GnRH Analogues in the Management of Endometriosis

GnRH Analogues in the Management of Endometriosis
by K Bühler & KW Schweppe
GnRH Analogues in the Management of EndometriosisSlide 2 of 28Slide 3 of 28Slide 4 of 28Slide 5 of 28Slide 6 of 28Slide 7 of 28Slide 8 of 28Slide 9 of 28Slide 10 of 28Slide 11 of 28Slide 12 of 28Slide 13 of 28Slide 14 of 28Slide 15 of 28Slide 16 of 28Slide 17 of 28Slide 18 of 28Slide 19 of 28Slide 20 of 28Slide 21 of 28Slide 22 of 28Slide 23 of 28Slide 24 of 28Slide 25 of 28Slide 26 of 28Slide 27 of 28Slide 28 of 28The End



Dr Klaus Bühler:

Despite the tremendous work of research during the last decades (more than 10,000 papers on this topic are listed in the National Library of Medicine) the pathophysiology is understood only in some steps of a very complicated pathway. It was Hans Evers who gave us an educational overview demonstrating the principles of aggression and defence. Viable endometrium fragments are the aggressors, whereas peritoneal membranes and cellular and humeral auto-immunity are the defence mechanism. Due to the very increased number of monthly menstruations, 480 in modern society, in comparison to 200 menstruations 100 years ago, or only 10 menstruations 2,000 years ago, endometriosis is an increasing disease in modern civilisations.

Whereas the aggression has increased in amount and in rhythm, the defence mechanism did not develop to the same extent. According to Evers, five lines of defence are very important: We have the cell adhesion molecule expression, the peritoneal fluid, the peritoneal cells and intact peritoneal lining, and the critical tissue volume for angiogenesis. As more often menstrual material reaches the peritoneal cavity, the higher the amount of aggressive tissue it is more likely that at least one of the defence mechanisms that will be overwhelmed and endometriosis will have the chance to develop.

Despite the unknown details of adhesions, invasion, and proliferation, the disease is causing two problems for the patients: more or less reduced fertility and different types of pain. These two clinical problems were widely presented under the aspects of pitfalls that have influenced our treatment in the past in the view of the current place of GnRH analogs in the management and in the perspectives for the future.

The controversial data in the literature of decreased fertility, caused by or associated with endometriosis, were systematically discussed by myself. There is no discussion in the different research groups that severe endometriosis is causing infertility due to mechanical problems. But which of the different possible functional disturbances is reducing fertility in minimal and mild endometriosis is still a matter of controversial debate.

The five well-known comparative studies from the ‘80s did not show a beneficial for medical treatment of endometriosis, but the statistical power is limited because the number of patients is very low.

The good results from the Schindler group of Essen are impressive, but not randomised and not controlled. The significant benefit that Schweppe has shown, due to a six-month GnRH agonist treatment after laparoscopic surgery, is perhaps not significant if the results are adjusted to the time of the first laparoscopy and not to the time of the start of medication. Because endometriosis is often associated with other known and unknown infertility factors, from the patient’s point of view, active treatment is always better than expectant management, which has been nicely demonstrated in a prospective randomised study for super-ovulation or IUI by Fidele and Peterson.

For IVF, the literature is also controversial. What type of endometriosis is influencing the results of treatment? In an excellent prospective randomised study, Kleinstein and his group demonstrate significant better results with ultraline GnRH application up to six months in ART cycles, in IUI, as well as in IVF.

He saw beneficial effects due to different mechanisms. Atrophy and inactivation of endometriotic implants enhanced implantation of functional alterations of the endometrium that disappears after a longer period of amenorrhea. The alleged reduction and change of the endocrine situation to an artificial WHO1 constellation due to defences in the patient of the pituitary gland lead to a better oocyte quality, especially in progressed stages of endometriosis. ART cycles immediately after medical treatment guarantee a higher pregnancy rate per patient.

The opinion of lower oocyte quality is in accordance with the studies of Garcia and his group from Valencia and Madrid. The presented clinical data using the oocyte donation model showed evidence that the endometrium in patients with endometriosis is not altered, but the decreased oocyte embryo quality seems to be the main cause of endometriosis-related infertility.

Functional studies of endometrium and endometriosis do not, in contrast to animal models, support the hypothesis of altered endometrial environment.

Also, and this is to conclude the fertility part, a lot of details in oocyte development, ovulation, fertilisation, and implantation, remain unclear and controversial. From a clinical point of view, it is also clear that there is reduced fertility in endometriotic patients, and the end point of our GnRH agonist co-treatment is not elimination of the implants, but rather the inactivation or neutralisation of these negative influences. And for pain, Professor Schweppe will continue.

Professor Karl-Werner Schweppe:

Professor Lunenfeld, dear colleagues, the second main problem caused by endometriosis is pain. In the pain patients, there are two unsolved problems in the management of endometriosis. One is the problem of recurrences. We have to deal with recurring disease, and the consequence of this is we have to discuss the side effects because medication has to be applied over a long period of time or even recurrent.

Ricardo Felberbaum tested the concept that with the GnRH antagonist, cetrorelix®, in a dosage of 0.3 milligrams as a mini-depro formulation injected every 4 or every 7 days, it is possible to reduce the oestradiol levels low enough that endometriosis is not progressing, in myomas also, is high enough that no symptoms of oestrogen deprivation, like hot flushes and bone demineralisation, will occur in the patient.

