Expert Opinion on Pharmacotherapy
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PHARMACOLOGIC TREATMENT OF THE OVARIAN ENDOMETRIOMA Giuseppe Benagiano, Sun-Wei Guo, Paola Bianchi, Patrick Puttemans, Stephan Gordts, Felice Petraglia & Ivo Brosens To cite this article: Giuseppe Benagiano, Sun-Wei Guo, Paola Bianchi, Patrick Puttemans, Stephan Gordts, Felice Petraglia & Ivo Brosens (2016): PHARMACOLOGIC TREATMENT OF THE OVARIAN ENDOMETRIOMA, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2016.1229305 To link to this article: http://dx.doi.org/10.1080/14656566.2016.1229305
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Date: 15 September 2016, At: 00:32
Publisher: Taylor & Francis Journal: Expert Opinion on Pharmacotherapy DOI: 10.1080/14656566.2016.1229305 Review
PHARMACOLOGIC TREATMENT OF THE OVARIAN ENDOMETRIOMA Giuseppe Benagiano1, Sun-Wei Guo2, Paola Bianchi3, Patrick Puttemans4, Stephan Gordts4, Felice Petraglia5, Ivo Brosens6 1
Department of Gynaecology, Obstetrics and Urology, Sapienza, University of Rome, Rome, Italy.
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Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People's Republic of China. 3
Department of Surgical and Medical Sciences and Traslational Medicine, Sant'Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy. 4
Leuven Institute for Fertility and Embryology, Leuven, Belgium
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Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Siena, Italy. 6
Department of Obstetrics and Gynaecology, Catholic University of Leuven, Leuven, Belgium.
Corresponding Author: Paola Bianchi:
[email protected] Department of Surgical and Medical Sciences and Traslational Medicine, Sant'Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
Funding This paper was not funded Declaration of Interest
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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Abstract Introduction: Treatment of ovarian endometriomas is commonly achieved through laparoscopic surgery and this can be effective in eliminating the disease, although a majority of recent trials documented an adverse effect of surgery on ovarian reserve markers. With the advancement in imaging techniques, ovarian endometriomas are increasingly diagnosed at an earlier stage when the endometrioma may be smaller, less fibrotic and more responsive to medical treatment, making an evaluation of medical options critically important. Areas covered: The review focuses on currently utilized pharmacologic therapies for endometrioma (oral contraceptives, the levonorgestrel-releasing IUS, the hormone-releasing subdermal implant, Implanon); experimental and future treatments are also mentioned (GnRH antagonists, progesterone receptor modulators, antioestrogens, newer subdermal implants and intracystic administration of pharmacologic agents). Finally, the usefulness of post-operative adjuvant medical treatments is discussed Expert opinion: Today, reliable, non-invasive diagnostic procedures of an ovarian endometrioma are available and should be utilized to identify its presence and type of pathology. In a young patient, classic medical therapies such as oral contraceptives and synthetic progestins should be tried first to alleviate symptoms. Only when these regimens fail, should a minimally invasive surgery be envisaged. Following endoscopic surgery, adjuvant medical treatment may reduce recurrence of both symptoms and the lesion. Key words: aromatase inhibitors; combined oral contraceptives; gonadotropinreleasing hormone analogues; intra-uterine systems; ovarian endometrioma; progestins; subdermal implants.
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1.
INTRODUCTION
Endometriosis is considered a common gynaecologic disease, although its true incidence has never been firmly determined in the general population of reproductive-age women. Estimates vary between 5 and 15% [1, 2] and it has been ascertained that its early presence will inevitably affects over time future fertility) [3, 4]. It has been argued that endometriosis can manifest itself with different phenotypes: superficial peritoneal, deep infiltrating; cystic ovarian [5] and that modern imaging can distinguish these variants in a non-invasive manner [6]. Of particular importance is the ovarian endometrioma, especially the early-onset variant that may possess a more haemorrhagic and less fibrotic pathology. In addition, an endometrioma can remain small or progress rapidly, thereby necessitating early diagnosis and timely management [7]. The prevalence of the specific ovarian variant is basically unknown: not a single epidemiologic study exists on its incidence or prevalence in the various stages of a woman’s life. However, it appears to be the most frequently diagnosed variant of endometriosis, due, perhaps in no small part, to the relatively ease and accuracy in detecting an ovarian endometrioma using modern imaging compared to other types of the disease. Of importance is the fact that cystic images smaller than 3 cm in diameter can in fact represent hemorrhagic dysfunctional cysts and need to be carefully differentiated. Disregarding small endometriomas may be one of the causes of the delayed diagnosis of the ovarian endometrioma [7]. At present, laparoscopic treatment is commonly utilized because it is felt by many that there is no effective medical cure for the ovarian endometrioma. At the same time, as pointed out by Burkhardt and Renner [8], any surgical intervention for ovarian endometriomas causes loss of oocytes; therefore, the indication for surgery should be very carefully considered, taking its advantages and disadvantages into account, as well as the psychological strain and the age of the patient. Clearly, the issue is still controversial, but pathophysiology tells us that the typical ovarian endometrioma is a pseudo-cyst without a wall of its own. Therefore “cystectomy” by definition entails loss of ovarian tissue and is potentially detrimental because of the loss of growing follicles. 4
