Endometriosis is an estrogen-dependent, gynecological disease, defined as the presence of endometrial tissue outside the uterus affecting the pelvic organs and the peritoneum, although in rare cases, extra peritoneal locations, such as the lungs. Endometriosis is a non-cancerous disorder in which pieces of endometrial tissue - normally occurring only in the lining of the uterus (endometrial) - grows outside the uterus. The conventional approach is to block production of female hormones (estrogen and progesterone) or to prevent ovulation with other hormonal effects. Due to advancement in understanding of the (patho) physiological mechanisms involved in disease etiology has led to the development of novel therapeutic approaches for endometriosis like targeting the hypothalamic-pituitary-gonadal axis, selective modulation of estrogenic and progestogenic pathways, inhibiting angiogenesis or by interfering with inflammatory and immunological factors. To precise, novels are Aromatase inhibitors (anastrozole, letrozole, exemestane, and vorozole), Leukotriene-Antagonists (zafirlukast accolate), montelukast (Singulaire), and zileuton (Ziflo) and Selective Estrogen-Receptor Modulators (SERMs) raloxifene (Evista) or tibolone).
Women of reproductive age are more affected by endomeriosis than the post-menopausal women. Chronic pelvic pain, dysmenorrhoea, dyspareunia and infertility are prominent symptoms. Pathogenesis includes retrograde menstruation followed by implantation of viable endometrial cells onto the peritoneum and the pelvic organs. The appearance of endometriosis ranges from small peritoneal lesions to large ovarian endometriosis cysts (endometriomas) and extensive fibrosis and adhesions leading to significant distortion of pelvic anatomy. Endometriosis is progressive in a considerable number of cases. Peritoneal lesions mainly result in pain symptoms, but are also associated with sub fertility, whereas the more severe forms may cause pain and impair fertility and may lead to pelvic organ dysfunction, often requiring extensive surgery. Disease severity is usually classified into four stages (I - IV or minimal - severe), using the revised American Fertility Society (rAFS) system based on the observations acquired during laparoscopy.
Current treatment approaches
The basic aim of endometriosis treatment is to remove or decrease the size and number of ectopic endometrial implants, to alleviate pain and possibly improve endometriosis-related sub fertility. The two major approaches to achieve these goals are chemotherapy and surgery. Based on the fact that endometriosis is an estrogen-dependent disease with pelvic pain as a major symptom, most pharmaco-therapeutic strategies are designed to lower the estrogen milieu and/or to relieve pain viz. hormonal and non-hormonal approach.
The ideal endometriosis drug should:
■ prevent the development of endometriosis
■ permanently extinguish the endometriotic lesions and disease symptoms
■ prevent recurrence after cessation of the treatment
■ not interfere with the menstrual cycle
■ have no or negligible side-effects
■ provide the possibility of pregnancy even during treatment
The minimal requirements would be:
■ efficacy equivalent to or better than that of the presently available medications
■ significantly better side-effect profile and tolerability
■ convenient administration possibilities
■ affordability over a long period of time
■ the potential to decrease the number of necessary surgeries
Newer approaches exert their effect by:
■ influencing the hypothalamic-pituitary-gonadal regulation hormone homeostasis
■ selectively modifying estrogenic pathways
■ selectively modifying progestogenic pathways
■ inhibiting angiogenesis of the endometriotic lesions
■ interfering with inflammatory and immunological factors
Hormonal approaches
Gonadotropin-releasing hormone agonists (GnRH): The GnRH analogues causes suppression of hormone production via desensitization and down regulation of pituitary GnRH receptors, resulting in the blockade of gonadotropin - follicle-stimulating hormone (FSH) and luteinising hormone (LH) - release from the anterior pituitary gland. GnRH agonists bind to pituitary GnRH receptors and result in a stimulation of FSH and LH release. GnRH agonists are synthetic derivatives of the natural decapeptide for e.g., nafarelin, goserelin and triptorelin are decapeptides, whereas buserelin, leuprorelin (leuprolide) and histrelin are nonapeptides. Avorelin (Mediolanum, Italy), a novel GnRH agonist.