The plasma levels of oestradiol confirm his hypothesis as, say, between 40 and 70 picograms per ml using the depo preparation every week. The results of his study are very encouraging. All 15 patients were completely free of pain. Three were claiming headache during the initial treatment phase and only three others had some vaginal bleeding in the second half of the treatment time.

The objective laparoscopic-controlled regression was 60%, according to the classification of the revised American Fertility Society, and the endometrium showed atrophy and no ovarian cysts developed during the treatment with the GnRH antagonists. Felberbaum concluded that the sequential menstruation of the GnRH antagonist, cetrorelix®, creates a new therapeutic approach reducing adverse events but preserving a threshold oestradiol production that does not compromise the efficacy of the treatment of endometriosis.

Patients suffering from pain from endometriosis often have, in addition, uterine fibroids and/or adenomyosis of the uterus. The old definition of Robert Meyer that adenomyosis and endometriosis are synonymous because all implants and cysts contain glands, stroma and peristromal muscle tissue with more or less adenomyosis, was recently confirmed by data from Leyendecker and his group showing that endometriotic foci are rising from dislocated endometrium of the basalis, the basal layer of the endometrium.

From a clinical point of view, it is unimportant for the treatment if edema neoplasia is a special entity or only another location of the endometriosis. Köpke drew new attention to this old problem with the modern method of diagnostic procedures, like MRI. The concept of medical treatment is new and very interesting, despite the lack of sufficient data. A case report using cetrorelix® seemingly runs weekly for eight weeks and demonstrates the reduction in the size of the uterus markedly with a volume of about 50% and the adenomyosis was changed regressively, as demonstrated by the pathologist after the hysterectomy.

The problem of recurrent endometriosis and the treatment options of a chronic pain disease were focused on in my talk. Independent of the primary treatment, surgical removal of implants and cysts, medical ovarian suppression, or the combination of both, the long-term results are insufficient in the treatment of endometriosis and recurrence rates are highly saturated, between 20% and 80% after five years of follow-up.

Therefore, an effective medical treatment of symptoms is necessary. We have three options:

1. oral contraceptive continuously
2. progestins
3. GnRH agonist with a back medication, using continuous or intermittent application.

The three-year results of a long-term treatment study were presented and the GnRH application with a back medication, one milligram oestrodiol or 0.3 milligrams conjugated oestrogen, in combination with 5 milligrams progestin daily, is the most effective, but also the most expensive, treatment.

You see here the patient free of symptoms - the red bars - very effective in the GnRH treatment with add-back medication. The repeated treatment for three months is similarly effective and well-tolerated and, three years after treatment, 70% of patients in this group were free of symptoms and no drop-outs related to the side effects were observed.

Progestins continuously are effective in two-thirds of the patients. But side effects are reported in up to 60% and OCs are effective, but only over a limited period of time. Less than 20% of the patients are pain-free at the end of the three-year period. Because these long-term follow-up studies need many years to create valid data, to create valid data is difficult to realise because of drop-out problems. Studies with new components now developed need follow-up studies from the very beginning onward.

A very remarkable topic was discussed by Zev ev Blumenfeld. He reviewed the literature and found a risk of up to 1.6 of malignant transformation of endometriosis. In addition, a higher incidence of breast cancer, ovarian cancer, and non-Hodgkin’s lymphoma was associated with endometriosis. Since multiple chromosomal operations were found in cells from endometriotic implants or adenomyosis, he assumes that unaltered cells bearing chromosomal operations are more prone to malignant transformation, the normal deployed cells. He speculates hormonal ablation therapy may suppress normal or eucariotic cells in endometriotic implants more than the unaltered cells. Because primum non nocere is a valid ancient rule of good medical practice, we have to pay attention in the future to this possible negative selection of cells by the ovarian suppressive therapy.

A completely new group of substances offers additional chance of treatment for chronic pain patients in endometriosis: the selective, progesterone receptor modulators. Chwalisz from Chicago presented preliminary data that these substances have agonistic and antagonistic effects. In vivo experiments with monkeys showed marked regression of endometrium and changes of the spiral arteries. In humans, a non-philological secretory arrest was seen. The pelvic pain was reduced dose-dependently and the volume of uterine fibroids was reduced up to 36%.

In patients with endometriosis, this can improve the pain symptoms without the systemic effect of oestrogen deprivation. The relief of pain is independent of the degree of amenorrhea and further studies are needed in order to establish this product as an alternative variation in the treatment of endometriosis-caused pain.

We can summarise that the state-of-the-art use of GnRH agonists as a treatment of endometriosis has been defined today. First, in infertility problems in endometriotic patients, the use of a GnRH agonist will not heal endometriosis, but the co-treatment with GnRH analogs, together with surgery or together with ART procedures, seems to ameliorate the environmental conditions and to improve the pregnancy rates. In pain problems, relief of symptoms can be achieved with different types of ovarian suppression. But GnRH agonists with add-back are very effective, can be given for long periods of time and are, as an intermittent treatment, cost- effective.

Also, we still do not understand the disease completely. We have improved the individual treatments of several problems correlated to the disease.

Thank you.

Would you like to submit your own presentation?
Send an e-mail to the EndometriosisZone.org Editor


© www.EndometriosisZone.org