Under the circumstances, consensus is emerging that there are situations where medical therapy would be beneficial, especially today when surgery is often postponed [9]. Given that ovarian endometriomas are increasingly detected by systematic use of imaging techniques in symptomatic adolescent and young women, there is a need for a therapeutic strategy aimed at preventing progressive damage to the ovary [10]. This has caused a paradigm shift with attention focussing on new medical therapeutic options [11], such as aromatase inhibitors or the ultrasound-guided drainage followed by intracystic drug injection. On the other hand, data on the socalled ethanol sclerotherapy have been considered as not fully convincing [12]. Different medical therapies have been proposed for women affected by peritoneal endometriosis who do not wish to become pregnant [9, 13]; much less investigated is medical treatment of the ovarian endometrioma. The singling out of this particular subtype of endometriosis seems justified by its early occurrence in young women, commonality and the documented distinction between other subtypes of endometriosis [5, 6]. We have recently proposed a new approach to the management of the ovarian endometrioma capable of preserving future fertility; specifically we believe that – following cyst aspiration – endometrial growth in an endometrioma can be suppressed by intra-cystic or local application of synthetic progestins, such as danazol or levonorgestrel, selective progesterone receptor modulators (SPRM or PRM), such as mifepristone, ulipristal or asoprisnil, without affecting ovarian activity [12]. Here we wish to recommend specific indications for medical treatment based on pathophysiology and review existing, experimental and possible future pharmacologic options. Specifically, the review will deal with agents capable of restoring progesterone receptors’ ratio, such as progestin or selective progesterone receptor modulators, or decreasing local oestrogen production through an aromatase inhibitor. Emphasis will be placed on modalities considered valid today, such as adjuvant medical treatment in connection with cyst aspiration or surgery. In addition, mention will be made of possible future therapeutic modalities, such as use of antioxidants that can block free radicals production and agents capable of increasing apoptosis and therefore enhance the autophagic 5
process. Also, metalloproteinases and relaxin activity, as well as the inflammatory process can be controlled through pharmacologic means. Finally, anti-angiogenic agents may be especially indicated in the juvenile haemorrhagic form of the disease. The principal pathophysiologic mechanisms involved in endometriosis are summarised in Figure 1.
2.
METHODOLOGY
The scope of this review is to highlight new or updated information on the role of medical therapies in the management of the cystic ovarian form of endometriosis. To this end, a Scopus search between 1980 and 2016 using the key-words "endometrioma or endometriotic cyst or cystic endometriosis" and "medical therapy" provided 129 references that were all individually evaluated. In the end, we selected all data that were considered useful for a modern management of endometriomas. During the revision process, we also added several additional very recent references.
3.
PATHOPHYSIOLOGY AS A BASIS FOR TREATMENT
While the natural history of endometriomas is largely unknown, recent studies suggest that endometriotic lesions are fundamentally wounds that undergo repeated tissue injury and repair (ReTIAR) [14-16]. This theory is still controversial, but evidence is accumulating that endometriotic lesions undergo platelet-driven epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, leading to smooth muscle metaplasia and ultimately fibrosis [16, 17]. Also, it has been shown that in ovarian endometriomas, mesenchymal stem cells significantly promote fibrogenesis [18]. What has not yet been shown is whether the extent of fibrosis is correlated positively with the severity of dysmenorrhea; this may be the case in the presence of increased adhesion and distorted anatomic structure resulting from endometriosis. Conceivably, fibrosis in 6
endometriotic lesions accounts for decreased vascularity, progesterone responsiveness and increased deposits of extracellular matrix (ECM) proteins in the interstitial space. This, in turn, leads to reduced cellularity, making drug delivery to the target tissues more difficult. This may explain why endometriosis is generally refractory to medical treatment, since fibrosis is difficult to treat, let alone cure. The wound theory is further demonstrated and substantiated by the work of Kitajima et al. [19, 20]: regardless of surgery, ovaries with endometriomas already show a significantly lower follicular density compared to normal ovaries [19] and their local and chronic inflammatory reaction apparently induces an activated, i.e. accelerated, follicular recruitment and atresia of early follicles [20]. The so-called ‘burnout’ hypothesis may explain the mechanism partly responsible for the reduced ovarian reserve in women with endometriomas: focal inflammation, manifesting as massive fibrosis and loss of cortex-specific stroma that maintains follicular nests, results in a focal loss of follicular density that may be associated with a vicious circle of dysregulated folliculogenesis that eventually results in a burnout of the stockpile of dormant follicles. An additional reason to pursue a correct differential diagnosis between hemorrhagic dysfunctional cysts and true small endometriomas without any delay, especially in adolescents and young women, and, by doing so, avoid any delay in applying the most appropriate treatment to halt this vicious circle. Because of wounds undergoing ReTIAR, hormonal treatment merely temporarily freezes the development process, as progestins suppress inflammation and GnRH agonists action results in a hypo-oestrogenic state due to ovulation block and thus stoppage of menstruation both at eutopic and ectopic endometrium (with a consequent tissue injury and subsequent repair). Once the treatment is discontinued, however, the process towards fibrosis is resumed. And once the fibrotic content of the lesion reaches a certain extent, any medical treatment would become problematic, if not altogether ineffective. A promising approach to disrupting this process would be stopping the injury or bleeding. As pointed out by Brosens et al. [21], all existing drugs for treating endometriosis have the capability of stopping menstruation. Alternatively, antiplatelet therapy may hold promise [22, 23]. In fact, many drugs that seem to be
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promising in pre-clinical studies are actually anti-platelet or anti-thrombotic agents. Given the current status of medical treatment of endometriosis, and knowing the history of how these drugs came into existence (progestins were introduced following a serendipitous finding that pregnancy can alleviate pain, and GnRH agonists were introduced mostly as a by-product, not as a result of extensive research), perhaps it is not that outrageous to question whether treatment modalities (mostly hormonal) we have practiced so far are optimal.
