From pathogenesis to clinical practice: Emerging medical treatments for endometriosis

Endometriosis is a chronic disease, and a lifelong management plan should be developed by using pharmacological treatment and surgical procedures. The pathogenesis of endometriosis is complicated and has not been definitively established. The mechanisms involved are numerous, and their understanding is constantly evolving. Currently, the first-line drugs act by blocking ovarian function, creating an hypoestrogenic environment. The blockade of estrogen secretion and receptor activity and the activation of progesteron receptors are the main target of several current drugs, as well as those under development. The oral GnRH antogonists, the aromatase inhibitors, SERMs, and SPRMs are the hormonal drugs currently studied for treating endometriosis. The increasing knowledge of the pathogenesis has allowed the development of new treatments. The most studied are the anti-inflammatory drugs, starting from the new NSAIDs to the monoclonal antibodies and the statins. Among the antiangiogenic compounds, a role is suggested for Icon, PPARs, and HDACIs. A new class of drugs is the cannabinoids. The aim of this review was to investigate the new therapeutic hormonal and non-hormonal alternatives to standard treatments.     

Medical treatments for endometriosis

Despite the extensive research, endometriosis remains an enigmatic disease as up to now there is no consensus regarding the exact underlying mechanisms which could explain its development and progress. A local environment enriched in estrogens, progesterone resistance, local inflammatory response and multiple other molecular alterations appear to be pivotal events in the establishment and development of ectopic tissue. In the light of the evidence produced by molecular pathology research, in vivo and in vitro studies, modifications in current treatment options are anticipated. Current management of endometriosis is based on pharmacologic treatment and surgical intervention. In particular, combined oral contraceptives, danazol, gonadotropin-releasing hormone (GnRH) analogues and progestins have been extensively used in clinical practice. Novel agents that will hopefully improve the therapeutic potential include aromatase inhibitors, immunomodulators, anti-inflammatory agents, steroids receptor modulators and GnRH antagonists. It is still early for enthusiasm as there is limited knowledge about their short- and long-term side effects, their optimal administration route, their selectivity towards their target genes and the duration of treatment. Although there is a continual report of novel findings, the application of them in clinical practice is a long-lasting procedure requiring longitudinal clinical trials so as to achieve a balance between efficacy and safety.     

The medical management of endometriosis

• •Endometriosis is a chronic recurring disease in many women.
• •Can be asymptomatic but usually presents as pelvic pain or infertility.
• •The COCP, Danazol, progestogens and GnRHa have similar efficacy in relief of symptoms.
• •Treatment needs to be individualised, and may be determined by the side effect profile.
• •There is no role for medical therapy in the treatment of endometriosis infertility.

     

New treatments for erectile dysfunction

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Erectile dysfunction (ED) is an increasingly common problem, affecting up to 30 million American men. This largely results from increased risk factors and an aging population. ED is now also recognized as a marker for cardiovascular disease. The ED patient should be thoroughly evaluated for coexisting vascular disease. The pathophysiology of ED is becoming better understood, largely as a result of the development of new therapies. Once the underlying processes are known, more selective targeting of these will lead to novel “designer drugs.”     

New treatments for erectile dysfunction

Erectile dysfunction (ED) is an increasingly common problem, affecting up to 30 million American men. This largely results from increased risk factors and an aging population. ED is now also recognized as a marker for cardiovascular disease. The ED patient should be thoroughly evaluated for coexisting vascular disease. The pathophysiology of ED is becoming better understood, largely as a result of the development of new therapies. Once the underlying processes are known, more selective targeting of these will lead to novel "designer drugs."     

Combination medical and surgical therapy for infertile patients with endometriosis

Endometriosis is a difficult problem for practicing gynecologists and is commonly associated with infertility. The diagnosis of endometriosis should only be made at the time of laparoscopy or laparotomy and should be confirmed with biopsy if possible. Once the diagnosis is made, it should be classified according to the revised AFS system. The treatment of infertility associated with endometriosis is controversial and usually consists of either medical therapy with hormonal manipulation designed to suppress the disease, surgical therapy designed to debulk the disease and repair anatomic distortion, or a combination of both. Despite an abundance of research on the treatment of endometriosis, the pregnancy rate for patients with endometriosis remains lower than that of the normal population. The reasons for this are obscure. Endometriosis does not respond to hormonal changes the same way that normal endometrium does and has been shown to persist despite extensive medical therapy. The recurrence rate of the disease is impressively high after either medical or surgical therapy. Interestingly, expectant management of minimal or mild disease is associated with pregnancy rates equal to those of any other type of therapy. Only when the disease is more extensive does aggressive treatment appear to show improvement in pregnancy rates. Whether combination therapy of endometriosis is better than single agent therapy remains open to debate. Some of the best-designed studies using combination therapy have shown no difference in pregnancy rates. Yet, when taken as a whole, it would appear that if combination medical and surgical therapy is chosen, the medical therapy should be given preoperatively. The literature abounds with a wide variety of classification systems, methods of calculating pregnancy rates, and inclusion of control groups. Because of this disparity between studies, reliable conclusions cannot be drawn.     

