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
1101
the human body itself or are produced by techniques of molecular biology will be single isomers. However, about 90% of
that are derived from plants
or
synthetic chiral compounds, including many common drugs such as labetalol, propranolol, mexiletine, terbutaline, and warfarin, are supplied only as racemic mixtures. Consequently, half the drug given to the patient will not produce the effect that had been observed in animal pharmacology tests, for which pure stereoisomers are used. Pharmaceutical companies have long been aware of these difficulties, but the second stereoisomer has been regarded as inactive harmless ballast. Because of the high purification costs, it has seldom been judged worthwhile to produce large quantities of single stereoisomers.33 However, evidence has been accumulating slowly, especially over the past decade, that these "inactive" stereoisomers, in addition to exerting different effects, may also produce unwanted side-effects. For example, propoxyphene is a chiral compound whose two stereoisomers have very different properties--dextropropoxyphene is an established analgesic, whereas levopropoxyphene is an antitussive. (The chirality of the two products is even reflected in their trade names, ’Darvon’ and
’Novrad’.) Thalidomide provides a dramatic illustration of the side-effects of stereoisomers. German researchers showed that, in mice, although the two stereoisomers were sedative only one was responsible for the teratogenicity.4 Although this example has been used to support the case for the supply of single pure isomers as drug substances, further work showed that both isomers were teratogenic in rabbits,and we shall probably never determine what happened in pregnant women.
Advances in analytical chemistry have simplified the separation of stereoisomers, and we now know that they have different pharmacokinetic properties, particularly with respect to distribution and elimination.6 Some non-steroidal anti-inflammatory agents have been shown to convert from one stereoisomer to the other in the body.7 Such differences are especially important for drugs with a low therapeutic index. This knowledge is of little help to prescribing doctors, who are entirely dependent on what the companies choose to supply. Pharmaceutical companies have been severely criticised for not being quicker to act and also for not making clear in much of their promotional material that their chiral products are supplied only as racemic mixtures.8 However, things are changing—eg, the racemic product, fenfluramine, has already been relicensed by one company as the active stereoisomer, dexfenfluramine. Some companies who have taken racemic mixtures off the market because of sideeffects may even decide to re-examine the single isomers. Regulatory authorities are now starting to ask for more detailed information about the relative
pharmacokinetics of stereoisomers.9 Since January, 1989, the US Food and Drug Administration Center for Drug Evaluation and Research has had a stereoisomer committee, and from 1992 the FDA will insist that US companies show that the active stereoisomer of their chiral drugs is safe and effective and that the other isomer is harmless. Those companies who are already producing single stereoisomers may well start to emphasise this fact
when
promoting their products. Nevertheless, separation of individual stereoisomers from racemic industrial scale is not easy and stereospecific synthesis still has a long way to go, although progress is being made. 10 Single stereoisomers will be more expensive to produce than racemic mixtures. A wider issue that concerns us all and that probably poses a greater threat is the fact that several pesticides and fungicides are chiral. These agents are used in large quantities and it is unsettling to think that only half of what is used is doing what it is intended to do. A review1 lately used the very apposite words of Lewis Carroll-"Perhaps, looking-glass milk isn’t good to drink?"
mixtures
on
an
1. Ariens JE, Wuis EW, Veringa EJ. Stereoselectivity of bioactive xenobiotics. Biochem Pharmacol 1988; 37: 9-18. 2. Mason S. The origin of chirality in nature. Trends Pharmacol Sci 1986; 7: 20-23. 3. Laird T. Development and scale-up of process for the manufacture of new pharmaceuticals. In: Hansch C, Sammes PG, Taylor JB, eds. Comprehensive medicinal chemistry, volume 1. Oxford: Pergamon, 1990: 321-60. 4. Blaschke G, Kraft HP, Fickentscher K, Kohler F. Chromatographische Racemattrennung von Thalidomid und teratogene Wirkung der Enantiomere. Arzneim Forsch 1979; 29: 1640-42. 5. Fabro S, Smith RL, Williams RT. Toxicity and teratogenicity of optical isomers of thalidomide. Nature 1967; 215: 296. 6. Lee EJD, Williams KM. Chirality: clinical pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 1990; 18: 339-45. 7. Lee EJD, Williams KM, Graham GG, Day RO, Champion GD. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 1985; 19: 669-74. 8. Ariens EJ. Implications of the neglect of stereochemistry in pharmacokinetics and clinical pharmacology. Drug Intell Clin Pharmacol 1987; 21: 827-29. 9. Weissinger J. Considerations in the development of stereoisomeric drugs: FDA viewpoint. Drug Inf J 1989; 23: 663-67. 10. Emsley J. Chemists tame the wild side of drugs. New Scientist 1990; 127: 32. 11. Tucker GT, Lennard MS. Enantiomer specific pharmacokinetics. Pharmacol Ther 1990; 45: 309-29.
