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15.03.2000

Newsletter No. 2

Pathological oestrogen formation in endometriosis lesions. Are aromatase inhibitors a new approach to treating endometriosis?. Is endometriosis primarily a disease of the uterus? Drop the"tunnel view” in the event of a PCO syndrome? Oral antidiabetics against infertility in the event of a PCO syndrome? 1. Pathological oestrogen formation in endometriosis lesions. Are aromatase inhibtors a new approach to treating endometriosis? A specific enzyme, (see Glossary), P450 aromatase, controls the formation of oestrogens from its precursors, the male gonadal hormones. Except during a pregnancy, women normally produce oestrogen mainly in the ovaries. However, oestrogens can be formed in all parts of the body where this enzyme is expressed (present), for example in the fatty tissue of the breast gland. This gland produces oestrogens from the male gonadal hormones transported there by the blood stream. This enzyme is normally not formed in the endometrium (mucous tissue of uterus). In recent years it was established that the presence of P450 aromatase in endometrial tissue inside and outside the uterus was pathological, so that oestrogens are formed in the endometriosis lesions. The pathological expression of P450-aromatase is assumed to constitute a major factor in the development of an endometriosis from a normal endometrium. The chronic formation of oestrogen in the endometrial tissue implies constantly increased concentration thereof, stimulating and sustaining growth processes, and thereby the formation of endometriosis lesions. An additional factor is that there apparently is a further disorder in the oestrogen metabolism of endometriosis lesions, namely a missing enzyme which deactivates the oestrogens in normal endometrial tissue. This further promotes the oestrogen effect in endometriosis lesions. The medication currently used to treat endometriosis had the aim of either reducing the estradiol levels in the blood with GnRH-analogues, and/or use gestagens to attenuate the effect of the oestrogens in the endometrial tissue and thereby in the endometriosis lesions. As these treatments always have the double effect of also subduing the functions of the ovaries and reducing emission of male gonadal hormones, which in turn reduces the substrate offer (see glossary) for P450-aromatase, the endometriosis lesions also produce less oestrogen. The use of highly effective aromatase inhibitors would constitute a new treatment approach, whereby local oestrogen production in the endometriosis lesions is directly suppressed. If it is true that locally produced oestrogens are more important for sustaining an endometriosis, direct and complete suppression of local oestrogen production might be very effective, in particular as the androgens deriving from the adrenal cortex would also no longer be transformed into oestrogen. An impressive success was recently reported in the case of a post-menopausal patient with a severe endometriosis. This new approach might also be suited for the treatment of young women, however, then in conjunction with an oral contraceptive (anti-baby pill). In this case the pill would be responsible for suppressing the ovarian functions while simultaneously supplying the body with female gonadal hormones, while the aromatase inhibitor would completely suppress local oestrogen formation in the endometriosis lesion. It has been known already for some time that administration of anti-baby pills, if possible without the customary pause after four weeks, has a favourable effect on endometriosis. Scientists will now have to establish whether the theoretical expectations are justified, namely that this effect can be enhanced by the additional administration of an aromatase inhibitor. For more detailed information, please read the article "Endometriosis" under www.Ferticonsult.de. Reference List Kitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Yamamoto T, Fushiki S, Osawa Y, Honjo H (1997) Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol. Reprod. 57: 514-519 Leyendecker G, Kunz G, Noe M, Herbertz M, Mall G(1998) Endometriosis: a dysfunction and disease of the archimetra. Hum. Reprod. Update 4: 752-762 Leyendecker G (2000) Endometriosis is a disease with extreme pleimorphism. Hum. Reprod. 15: 4-7 Noble LS, Simpson ER, Johns A, Bulun SE (1996) Aromatase expression in endometriosis. J. clin. Endocrinol. Metab. 81: 174-179 Noble LS, Takayama K, Zeitoun KM, Putman JM, Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr BR, Bulun SE (1997) Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J. clin. Endocrinol. Metab. 82: 600-606 Zeitoun K, Takayama K, Sasano H, Suzuki HAT, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE (1998) Deficient 17ß-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17ß-estradiol. J. Clin. Endocrinol. Metab. 