GnRH antagonists: Chronic administration of GnRH antagonists desensitizes the pituitary gland by down regulating GnRH receptors and is applied clinically for treatment of sex hormone-dependent cancers and a number of gynecological conditions. However, in clinical situations in which an immediate suppression of gonadotropins is desired, GnRH agonists have the disadvantage of producing an initial flare-up of gonadotropin secretion. Therefore, the use of GnRH antagonists, which cause a prompt and dose-dependent inhibition of gonadotropin release by competitive blockade of the GnRH receptors, is more advantageous. It is hypothesized that all sex hormone-dependent disorders, including endometriosis, currently treated with GnRH agonists, may be indications for GnRH antagonists too. GnRH antagonists elicit their effects by competing with endogenous GnRH for pituitary binding sites. Due to the lack of any intrinsic activity, GnRH antagonists have no initial 'flare-up' effect. At present, GnRH-antagonists are used clinically mostly for premature LH surge prevention in controlled ovarian hyper stimulation. The rationale for using GnRH antagonists in endometriosis is provided by the so-called estradiol threshold theory, proposing that estrogen within a certain concentration range may prevent bone loss, while still effectively inhibiting growth of the endometriotic lesions. For endometriosis, the efficacy of GnRH agonist-induced hypogonadism plus steroid add-back has been confirmed by a number of clinical trials.
Progestogens: Progestogens, on continuous treatment, induce an anovulatory, hypoestrogenic state via suppression of pituitary gonadotropin release, and decidualisation of both normal and ectopic endometrium, leading to atrophy of the endometriotic implants. In addition, progestogens also have anti angiogenic properties which impede the survival of endometriotic lesions. The typical side-effects of progestogens are irregular menstrual bleeding, typically followed by amenorrhoea, body weight gain, depression, bloating and prolonged period of anovulation.
Antiprogestogens: Antiprogestogens (PAs) inhibit ovulation by inducing a hypoestrogenic state, for e.g. mifepristone and gestrinone. The therapeutic effect of mifepristone in endometriosis are due to its anti proliferative and pro apoptotic effect. Dienogest progestrogen with oral activity, synthetic steroid that has been used in contraceptive pills. It is also reported that dienogest could potentially suppress the growth of endometriotic implants. Tanaproget (TNPR), a nonsteroidal PR agonist, showed a four to six fold higher relative binding affinity as compared with trimegestone (TMG) on human PRs. As it competes for SHBG binding sites, it may offer advantages over steroidal progestins as in it will not affect blood sex hormone levels. Selective progesterone receptor modulators mifepristone (RU-486) and numerous related compounds have been synthesised with activities ranging from pure PR antagonists to mixed agonists/antagonists. Selective estrogen receptor modifiers (SERM) act by competing with estrogen for binding to the estrogen receptor. Raloxifene, a well-known representative of the SERMs, is a nonsteroidal substance primarily developed to treat postmenopausal osteoporosis. At present, no literature data are available regarding the effect of SERMs in women with endometriosis, possibly because so far SERMs have been investigated mainly in the context of hormone-dependent tumours. Estrogen receptor- a-agonists (ER Alpha) is thought to be responsible for mediating many of estrogen's actions, such as its tropic effects on the uterus and feedback of the hypothalamic-pituitary-ovarian axis. The second form (ER) was discovered more recently and its function is not completely understood, but it is not the dominant ER in the uterus, suggesting that a selective ER Alpha ligand could mimic estradiol's actions in a variety of target tissues, without significantly interfering with the uterus.
Combined oral contraceptives (COCs): The COCs containing both estrogen and progestogen, create a hormonal environment similar to that observed during pregnancy, which served as the basis for their introduction as endometriosis treatment. COCs results in anovulation, decreased gonadotropin levels, reduced menstrual flow, decidualisation of endometriotic lesions, downregulation of cell proliferation and enhanced apoptosis in the eutopic endometrium. Side effects include dysmenorrhoea and amenorrhoea. COCs have better side effects profile relative to others so preferred for longer use.
Androgens: Mechanism includes attenuation of the mid cycle peak of LH secretion necessary for ovulation, inhibit enzymes in the steroidogenic pathway and increase free testosterone concentrations by displacement of testosterone from sex hormone-binding globulin (SHBG) and decreasing the production of SHBG. e.g. Danazol.
Non-hormonal targets
Antiangiogenic agents: Angiogenesis is essential for the establishment and growth of endometriotic lesions. Increased levels of proangiogenic factors have been demonstrated in endometriotic tissue and peritoneal fluid from women with endometriosis. Because endometriotic lesions and the surrounding tissues are highly vascularised, inhibition of angiogenesis seems to offer a new therapeutic option. Using the chicken chorioallantoic membrane (CAM) model, Nap et al. demonstrated that transplantation of human endometrium onto the CAM leads to a strong angiogenic response and to the formation of endometriosis-like lesions. Administration of angiostatic agents TNP-470, endostatin, anginex and antihuman VEGF antibody significantly inhibited this angiogenic response and reduced endometriosis-like lesion formation.