4.
CLINICAL PHENOTYPES
The pathology of the endometrioma differs between the adolescent or young woman and the older, mature woman and depends on the progressive fibrosis and devascularisation of the endometrioma bed. Transvaginal endoscopic inspection of the ovary with endometrioma under hydroflotaton allows observing the stigma of invagination at the site of adhesions (Figure 2a) and the endometrial-like mucosa lining the inverted cortex (Figures 2b). This endoscopic technique allows without manipulation to explore the cavity and to distinguish between the red phenotype lined by the marble white cortex partially or fully covered with a thin, yet highly vascularized endometrial-like mucosa (Figure 3a) and the brown-black phenotype lined by an amorphous dark and fibrotic wall. The transvaginal endoscopic approach under hydroflotation allows to ablate under vision the vascularized endometriotic lining (Figures 3b) [24]. The two different phenotypes also lead to the postulation that the response to medication may vary depending on the degree of fibrosis and devascularisation. The presence and extent of fibrosis and devascularisation can be evaluated by Colour Doppler sonography [25]. The fact that in most cases the endometrioma at the site of invagination is adherent to the fossa ovarica or uterine wall explains the tendency to rupture at the time of surgical manipulation. For this reason any manipulation of the ovarian endometrioma at the time of intracystic insertion of a medication-releasing device
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may cause a rupture of the pseudocyst and cause spillage of the chocolate content.
5. SPECIFIC INDICATIONS FOR MEDICAL TREATMENT At present, there are two main indications for a pharmacologic management of ovarian endometriomas: the presence of a cystic lesion with a diameter >3 cm (especially in young patients) and recurrence and pain prevention following surgery. In 2005 ESHRE issued guidelines for the treatment of endometriosis, specifying when medical management was warranted [26]. New, updated guidelines were presented in 2014 [27] when ESHRE recommended that “the decisions involved in any treatment plan are individual” and stress that every patient must be able to make her choice for treatment following clear information and proper understanding of “what is happening to her body”. Unfortunately, in discussing pharmacologic options these guidelines do not distinguish between ovarian and peritoneal endometriosis, although they state that if surgery is selected, clinicians should perform cystectomy instead of drainage and coagulation, or CO2 laser vaporization because they reduces pain and recurrence rate [28, 29]. However, in their Cochrane review, Hart et al. [28] agreed that published studies were insufficient to derive information with regard to subsequent ovarian function and quality of life measures, while in the Carmona et al. study [29] the differences were not statistically different at 60 months of follow-up. These studies underline the complex pathology of the ovarian endometrioma and the present inadequate diagnosis of disease progression. A flow-chart detailing the path to be followed in the management of pelvic pain due to endometriosis is presented in Figure 4. A variety of agents through diverse routes of administrations have been tested for the medical treatment of an endometrioma, mostly in preliminary trials. Some of them may today be utilized for conservative local treatment. After a systematic search of all compounds tested pre-clinically and clinically, Guo [30] concluded that, besides the three main classes of drugs, i.e. GnRH agonists, 9
progestins and androgenic agents, there are several classes of compounds that have been tested and are listed as completely evaluated, yet no information on their outcomes is available in the public domain.
6.