83: 4474-4480 Zeitoum KM, Bulun, SE(1999). Aromatase: a key molecule on the pathophysiology of endometriosis and a therapeutic target. Fertil Steril 72: 961-969 TOP 2. Is Endometriosis primarily a disease of the uterus? Endometriosis is a disease appearing in a multitude of variations which cannot be explained on the basis of presently prevailing theories. One theory is that normal endometrial cells (cells from the endometrium = mucous tissue in the uterus) and other tissue elements are transported through the Fallopian tubes by retrograde menstruation. Acccording to another theory, cells of the pelvic peritoneum are transformed into endometrial cells by metaplasia. However, several lines of evidence point to that part of the uterus immediately underlying the endometrium, i.e. the archimetra and thus to the uterus as the primary site of disease development. This view is of fundamental importance with respect to treatment and management of the disease. Firstly: In affected women the eutopic (local) endometrium shows alterations similar to those seen in the endometriotic lesions which are not found in the endometrium of healthy women. These alterations include signs of increased inflammatory response, increased proliferation and increased biochemical activity such as the pathological expression (formation) of P450aromatase. Secondly: In women with endometriosis the uterus displays disordered and increased peristaltic movement to an extent that bears no relation to the severity of the disease. Hyper- and dysperistalsis result in a break down of rapid and sustained sperm transport, i.e. the uterus fails to aid in transporting the sperm into that Fallopian tube where ovulation occurred, a fact that may explain sterility and subfertility in women with mild-to-moderate endometriosis. Moreover, the internal pressure of the uterus is increased in comparison to that of healthy women. Finally: In women with endometriosis all elements of the endometrium expand, proliferating and infiltrating the the archimetra into the outer myometrial layers (outer wall of the uterus). Again, the extent of this infiltration is out of context with the grade of endometriosis. With increasing age of the patients, the depth of the infiltration increases. In MR imaging these findings are similar to or identical with those found in adenomyosis. CONCLUSIONS: Pelvic endometriosis constitutes a secondary phenomenon, the primary disease being a uterine lesion, which has long been know as adenomyosis. The adenomyotic lesions may spread altered cells into the peritoneal cavity, where they show an increased, though variable, potential of implantation and infiltrative growth. They are usually but not exclusively transported through the tubes. The extreme variability of endometriosis is a consequence of the numerous factors contributing to that disease: the course taken by adenomyosis as the underlying disease, the quality of the spread cells, figuratively speaking the seed, then the topography and the response of the peritoneal cavity with its serosa and its organs, where the cells implant. Present treatment modalities focus on eradication of the pelvic lesions, while maintaining the organs and supporting fertility. Treatment strategies have to take into account that the primary site of the disease can hardly be eradicated and may not be curable. Further information may be obtained from www.ferticonsult.net Reference List Kunz G.1), Herbertz, M.2), Noe, M.1), Leyendecker, G (1998). Sonographic evidence for the involvement of the utero-ovarian counter current system in the ovarian control of directed uterine sperm transport. Hum. Reprod. Update 4: 667-672 Leyendecker, G., Kunz, G., Wildt, L., Beil, D., Deininger, H. (1996) Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility.Hum. Reprod. 11: 1542-1551 Leyendecker G, Kunz, G, Noe, M, Herbertz, M, Mall G (1998) Endometriosis: A dysfunction and disease of the archimetra. Hum. Reprod. Update 4: 752-762 Leyendecker G (2000) Endometriosis is an entity with extreme pleiomorphism. Hum Reprod. 15: 4-7 TOP 3. Drop the "tunnel view” in the event of PCO syndromes. Women with the syndrome of polycystic ovaries (PCO syndrome) suffer bleeding disorder and fail to have an ovulation (anovulation) with consequent infertility. Frequently the syndrome includes the growth of hair akin to men (hirsutism), and often also overweight. Depending on which ailment is viewed as more distressing, the patient will turn a gynecologist (cycle disorder, failure to conceive), to a dermatologist, (hair) or to an internist or general practitioner (overweight). Each of these will then treat the disorder as he is professionally trained to do ("tunnel view"): cycle disorder and wish to conceive with hormones to the point of artificial insemination, male hair growth with hormone preparations, and overweight with diet consultations. Anovulation and infertility as well as hirsutism are related to increased production of male gonadal hormones in women with a PCO syndrome. As growth of male hair is generally treated with a hormonal contraceptive containing an androgenic gestagen, simultaneous treatments of infertility and hirsutism are mutually exclusive. New research on the causes of the PCO syndrome has paved the way for treating the causes of the disease, rather than the symptoms, as in the past. This is certainly all the more desirable as the PCO syndrome involves substantial health risks. These include possible development of a diabetes type II and the risk of cardiovascular diseases, which would be avoided, or at least reduced, if the causes were treated. Many if not all women with a PCO syndrome show an insulin resistance. It is found in overweight PCO patients as well as those of low to normal weight, whereby overweight enhances the insulin resistance. Insulin resistance implies that in order to sustain a normal glucose level in the blood, the pancreas must secrete increased amounts of insulin. The resulting hyperinsulinemia (enhanced insulin level in the blood stream) together with the gonadotropic hormones from the pituitary gland stimulating the ovaries causes increased formation of male gonadal hormones in the ovaries, namely the PCO syndrome. Accordingly, the PCO syndrome is primarily a metabolism disorder affecting many organ systems. Disorder in the insulin metabolism in cases of a PCO syndrome has already been proven to exist in patients who are not yet sexually mature. www.Ferticonsult.de will soon publish a comprehensive article on the PCO syndrome which is easy to understand. Reference List Nestler JE (1998) Polycystic ovary syndrome: a disorder for the generalist. Fert. Steril. 