Update on the medical treatment of endometriosis

The treatment of women with endometriosis can be a challenge. Therapeutic strategies must be tailored to the individual symptoms, age, and desire for fertility. Medical therapy continues to be based on endocrine treatment, such as oral contraceptives, progestins, danazol, and GnRH agonists. Unfortunately, recurrence rates are high after discontinuation of therapy. Recent clinical research on GnRH analogues plus add-back therapy has produced favorable results. Long-term treatment of patients using this approach has successfully reduced pain while minimizing symptoms of hypoestrogenism and adverse metabolic effects, such as loss of bone mineral density. Currently, GnRH analogues given with add-back therapy seems to be the most effective long-term approach to the treatment of symptomatic endometriosis. In the future, other modalities, such as medicated vaginal rings, inhibitors of steroidogenic enzymes, and GnRH antagonists, will most likely be options.     

New considerations for the pathogenesis of endometriosis.

OBJECTIVES: To review the available evidence regarding the immunological, epidemiological and other factors involved in the pathogenesis of endometriosis. METHODS: Literature review. RESULTS: Endometriosis remains a poorly-understood disease of unknown etiology and pathogenesis. CONCLUSIONS: There is evidence to suggest that alterations in the immune response, whether genetically transmitted or environmentally induced, predispose women to the ectopic implantation of endometrial cells transported into the peritoneal cavity by way of retrograde menstruation. This predisposition may exist because of an impaired peritoneal clearing of endometrial cells and fragments or because of pathological angiogenesis.     

不同治疗方案对子宫内膜异位症合并不孕患者生育影响的研究进展

近年来,子宫内膜异位症(EMs)与不孕的关系受到广泛关注。EMs患者的临床妊娠率明显低于正常女性,不同的治疗方案对其生育的影响不同。轻度EMs可先期待妊娠,继而考虑药物、促排卵、手术、辅助生殖技术(ART)等治疗方法;中、重度EMs期待妊娠率较低,建议先手术治疗,手术中应用生育指数(EFI)评分评估患者生育力,手术后可行期待妊娠或促排卵、ART等方式助孕;不建议单纯药物治疗及手术后药物治疗。根据患者EMs的程度及EFI评分制定个体化治疗方案,可以有效提高临床妊娠率。     

Current and future medical treatments for menometrorrhagia during the premenopause

Excessive menstrual bleeding reflects aberrant angiogenesis, generally due to submucosal myomas and endometrial polyps, although it is also frequently observed with long-term progestin-only contraception, impaired haemostasis and hormonal disorders. Surgery (hysterectomy, endometrial ablation) is used too frequently. Uterine artery embolisation is also an option for myomas. Medical treatments include combined oral contraception, progestins and levonorgestrel-releasing Intrauterine System. Gonadotropin-releasing hormone agonists provide significant improvements in bleeding for myomas, but also decrease estrogen secretion (e.g. hot flushes, decreased bone mass). Progestins, although used widely, remain poorly effective as they promote myoma cell growth. Recently, Selective Progesterone Receptor Modulators (SPRMs) have been shown to induce amenorrhea whilst maintaining endogenous estrogen secretion. Phase II studies have also demonstrated decreased fibroid size in SPRM-treated women. Although the mechanism of amenorrhea observed after SPRM treatment is still poorly understood, they may control uterine bleeding via a direct effect on endometrial blood vessels. Suppression of bleeding in women with uterine fibroids receiving SPRMs is associated with moderate reductions in uterine artery blood flow, without major changes in angiogenic factors and extracellular matrix composition; a clear difference to modifications observed with progestins. These data suggest major progress in the treatment of excessive menstrual bleeding.     

Laparoscopic CO2 laser vaporization of endometriosis compared with traditional treatments

This study reports on 108 infertile patients with endometriosis diagnosed at laparoscopy. Sixty-four patients had endometriosis and adhesions vaporized with a CO2 laser (LAS) and were prospectively compared with a control group (CON) of 44 patients who had laparoscopy. The 6- and 12-month estimated cumulative pregnancy rates for LAS were 0.32 +/- 0.07 and 0.55 +/- 0.09 respectively, and for CON 0.17 +/- 0.06 and 0.43 +/- 0.09 (Breslow P = 0.10). Monthly fecundity rates were 6.7% in LAS and 4.5% in CON. Survival analysis with fixed covariates showed that pregnancy rates were increased in patients with adhesions (P = 0.002) and other pelvic disease (P = 0.0001). Pregnancy rates were reduced by age (P = 0.02), previous adhesiolysis (P = 0.0000) and post-laparoscopy medical treatment (P = 0.0002). Our findings indicate that CO2 laser laparoscopy vaporization of endometriosis can be a safe, effective, and possibly improved modality for treating endometriosis.     