CURRENTLY AVAILABLE DRUGS LABELED FOR ENDOMETRIOMA
6.1. GnRH agonists A number of basic investigations have evidenced several mechanisms through which GnRH agonists (GnRHa) can block endometrioma growth, all involving the hypo-oestrogenic state they induce. Among them, is the ability to directly reduce the expression of aromatase cytochrome p450 and cyclooxygenase-2 in both the ectopic and eutopic endometrium of patients with ovarian endometriomas [31]. Khan et al. [32] found that the endometrium in women with endometriomas (and other forms of endometriosis) expresses GnRH receptors; under the circumstances, besides the hypo-estrogenic effect, a direct anti-proliferative action of GnRHa may help in achieving regression of endometriomas. The same group [33] also observed that infiltration of the CD68-positive macrophage marker and of the vessel marker von Willebrand factor were significantly decreased in the endometria of women with ovarian endometriomas following GnRHa therapy. After treatment there was also a marked decrease in inflammatory and angiogenic responses with a significant increase in apoptotic index. Although these and other basic investigations show that GnRH agonists can be successfully employed in the medical treatment of the ovarian endometrioma, today interest in their use focuses on adjuvant therapy (see Section 9 on adjuvant treatment). Recently, a comparison has been carried out of the effect of the GnRHa triptorelin acetate and the dopamine agonist cabergoline on endometrioma size [34]. The study measured by vaginal ultrasound, changes in the endometrioma size at the end of a three-month period and considered significant any reduction by more than 25 % of the pretreatment size. A significant decrease was observed in 64.7% (46 out of the 71) of subjects treated with cabergoline and in only 21.7% (15 out of 69) of patients who received triptorelin acetate (p0.999). Pain in the case of severe endometriosis (stage III and IV) improved more rapidly than 12
in the event of milder disease. One of the advantages of LNG-IUS is the fact that it does not provoke hypo-oestrogenism and that it requires only one medical intervention for its introduction every 5 years. Although no details on the localisation of endometriosis are given, the fact that symptoms in severe disease substantially improved suggests that Mirena was probably also effective in the presence of an ovarian endometrioma that is frequently associated with adherent endometriosis in the fossa ovarica (Fig 1a). Thus, a rationale exists for treating this condition with a progestogen. The LNG-releasing system has been utilised also to improve results after surgery for endometriosis. In a randomized study, Bayoglu-Tekin et al. [48] compared the efficacy of the LNG-IUS with that of a depot GnRHa (Zoladex©) on endometriosisrelated CPP in patients with severe endometriosis during 12 months. Both treatment modalities showed comparable effectiveness in the treatment of CPPrelated endometriosis. In a double-blind randomized, controlled trial Tanmahasamut et al. [49] investigated 55 patients with endometriosis and moderate-to-severe dysmenorrhea undergoing laparoscopic conservative surgery. After surgery, patients were randomized to be inserted with Mirena (n=28) or expectant management (n=27) group. The two groups were comparable in age, body mass index, parity, and baseline pain scores. At 12 months, the levonorgestrel-releasing intrauterine system group had a significantly lower median value of dysmenorrhea and non-cyclic pelvic pain score. In a retrospective cohort study Cho et al. [50] compared the efficacy of postoperative use of LNG-IUS with oral contraceptives for preventing endometrioma recurrence. During the follow-up period of a mean of 17 months the recurrence rate was comparable, with 4.8% in the LNG-IUS group and 10.5% in the women receiving COC. In conclusion, there is initial evidence that intrauterine progestogen medication has a significant effect on ovarian endometrioma. 7.3. The Hormone-Releasing Subdermal Implant Implanon® A number of hormone-releasing subdermal implants and microsphere have been developed, initially as long-acting contraceptive devices, and the suggestion has been made that they can be utilised to relieve endometriosis-associated pelvic pain. Before any judgement can be passed on the effect of these systems on 13
peritoneal endometriosis and ovarian endometriomas, however, long-term controlled studies of these systems are required. At present only the Implanon® subdermal implant is available on the market. (Merck KGaA, Darmstadt, Germany). It consists of a subdermal single rod implant containing 68 mg of the progestin etonogestrel, the active metabolite of desogestrel. The product has been available worldwide since 1999. It was approved for use in the United States in 2006. The contraceptive rod is 4 cm in length and 2 mm in diameter, with a release ratecontrolling membrane of ethylene vinyl acetate [51]. Implanon provides contraception for up to three years. Preloaded, disposable, sterile applicators are provided for easy, subdermal insertion. The device is not radio-opaque. A release rate of 25-30 μg/day of etonogestrel is required to suppress ovulation. The etonogestrel in Implanon is released at an initial rate of approximately 60–70 μg/day, which slowly decreases to about 30 μg/day by years 2 and 3 [52]. Implanon prevents pregnancy primarily by suppressing ovulation [53], but also causes thickening of the cervical mucus so that it becomes impenetrable to sperm, and causes the endometrial lining to become thin and atrophic [54]. Of relevance here is the fact that the implant has been shown to be effective in improving symptomatic endometriosis [55, 56] and its therapeutic efficacy for pain relief is not inferior to that of depot-medroxyprogesterone acetate [57]. Unfortunately, no study of the effect of Implanon in women with the cystic, ovarian form of endometriosis seems to have been carried out.