70: 811-812 Guzick DS (2000) Cardiovascular risk in women with polycystic ovarian syndrome: evidence from a case-control study. Endocrine Basis of Reproductive Function, Tampa. Florida (USA) 20-22 January 2000 Legro R (2000) Metabolic derangements and diabetes risks in PCOS. Endocrine Basis of Reproductive Function, Tampa. Florida(USA) 20-22 January 2000 Arslanian S, Lewy V, Danadian K (2000) Adolescence, insulin resistance and PCOS. Endocrine Basis of Reproductive Function, Tampa. Florida (USA) 20-22 January 2000 TOP 4. Oral antidiabetics against infertility in the event of a PCO syndrome? In many ways gynecologists are gradually developing into a "general practitioner for women". This means they should treat function disorders as an ailment afflicting the entire body under the aspect of long-term health and not only as a given symptom. A good example is the syndrome of polycystic ovaries (PCO syndrome). The afflicted women suffer from irregularities in their menstrual cycle, infertility, frequently also of gaining weight and obesity, as well of varying degrees male hair growth (hirsutism). Usually, women with such problems turn to their gynecologists, whom they believe to have the most competence in this field. An experienced physician, in particular a gynaecological endocrinologist, will easily manage to establish the correct diagnosis. In the event of rapid changes in the direction of hirsutism the patient will naturally also have to be examined for an androgen-producing tumour; this also applies if one ovary is conspicuous in a sonographic image, because a PCO syndrome regularly is symmetrical, both ovaries being affected by the same typical structural changes. Treating the wish to conceive, i.e. ovulation induction in women with a PCO syndrome is generally a very trying business. Not only does ovulation induction by medication or hormone treatment rarely succeed with very obese women with a PCO syndrome, treatment cycles frequently having to be dropped. There is also the danger of polyovulation with multiple pregnancy and a severe overstimulation syndrome, which make this treatment more difficult and risky than in the case of other disorders leading to infertility. Should an exceptional insulin resistance inducing increased insulin levels actually prove to be the cause for the PCO syndrome, then the measures taken to relieve the insulin resistance and to reduce the hyperinsulinemia should actually be advantageous for patients who wish to conceive. Overweight ("truncal obesity") in the event of the PCO syndrome increases the insulin resistance, and indeed, in some women it has proven possible to restore normal cycles and fertility merely through weight loss. Ideal would be a monotherapy with medication suited for eliminating the hyperinsulinemia. Scientists were able to prove that antidiabetics lower the testosterone levels and counter-act the cycle irritations in women with a PCO syndrome. Prospective case studies on larger numbers of women will have to show to what extent such a monotherapy will constitute a "beak-through" in sterility therapy in the event of a PCO syndrome. The study will have to focus on drugs which directly cure insulin resistance. Insulin lowering medication (metformin) was recently reported to increase the rate of spontaneous ovulation, response to clomiphene and the occurrence of pregnancies in patients with a PCO syndrome. It has not yet been established to what extent the rate of ovarian overstimulation can be reduced within the scope of IVF programmes for women with PCO syndrome. There is justified hope that this is so. It will also take further studies to show if and which women with PCO syndrome should be treated on a permanent basis with such medication under the aspect of long-term health care, irrespective of their wish to have children. A treatment strategy for patients who do not wish to have children would be to administrate metformin together with a contraceptive. For women who also suffer from hirsutism (male hair growth) the therapy would include the additional administration of spironolactone. www.ferticonsult.de will publish a comprehensive article on the PCO syndrome which is easy to understand. Reference List Nestler JE (2000) Weight loss and the use of insulin lowering drugs in PCOS. Basis of Reproductive Function, Tampa. Florida (USA) 20-22 January 2000 Guzick D (1998) Polycystic ovary syndrome: symptomatology, pathophysiology, and epidemiology. Am J Obstet Gynec 179: 6/2, S89-S93 Taylor AE (1998) Understanding of the underlying metabolic abnormalities of polycystic ovary syndrome and their implications. Am J Obstet Gynec 179: 6/2, S94-S100 Legro RS (1998) Polycystic ovary syndrome: current and future treatment paradigms. Am J Obstet Gynec 179: 6/2, S101-S108 Berga SL (1998) The obstetrician-gynecologist’s role in the practical management of polycystic ovary syndrome. Am J Obstet Gynec 179: 6/2, S109-S113 TOP

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