suggested by Dr Stephen Hillier (Edinburgh)? Lower concentrations of FSH and a relative insufficiency of this gonadotropin have been suggested in PCOS, which is why a preparation of "pure" FSH virtually devoid of LH was produced and recommended for ovulation induction in infertile women with pca.6--8 However, whether pure FSH is any better is debatable. endocrine abnormalities such Other as are also associated with PCO. hyperinsulinaemia9 Could hyperinsulinaemia be the primary disturbance, which in turn entrains hyperandrogenisation and affects gonadotropin concentrations? There are also insulin-like growth factors (IGFs)--peptides with structural similarities to pro-insulin and insulin-that mediate the action of growth hormone and may be important in the aetiology of PCO, as discussed by Prof M. Seppala (Helsinki). IGFs have growth promoting and insulin-like metabolic effects and are secreted by human granulosa cells. They have also been detected in human follicular fluid. IGF-1 in particular stimulates LH-induced androgen production and some patients with PCO have ovum

1100

increased IGF-1 concentrations. IGF-1 potentiates the action of FSH in granulosa cells, so it could be considered a "co-gonadotropin". Whether it has a role in initiating or perpetuating the disturbance of ovulatory function in PCO remains to be established. There are other active ovarian regulatory proteins, about whose action little is known and whose interplay with other hormone regulators remains to be determined. Nevertheless, the number of links between insulin and androgen production, both in vitro and in vivo, and the evidence that hyperinsulinism is a feature of women with PCO, especially of those who are obese, could be a pointer for future therapy. Hyperinsulinaemia could also be responsible for the unfavourable lipid pattern of many women with this condition. Various

therapeutic options

are

now

being

proposed for PCOS. Whilst the standard management for clomiphene-resistant infertility in PCOS has been gonadotropin stimulant therapy, the success rate with this treatment as reported by Dr Jean Ginsburg (London), is less than 50% and is associated with a multiple pregnancy rate of about 20% and a miscarriage rate of 30%. There has also been a disturbing and as yet unexplained fall in responsiveness to gonadotropin stimulation over the past five years. Nevertheless, gonadotropin treatment should be tried before more complex and potentially dangerous therapy is contemplated. A new approach--down-regulation with GnRH agonists and subsequent gonadotropin stimulation-resulted in a two-fold increase in the pregnancy rate according to Dr J. R. Coutts (Glasgow). Similarly, Prof Marco Filicori (Bologna) reported a virtual doubling of the pregnancy rate in his patients by combined downregulation with GnRH agonists and subsequent pulsatile GnRH therapy. Thus, although GnRH agonists, as emphasised by Prof Shaw, have no long-lasting effect on gonadal function or structure, in the short term they may prove to be a valuable adjunct for treatment of infertility associated with PCO. What about surgery? Wedge resection, as first shown by Stein and Leventhal,l can result in resumption of regular menses and fertility in a high proportion of women with proven PCO. This operation was abandoned because of the high frequency of subsequent adhesions and fibrosis and consequent infertility. Multiple electrocautery at laparoscopy apparently achieves the same effect as wedge resection without the danger of adhesion formation or the need for the patient to undergo major surgery. Prof Abdel Gadir (formerly of the University of Kuwait) presented a study of 29 infertile women with PCO resistant to clomiphene citrate who underwent laparoscopic ovarian electrocautery. After electrocautery, LH and testosterone concentrations fell in all the women, while basal values of FSH increased in 22-ie, there were 7 non-responders. In the responders, regular menstruation with persistence

changes was then sustained for six months, although there was no consistent change in of the endocrine

or structural appearance on 10 women conceived during the ultrasonography. study period and 4 more after clomiphene. Similar results are being reported from other centres. As with wedge resection, the mechanism of action of electrocautery of the ovary, especially of small cysts, is

ovarian

volume

understood. So, is PCO a sign or a distinct disorder? Until we can pinpoint the primary lesion and decide whether it is in the gonad, pituitary, or even outside the not

hypothalamic/pituitary axis, answering this

we are no nearer to

question.

IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries Am J Obstet Gynecol 1935; 29: 181-91. 2. McArthur JW, Ingersoll FM, Worcester J. The urinary excretion of interstitial-cell and follicle-stimulating hormone activity by women with diseases of the reproductive system. J Clin Endocrinol Metab 1958; 18: 1202-15. 3. Yen SSC, Vela P, Rankin J. Inappropriate secretion of follidestimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab 1970; 30: 435-42. 4. Yen SSC. The polycystic ovary syndrome. Clin Endocrinol 1980; 12: 177-208. 5. Jacobs HS, Homburg RR. The endocrinology of conception Ballière’s Clin Endocrinol Metab 1990; 4: 195-205. 6. Raj SG, Berger MB, Grimes E, Taymor ML. The use of gonadotropins for the induction of ovulation in women with polycystic ovarian disease. Fertil Steril 1977; 26: 1280-84. 7. Seibel MM, McArdle C, Smith D, Taymor ML. Ovulation induction in polycystic ovary syndrome with urinary follicle-stimulating hormone or human menopausal gonadotropin. Fertil Steril 1985; 43: 703-08. 8. Sallam H, Scammel G, Massam G, et al. Ovulation and pregnancy after "pure" FSH therapy in sclerocystic ovarian change. Arch Gynecol 1985; 237 (suppl): 395 9. Burghen GA, Givens JR, Kitabachi AE. Correlation of hyperandrogenism with hyperinsulinemia in polycystic ovarian disease. J Clin Endocrinol Metab 1980; 50: 113-16. 1. Stein

Chirality Our left hand is the mirror image of our right; they are superimposable. In the world of organic chemistry any compound that has a carbon atom with four different groups attached can exist in two forms, one the mirror image of the other. Such a compound is said to be chiral (from the Greek, cheir, hand) and its mirror forms are called stereoisomers. About 25% of the drugs now in use are believed to be chira1.1 Nature has displayed what Mason2 called the "biomolecular homochirality sustained throughout the course of organic evolution". Thus, naturally occurring aminoacids are all L-form single stereoisomers, whereas sugars are all D-form. Compounds derived from plants (eg, alkaloids) or produced by organisms, if chiral, will be in the form of single pure isomers. However, manmade chiral drugs, produced by the techniques of synthetic chemistry, are mixtures of stereoisomers (racemates). Drugs usually act via receptors, enzymes, or second messengers; these three-dimensional inter-relations are complex and very specific. For example, one stereoisomer of a drug can have a potent effect on a certain receptor whereas the other stereoisomer may have an entirely different effect or be inactive. Drugs not

Polycystic ovaries--disorder or sign?

1099 EDITORIALS Polycystic ovaries—disorder or sign? feature. Consequently, the hypothesis that increased LH secretion is the lesion responsib...
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