BRIDGING THE GAP
Large defects in the skeleton arise for various reasonsbecause of injury, either early from traumatic bone loss, or later following debridement of bone for extensive sepsis or atrophic non-union; from wide excision of benign and malignant musculoskeletal tumours; or as a result of failed joint replacement. Patients often undergo several operations in the course of their treatment followed by lengthy immobilisation that leads to muscle wasting, joint stiffness, and considerable disability. Limb-sparing surgery is increasingly practised in preference to amputation, especially in patients with high-grade osteosarcomas, for whom adjuvant chemotherapy has improved the survival rate dramatically. Adequate wide local excision with removal of the tumour and a surrounding layer of normal
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
1101
the human body itself or are produced by techniques of molecular biology will be single isomers. However, about 90% of
that are derived from plants
or
synthetic chiral compounds, including many common drugs such as labetalol, propranolol, mexiletine, terbutaline, and warfarin, are supplied only as racemic mixtures. Consequently, half the drug given to the patient will not produce the effect that had been observed in animal pharmacology tests, for which pure stereoisomers are used. Pharmaceutical companies have long been aware of these difficulties, but the second stereoisomer has been regarded as inactive harmless ballast. Because of the high purification costs, it has seldom been judged worthwhile to produce large quantities of single stereoisomers.33 However, evidence has been accumulating slowly, especially over the past decade, that these "inactive" stereoisomers, in addition to exerting different effects, may also produce unwanted side-effects. For example, propoxyphene is a chiral compound whose two stereoisomers have very different properties--dextropropoxyphene is an established analgesic, whereas levopropoxyphene is an antitussive. (The chirality of the two products is even reflected in their trade names, ’Darvon’ and
’Novrad’.) Thalidomide provides a dramatic illustration of the side-effects of stereoisomers. German researchers showed that, in mice, although the two stereoisomers were sedative only one was responsible for the teratogenicity.4 Although this example has been used to support the case for the supply of single pure isomers as drug substances, further work showed that both isomers were teratogenic in rabbits,and we shall probably never determine what happened in pregnant women.
Advances in analytical chemistry have simplified the separation of stereoisomers, and we now know that they have different pharmacokinetic properties, particularly with respect to distribution and elimination.6 Some non-steroidal anti-inflammatory agents have been shown to convert from one stereoisomer to the other in the body.7 Such differences are especially important for drugs with a low therapeutic index. This knowledge is of little help to prescribing doctors, who are entirely dependent on what the companies choose to supply. Pharmaceutical companies have been severely criticised for not being quicker to act and also for not making clear in much of their promotional material that their chiral products are supplied only as racemic mixtures.8 However, things are changing—eg, the racemic product, fenfluramine, has already been relicensed by one company as the active stereoisomer, dexfenfluramine. Some companies who have taken racemic mixtures off the market because of sideeffects may even decide to re-examine the single isomers. Regulatory authorities are now starting to ask for more detailed information about the relative
pharmacokinetics of stereoisomers.9 Since January, 1989, the US Food and Drug Administration Center for Drug Evaluation and Research has had a stereoisomer committee, and from 1992 the FDA will insist that US companies show that the active stereoisomer of their chiral drugs is safe and effective and that the other isomer is harmless. Those companies who are already producing single stereoisomers may well start to emphasise this fact
when
promoting their products. Nevertheless, separation of individual stereoisomers from racemic industrial scale is not easy and stereospecific synthesis still has a long way to go, although progress is being made. 10 Single stereoisomers will be more expensive to produce than racemic mixtures. A wider issue that concerns us all and that probably poses a greater threat is the fact that several pesticides and fungicides are chiral. These agents are used in large quantities and it is unsettling to think that only half of what is used is doing what it is intended to do. A review1 lately used the very apposite words of Lewis Carroll-"Perhaps, looking-glass milk isn’t good to drink?"
mixtures
on
an
1. Ariens JE, Wuis EW, Veringa EJ. Stereoselectivity of bioactive xenobiotics. Biochem Pharmacol 1988; 37: 9-18. 2. Mason S. The origin of chirality in nature. Trends Pharmacol Sci 1986; 7: 20-23. 3. Laird T. Development and scale-up of process for the manufacture of new pharmaceuticals. In: Hansch C, Sammes PG, Taylor JB, eds. Comprehensive medicinal chemistry, volume 1. Oxford: Pergamon, 1990: 321-60. 4. Blaschke G, Kraft HP, Fickentscher K, Kohler F. Chromatographische Racemattrennung von Thalidomid und teratogene Wirkung der Enantiomere. Arzneim Forsch 1979; 29: 1640-42. 5. Fabro S, Smith RL, Williams RT. Toxicity and teratogenicity of optical isomers of thalidomide. Nature 1967; 215: 296. 6. Lee EJD, Williams KM. Chirality: clinical pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 1990; 18: 339-45. 7. Lee EJD, Williams KM, Graham GG, Day RO, Champion GD. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 1985; 19: 669-74. 8. Ariens EJ. Implications of the neglect of stereochemistry in pharmacokinetics and clinical pharmacology. Drug Intell Clin Pharmacol 1987; 21: 827-29. 9. Weissinger J. Considerations in the development of stereoisomeric drugs: FDA viewpoint. Drug Inf J 1989; 23: 663-67. 10. Emsley J. Chemists tame the wild side of drugs. New Scientist 1990; 127: 32. 11. Tucker GT, Lennard MS. Enantiomer specific pharmacokinetics. Pharmacol Ther 1990; 45: 309-29.
BRIDGING THE GAP
Large defects in the skeleton arise for various reasonsbecause of injury, either early from traumatic bone loss, or later following debridement of bone for extensive sepsis or atrophic non-union; from wide excision of benign and malignant musculoskeletal tumours; or as a result of failed joint replacement. Patients often undergo several operations in the course of their treatment followed by lengthy immobilisation that leads to muscle wasting, joint stiffness, and considerable disability. Limb-sparing surgery is increasingly practised in preference to amputation, especially in patients with high-grade osteosarcomas, for whom adjuvant chemotherapy has improved the survival rate dramatically. Adequate wide local excision with removal of the tumour and a surrounding layer of normal