8.0 EXPERIMENTAL AND FUTURE PHARMACOLOGIC TREATMENTS FOR THE ENDOMETRIOMA Given the unsatisfactory situation existing today on ways to pharmacologically treat an ovarian endometrioma, a number of attempts have been made to identify novel treatment modalities. Some of the new ideas seem promising and they will be detailed here. 8.1 GnRH antagonists 14
GnRH antagonists may also be utilised with the advantage of having more precise control over systemic oestrogen levels, due to the lack of the “flare-up” phenomenon seen in their agonist counterpart. Their mode of action should be identical to that of GnRH agonists, i.e. deprivation of oestrogens, the fuel for the growth of endometriotic implants. Several antagonists are available today and clinical trial results appear to be encouraging; specifically, they have been utilised to control pain in endometriosis patients with an acceptable safety and tolerability profile [58, 59], although no specific use in the management of the ovarian endometrioma has been published. However, two issues stand out: one is their efficacy in relation to their predecessors, the GnRH agonists; the other is pricing. Given their novelty and the investment in drug research and development, it is expected that their price would be higher than that of GnRH agonists. Undoubtedly, cost-effectiveness analysis with head-to-head comparison with GnRH agonists will be highly desirable, especially given the financial strain faced in many health care systems. 8.2. Selective Progesterone receptor Modulators (SPRM or PRM) One class of drugs that might be utilised to inactivate the ovarian endometrioma because of their reported effective inhibition of endometrial proliferation and reduction of endometriotic lesions in animal models [60] is selective progesterone receptor modulators. These drugs, however, produce endometrial changes following medium- to long-term (3 to 6 months) continuous daily dosing [61]. Specifically mifepristone (RU486) and asoprisnil have been shown to cause unusual changes termed “progesterone receptor modulator-associated endometrial changes” (PAECs) characterized by dilated, weakly secretory endometrial glands with few mitotic figures, and stromal effects ranging from compaction to non-uniform oedema [62, 63]. Although a group of pathologists concluded that the changes revealed nothing that should be considered a safety concern, a “Dictionary of Endometrial Biopsy Diagnoses for Clinical Trials with SPRMs” was developed to supplement conventional criteria [63]. Long-term studies are needed, especially if SPRMs are to be used for more than 3 months. However, a recent survey on clinical trials on endometriosis found that a number 15
of them testing several SPRMs were either terminated, withdrawn or failed to publish their results, even though some were completed over a decade ago [64]. Caution also should be exercised because a successful therapeutic effect demonstrated in preclinical studies does not automatically translate into clinical success due to the vast difference between humans and rodents, as well as the higher premium that is placed on the safety of anti-endometriotic drugs since endometriosis is not a life-threatening disease. Very little is known on the effect of SPRM on endometriosis: recently, an article summarized work by Chinese scientists and clinicians with mifepristone and analysed more than 100 articles; unfortunately, in their vast majority these publications are of inferior quality and cannot be utilised to show that MFP is truly efficacious [65]. Interestingly, a phase II/III trial intended to recruit 360 patients on the use of mifepristone to treat endometriosis (NCT02271958) was completed in 2013, but so far its outcome has not been published as of the time of writing [64]. 8.3 Anti-oestrogens Aromatase P450 is the enzyme catalysing the conversion of C19 steroids to oestrogens and it is not present in normal endometria. In 1996, Noble et al. [66] detected P450 aromatase transcripts in endometriotic implants and all eutopic endometrial tissues from patients with endometriosis, posing the basis for a new form of treatment, the use of anti-oestrogens. Then, in 1999, Takayama et al. [67] successfully treated with the anti-oestrogen anastrozole a 57-year-old woman with severe endometriosis recurring after hysterectomy and bilateral salpingooophorectomy. This led to the proposal of a novel therapeutic strategy for endometriosis targeting molecular aberrations that increase local oestradiol concentrations in the endometrium [68-70]. The specific application of aromatase inhibitors to the medical treatment of peritoneal endometriosis soon followed; the same group [71] tested in 10 patients a daily regimen of 2.5 mg letrozole plus 2.5 mg norethisterone acetate for 6 months patients with good results and some problems. Finally, in 2011, Lall Seal et al. [72] published 5 cases of recurrent endometriomas in which, after a period of washout of any hormone therapy, they administered letrozole (2.5 mg), desogestrel (0.15 mg) and ethinyl oestradiol (0.03 mg) during an additional 6 months. They reported disappearance of the cystic 16
lesions and reduction of pelvic pain in all 5 cases. In reviewing the literature, the question then arose whether the addition of the progestin is really useful. To investigate this point, Ferrero et al. [73] carried out in two groups of 20 patients a comparative evaluation of the use of norethisterone acetate alone or in combination with letrozole and determined that the combined treatment is more efficacious in reducing the volume of endometriotic cysts. Contrary to what found by Lall Seal et al. [72] in no instance did the endometriomas disappear. The effectiveness of anti-oestrogens in the medical management of ovarian endometrioma has been recently confirmed by Agarwal and Foster [74] who treated 8 women for a total of 14 endometriomas with letrozole plus 5mg norethisterone acetate over three months. They documented through ultrasound a reduction in the size of the mean endometrioma diameter of 50% from 4.6 ± 1.6 cm to 2.3 ± 1.6 cm (mean ± SD); the reduction in volume was on the average of 75%. Finally, symptomatology (dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain) also improved with treatment. At this stage, while clearly the hypo-oestrogenic state produced by antioestrogens