Selective COX-2 inhibitors: The expression of COX-2 protein and mRNA is reported to be increased in endometriotic implants when compared with eutopic endometrium. Over expression of COX-2 is also present in certain human cancers and is linked to angiogenic activity, which is also important in the pathogenesis of endometriosis. Increased activation of COX-2 by estrogen may also be implicated in endometriosis. Estradiol induces COX-2 activity, leading to increased PGE2 production, which in turn stimulates aromatase activity resulting in increased local estradiol production. In this manner, a positive feedback cycle is established, favouring the proliferative and inflammatory characteristics of endometriosis. Based on these two major mechanisms, angiogenesis and aromatase activation, it is attractive to hypothesise that selective COX-2 inhibition may offer an effective prevention or treatment modality in endometriosis.
Aromatase inhibitors: The aromatase enzyme catalyses the conversion of C19 steroids nucleus, mainly androstenedione and testosterone, to estrogens, which is a key step in estrogen biosynthesis. In women of reproductive age, the main sources of estrogen are the ovaries while in post menopausal women, estrogen is mainly synthesized in extra ovarian tissues, such as the adipose tissue and skin. The major substrate for aromatase in these peripheral tissues is androstenedione mainly originating from the adrenal glands and androstenedione is converted to estrone, which is further converted to estradiol. This may result in serum levels of estradiol, which are capable of causing endometrial hyperplasia or even endometrial carcinoma. High levels of aromatase mRNA have been reported in extra ovarian endometriotic implants and endometriomas, suggesting increased local estrogen production. Estrogen can increase prostaglandin E (PGE)2 formation by stimulating the COX-2 enzyme in uterine endothelial cells in culture. PGE2 is the most potent known inducer of aromatase activity in endometriotic stromal cells, a positive feedback loop could be established, continuously producing estrogen and prostaglandins locally, favouring the proliferative and inflammatory characteristics of endometriosis. aromatase mRNA has been detected in the eutopic endometrial samples of women with moderate- to-severe endometriosis, although in much smaller quantities than in endometriotic implants . In contrast, aromatase seems to be absent in disease-free endometrium and myometrium. Modern steroidal (e.g., formestane, exemestane) and non steroidal aromatase (e.g., aminoglutethimid, letrozole, anastrozole) inhibitors have been intensively examined and are now an integral part of post menopausal breast cancer therapy.
TNF-alpha inhibitors: TNF-alpha, ?is a pro-inflammatory cytokine. It is able to initiate inflammatory cascades, which is suggested to play a major role in the pathogenesis of endometriosis. TNF-alpha ??concentrations are increased in the peritoneal fluid of women with endometriosis, and its levels correlate with the stage of the disease. TNF-alpha has also been shown to increase the adherence of cultured stromal cells to mesothelial cells in vitro, thus suggesting that the presence of TNF-alpha? in peritoneal fluid may promote adhesion of ectopic endometrial tissue to the peritoneum.
PPARs activators: PPARs are ligand-activated transcription factors with effects on physiological processes such as adipocyte differentiation, lipid metabolism, monocyte/macrophage activation and cytokine expression. There are three types of PPARs: -alpha, beta and gamma. Although all three PPARs are widely expressed, their relative levels differ greatly between tissues in reflection of their distinct biological functions. All PPARs are present in cells of the vascular wall and the immune system. PPARs are activated by natural ligands such as fatty acids, eicosanoids and oxidised fatty acids. Pharmacological compounds such as the antihyperlipidaemic fibrates and the antidiabetic thiazolidinediones (TZDs) are also ligands for PPAR-alpha and -gamma respectively.
Conclusion
Currently available drugs can improve endometriosis-associated pain, but are useless for endometriosis-associated sub fertility and are limited in terms of duration of drug application, side effects and disease recurrence after cessation of therapy. Some of these new drugs and drug candidates, such as GnRH antagonists, progesterone agonists, SPRMs, SERMs and ER alpha ?agonists, have the potential to provide a more efficient therapy for endometriosis with fewer and/or less severe side effects. However, based on the data available, these drugs all seem to interfere with the physiological menstrual cycle, suggesting that these novel approaches will still not be able to treat endometriosis effectively and allow spontaneous conception simultaneously. Therefore, other non-hormonal drug candidates are more attractive, as they appear to improve disease status without significantly influencing gonadal function, but their side-effect profile requires more studies. Most adverse effects and therapeutic limitations of both existing and investigation medications for endometriosis, are consequences of their nonspecific tissue targeting.
(The authors are with Dept of Pharma Management, Manipal College of Pharmaceutical Sciences, Manipal 576104 and Pharmacy Group BITS, Pilani 333031.)