is at the base of their mechanism of action, controlled, long-term studies are necessary to evaluate their real role in managing women with ovarian endometriomas who do not wish to get pregnant 8.4. Subdermal capsules and microspheres In addition to subcutaneous implants, preliminary information exists also for other types of long-term administration of progestins. Among them, two are worth of mention: (a) Poly-dimethyl-siloxane (Silastic) progesterone-releasing capsules Maginnis et al. [75] investigated the feasibility of treating endometriosis in macaques with chronic progesterone (P) as an alternative therapy for the disease. In macaques the disease is frequently advanced at the time of diagnosis and ovariectomy is the standard therapy. Seven adult rhesus macaques with advanced endometriosis were identified by clinical symptoms and endometriosis was confirmed by abdominal palpation, ultrasound examination, and/or aspiration of menstrual blood from abdominal cysts. The primates were chronically treated with Silastic capsules that released 5-7 ng P/ml in blood for up to 20 months. 17
During the first 2 weeks of treatment, endometriotic symptoms improved significantly in all patients. They concluded that continuous P treatment of rhesus monkeys provides therapeutic benefit to reduce symptoms of endometriosis and may provide an option for cases where ovariectomy is contraindicated. Here again, no application to the treatment of endometriomas has been attempted. (b) Biodegradable microspheres containing nomegestrol acetate These have been tested in a rat model of endometriosis and have been shown to significantly reduce the volume of endometrial autografts, as well as serum levels of oestradiol and progesterone, and of oestrogen receptor alpha expression [76]. The authors concluded that their findings warranted further investigations of sustained application of steroid hormones via microspheres for the treatment of endometriosis. Unfortunately, no additional information has become available. 8.5. Intracystic administration As mentioned, we have recently reviewed this topic [12] showing that a variety of agents have been utilised, including Recombinant Interleukin-2 [77, 78] and Methotrexate [79, 80]. Ethanol sclerotherapy has also been successfully employed [81-86], although questions remain. 8.6. Possible future pharmacologic options One class of drug that has not been tested formally in clinical trial settings is antiplatelet drugs. Preclinical studies seem to be promising [22, 23, 87]. Andrographolide, an NF-κB inhibitor [88], as well as anti-thrombotic agent [89], has been used in treating adenomyosis, giving encouraging results [90]. Histone deacetylase inhibitors (HDACIs), such as valproic acid, have been shown to exert desirable effects on endometriotic cells both in vitro and in vivo and indeed, aside many desirable properties that HDACIs have [91], they have been also shown to be anti-fibrotic [92]. Incidentally, valproic acid has been shown to have an anti-platelet action [93]. Among future options for treating endometriosis, a role may be played by statins. Recently, Vitagliano et al. [94] have reviewed both in vitro and in vivo studies on their efficacy in the treatment of endometriosis, emphasizing their potential due to the anti-proliferative/pro-apoptotic effects, their ability to reduce cell viability 18
and migration, and their anti-angiogenic and anti-inflammatory activity. They conclude that, as of today, uncertainty concerning their impact on gonadal function makes additional studies mandatory before this class of drugs could be safely employed in endometriosis. Finally, two recent publications have focused attention on the potential use of vitamin D. The first [95], pointed out that the vitamin D receptor is expressed in both central and peripheral organs involved in the reproductive process with tissue specific modulation of vitamin D levels. However, the effects of vitamin D on reproduction may not be direct, but secondary to hypocalcaemia, or oestrogen dysregulation. The second [96], investigated in vitro effects of vitamin D3 on human endometriotic stromal cells (ESCs). They found that vitamin D3 significantly reduced IL-1β- or TNF-α-induced inflammatory responses and also reduced the number of viable endometrial stem cell numbers and DNA synthesis and concluded that Vitamin D supplementation may represent a novel therapeutic strategy in women with endometriosis.
9.
POST-OPERATIVE ADJUVANT THERAPY
9.1. Oral contraceptives As mentioned, COC cannot be successfully utilised in the treatment of ovarian endometriosis, while, at the same time, ovulation suppression after endometriotic cyst excision has been considered protective against relapse. To evaluate this point, Vercellini et al. [97] have carried out a systematic review of the literature on the effect of long-term postoperative adjuvant medical therapy on the risk of endometrioma recurrence. They found four articles fulfilling their criteria (surgery for endometriotic cysts, postoperative medical treatment use for ≥ 12 months vs. expectant management, ultrasonographic and/or histological diagnosis of endometrioma recurrence) for a total of 965 women. In all four trials treatment consisted of a COC. They found recurrence in 8% (33 of 423) of women who fully used the COC and in 34% (117 of 341) of those who underwent expectant management (pooled OR 0.12; 95% CI 0.05-0.29). They concluded that postoperative COC use dramatically decreased the risk of ovarian endometrioma 19
recurrence, especially in those subjects who took the COC regularly and for a prolonged period of time. One point worth mentioning is that already in 2010, Serracchioli et al. [98] had shown the superiority of the continuous COC administration over the classic cyclic one. They randomly created three groups: non-users, cyclic and continuous users and treated the last two groups over a 24 month period with a low dose COC. They found a significantly lower crude recurrence rate in cyclic (14.7%) and continuous users (8.2%) compared with non-users (29%), although difference between the two treated groups was not significant. In addition, length of the recurrence-free survival was significantly lower in nonusers than in the two other groups. The usefulness of a continuous versus cyclic COC regimen has been the object of a recent systematic review concluding that, following conservative surgery, better results can be obtained with a continuous administration with a better delay and lower recurrence of dysmenorrhea and non-specific pelvic pain, and a reduction in recurrence rate for the endometriomas [99. This review has been criticised on several grounds [100, 101] and one the groups criticising it very recently published a new systematic review [102] comparing experience with continuous vs. cyclic COC regimens after surgical excision of ovarian endometriomas published through December 2014. Primary outcomes were pain (evaluated separately for dysmenorrhea, non-cyclic chronic pelvic pain, and dyspareunia) and endometrioma recurrence rates. Three randomized clinical trials and 1 prospective controlled cohort study were analysed for a total of 343 patients with ovarian endometriomas. They concluded that lower recurrence rates for dysmenorrhea were obtained with a continuous schedule (RR, 0.24; 95% CI, 0.06e0.91; P ¼ .04), whereas differences in reduction of chronic pelvic pain, dyspareunia and cyst recurrence rates were non-significant (RR, 0.54; 95% CI, 0.28e1.05; P ¼ .07). It seems that, although continuous regimens may offer some advantage, further randomized studies are required to reach a valid conclusion. Also, outcomes related to patient satisfaction and quality of life should be addressed [99]. COC have been used also as a long-term maintenance therapy after surgical excision of endometriomas, followed by GnRH analogue treatment. Park et al. 20
[103] assessed the effect of a cyclic COC regimen as long-term maintenance therapy (median 33.2 months) on endometriomas' recurrence following conservative surgery followed by GnRH analogue treatment. Over a follow-up period ranging 19-94 months, they found that no recurrence occurred in COC users. 9.2. GnRH agonists In 2001, Shaw et al. [104] tested the usefulness of monthly goserelin depot injections for 3 months following laparoscopic aspiration of endometriomas, by comparing it with laparoscopic aspiration alone and found significantly smaller endometriomas among treated women and a trend towards a greater reduction in the mean Additive Diameter of Implants (ADI) score. All subjects were then submitted to surgical excision and reassessed at 6 months post-surgery; the mean change in endometrioma size was -2.29 cm in the goserelin group and -1.29 cm in the medically-untreated patients, a statistically significant difference (P = 0.036, 95% CI -2.42 to -0.08 cm). In another study, Jee et al. [105] evaluated the influence of postoperative GnRHa treatment on disease recurrence after conservative laparoscopic surgery in one hundred nine patients divided into four groups: expectant management (n = 37); GnRH agonist therapy for 3 (n = 28); 4 (n = 21); and 6 months (n = 23). Subjects were followed for an average of 20.1 months. Although crude recurrence and cumulative probabilities of disease recurrence at 24/36 months tended to be lower in patients who received a GnRH agonist for 6 months compared with those who received it for 3 and 4 months and untreated subjects, differences did not reach statistical significance. Over the years, various combined adjuvant therapies have been investigated. In one study Kim et al. [106] have tested the efficacy and tolerability of two hormonal regimens as short-term add-back therapy during post-operative GnRH agonist treatment in patients with endometriomas. After the second month of agonist treatment patients were divided into two groups: 56 received tibolone and 61 received oestradiol valerate for five months. They found that incidence of uterine bleeding, hypo-oestrogenic symptoms and pelvic pain did not differ significantly between the two treatment groups. In another trial, Park et al. [107] 21
have tested the effectiveness of COC as a postoperative long-term maintenance therapy to prevent recurrence of endometrioma after conservative ovarian surgery followed by GnRH analogue treatment. During follow-up over periods ranging 19-94 months (median 41.2), they observed in 59 patients no recurrences of the endometrioma. Similar results were obtained by Lee et al. [108] when they evaluated retrospectively the efficacy of post-operative cyclic COC administration following GnRH agonist treatment for the prevention of endometrioma recurrence. They observed that patients receiving COC after the analogue had a significantly reduced recurrence risk of endometrioma (odds ratio = 0.20; 95 confidence interval, 0.10-0.38). Efficacy of post-surgery GnRHa therapy in patients with endometriosis has been the object of a just published metanalysis [109]. They identified 7 randomizedcontrolled trials, including 328 patients with postoperative GnRHa treatment and 394 patients who served as controls. The analysis made no distinction between peritoneal or ovarian disease and found that postoperative GnRHa treatment for endometriosis was superior to expectant or placebo treatment in prevention of the recurrence (pooled OR=0.71; 95% CI 0.52-0.96). As mentioned, one important concern of surgical treatment of endometriomas is an almost unavoidable negative effect on ovarian reserve. Recently, this subject has been indirectly addressed in the case of postoperative three month adjuvant GnRHa therapy. Yang et al. [110] carried out a prospective, controlled investigation of the effect of a three-month GnRHa treatment on circulating levels of FSH, and oestradiol and of FSH/LH ratio. They found that in the GnRHa treated group FSH returned to pre-surgery levels in 95.3% of the patients; this compared with 82.2% in the non-treated subjects (p < 0.05). Spontaneous pregnancy rate (57.1%) was also higher in the adjuvant than in the control group (36.8%) (p < 0.05). Finally, another just published study compared adjuvant therapy with GnRHa vs. that with dienogest following surgery for endometriosis [111]. Also in this case, no distinction was made between the various phenotypes. One hundred and eleven patients were randomly assigned to either dienogest (n=56) or goserelin (n=55) and followed for 24 months after laparoscopic surgery. No significant difference
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was observed in recurrence rates between the two groups, with menstrual pain and chronic pelvic pain improving significantly in both.
10. CONCLUSION To this day, no medical cure exists for any phenotype of endometriosis. This is particularly true for the ovarian form for which conservative surgery represents the management of choice. Critical in the management of the ovarian endometrioma, especially the earlyonset variant is the use of modern, non-invasive diagnostic procedures, especially three-dimensional ultrasound. In a young patient, approved medical therapies should be tried first to alleviate symptoms. Only when these regimens fail, should a minimally invasive surgery be envisaged. In all patients, pharmacologic agents, such as combined oral contraceptives, progestins and GnRH agonist analogues can be utilised as adjuvant treatment to prolong disease-free interval and reduce the incidence of recurrence. There is a need to conduct properly designed, controlled clinical trials of the several new agents and administration modalities that have been proposed and preliminarily tested, including GnRH antagonist analogues, progesterone receptor modulators and anti-oestrogens.
11. EXPERT OPINION A relatively large number of studies have been published over the years to guide in the treatment of peritoneal endometriosis. Some have shown effectiveness in blocking progression of the disease, as well as symptom recurrence. The situation is different when dealing with the specific cystic variant of endometriosis affecting the ovary. The main problem with this type of endometriosis has been the delay of diagnosis. In most cases, diagnosis is made when the woman complains of infertility; yet, the endometrioma may have formed from superficial endometriosis during adolescence. Today, the use of imaging in girls with dysmenorrhea or pelvic pain has provided vital information
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on the ovarian endometrioma in its early stage when it is formed by an adherent invaginated pseudocyst lined by a thin angiogenic endometrium-like mucosa. Before the advent of fibrosis and devascularisation, the haemorrhagic pseudocyst can be treated by appropriate medication. Unfortunately, the Cochrane guidelines for management of the ovarian endometrioma are based on endometriomas as seen in the older woman with infertility [28]. The early diagnosis of the red angiogenic type of endometrioma in the young woman opens the way for medical prevention of endometrioma recurrence. There, over the years, an array of drugs have been promised and tested pre-clinically and, in some cases, in limited clinical settings but, with the exception of the levonorgestrel-releasing Intra-uterine system Mirena, not in randomized clinical trials specifically designated for the treatment of ovarian endometriomas. Most of the pharmacologic agent utilised are hormonal drugs. Therefore, it seems that the only valid indications to treat women with endometriomas with existing drugs are the prevention of progression in young patients with haemorrhagic cystic lesions and the adjuvant postoperative therapy aimed at preventing recurrence and reappearance of symptoms. If we accept the ReTIAR hypothesis and the notion that, driven by plateletsinduced activation of the TGF-β1/Smad3 signalling pathway, endometriotic lesions undergo epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, leading to smooth muscle metaplasia and ultimately to fibrosis, one lingering question is whether all drugs will still work when endometriotic lesions are already highly fibrotic. This is important since when a lesion becomes fibrotic, its cellularity decreases, and so does its vasculature and hormonal response. Therefore, the success or failure of systemic administration of any drug will hinge on whether the drug is delivered properly to its intended target tissues (i.e. the endometriotic lesion). In this regard, intracystic delivery may be more attractive, but to what extent is unclear. But, even if the drug could be properly delivered to the target tissues, would it rectify fibrosis or reduce the extent of fibrosis? Given the dearth of any anti-fibrosis drug in general, this may questionable. In addition, a moment of reflection is needed in evaluating these potentially useful therapies, presumably intended to treat women with ovarian endometriomas who 24
complained of pains of various kinds. The reason is that it is unclear whether there should be any difference for women whose primary complaint is subfertility. More importantly, since to delay recurrence as much as possible is also one of treatment goals, little is known whether and which of these drugs should be used to minimize or even remove the recurrence risk. In particular, it is entirely unclear as whether the use of these drugs should be guided by the reported biomarkers for recurrence. In other words, there is a complete lack of biomarkers that can be used to monitor the progress, or lack thereof, of the treatment. Future research is badly needed. In conclusion, while the development of novel pharmacologic agents is eagerly awaited, even more important is the initiation of well-controlled clinical trials of existing drugs for the specific indication of ovarian endometriosis.
HIGHLIGHTS • •
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The ovarian form of endometriosis is the most frequently diagnosed variant of the disease when using modern imaging techniques. The condition can be considered an often progressive disease with wounds undergoing repeated tissue injury and repair, as well as platelet-driven epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, ultimately leading to fibrosis. Pathology of endometriomas differs between adolescent and mature subjects due to progressive fibrosis and devascularisation of the pseudo-cyst ovarian bed. Often the early onset form represents a more haemorrhagic and less fibrotic pathology. Laparoscopic surgery including ablation or excision is the most common form of treatment. Surgical intervention risks causing loss of oocytes and, for this reason, its advantages and disadvantages should be very carefully considered, taking also into account psychological strain and the patient’s age. Today attention focuses on medical therapeutic options, both approved and still off-label. Today, two are the main indications for a pharmacologic 25
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management: the presence of a cystic lesion with a diameter 3cm)
Medical treatment
Recurrence prevention
Medical treatment
Recurrence prevention
Medical treatment
NSAID: nonsteroidal anti-inflammatory drugs; DIE: deep infiltrating endometriosis; THL: transvaginal hydro-laparoscopy
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