The biological basis of medical treatment of endometriosis

Mitochondrial activity is critical for maintenance of correct glucose homeostasis and alteration in mitochondrial content or function may progressively lead to the development of insulin resistance. Evidence on the possible role of mitochondria in the pathogenesis of gestational diabetes mellitus (GDM) is conversely scanty and inconsistent. The aim was to evaluated mitochondrial DNA (mtDNA) content in peripheral blood of pregnant women with GDM. We selected 25 pregnant women affected by GDM and 50 controls with physiological pregnancies. A blood sample was collected at 32–36 weeks’ gestation, stored and thawed simultaneously. The mtDNA content was determined utilizing a quantitative real-time polymerase chain reaction by the Taqman method, using a genomic control and a target gene. Results are expressed as copy number per nuclear DNA. The median (interquartile range) mtDNA content in GDM and controls was 122 (107–198) and 170 (129–196), respectively (p = 0.039). The mtDNA content was also correlated to GDM treatment, self-blood glucose monitoring and newborns’ weight, but these analyses failed to document any statistically significant association. Attenuated mitochondrial function may play a role in the development of GDM. Further experiments are required to definitely clarify whether this defect represents a primary event in the pathogenesis of the disease.     

Future perspectives in the medical treatment of endometriosis

In the last few years, our understanding of the pathogenesis of endometriosis at the cellular and molecular levels has improved significantly. This may give us the opportunity to use new, specific agents for the treatment of this disorder. Despite the effectiveness of the available treatments, novel therapeutic strategies may improve our ability to eliminate endometriotic lesions when present and to prevent the recurrence of endometriosis after surgical treatment. This review focuses on the new, experimental approaches to the medical treatment of endometriosis and its symptoms. The blockage of aromatase activity in endometriotic lesions with an aromatase inhibitor may represent a new step in the medical treatment of endometriosis. Preliminary clinical studies have demonstrated the efficacy of third-generation nonsteroidal aromatase inhibitors (ie, anastrozole and letrozole) in reducing the intensity of pain symptoms associated with the presence of endometriosis. The new selective progesterone receptor modulators may represent a valid hormonal treatment option. Therapeutic manipulation of the immune system through TNFalpha inhibitors may be beneficial in women with endometriosis. New pharmaceutical agents affecting inflammation, angiogenesis, and matrix metalloproteinase activity may prevent or inhibit the development of endometriosis. Further clinical trials may determine if these new therapies are superior to current medical treatment strategies for endometriosis. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians Learning. OBJECTIVES: After completion of this article, the reader should be able to describe the new experimental medical treatments of endometriosis, state that the clinical use of nonsteroidal aromatase inhibitors for endometriosis appears to be efficacious but is based on preliminary clinical data, and recall that the drugs used for endometriosis in the future may include manipulation of the immune system.     

Patient satisfaction concerning assisted reproductive technology treatments in moderate to severe endometriosis

A prospective observational cohort study was performed to examine patient satisfaction after one Assisted Reproductive Technology (ART) treatment cycle in moderate to severe endometriosis patients. From May 2012 till September 2013, 25 patients with surgically proven endometriosis stage III-IV were included per group and received intrauterine insemination (IUI), in vitro fertilization (IVF) or IVF preceded by long-term pituitary down-regulation (IVF-ultralong). The median patient satisfaction scores were 8.3, 7.9 and 8.0 in patients receiving IUI (n?=?22), IVF (n?=?24) and IVF-ultralong (n?=?23), respectively (p?=?0.89). Both deterioration in pain and quality-of-life could not be identified as determinants of decreased patient satisfaction scores. Satisfaction was higher in women receiving their first ART treatment attempt (p?=?0.002), after treatment accomplishment (p?=?0.04) and after a positive pregnancy test (p?=?0.04). A median satisfaction score concerning preceding long term pituitary down-regulation of 6.1 (IVF-ultralong n?=?25, IUI n?=?8) was reported. Only three patients would refrain from this preceding therapy in a next treatment attempt. We concluded that patient satisfaction scores were comparable between the three different ART treatments. Since patient satisfaction was in particular dependent on treatment outcomes, it is recommended to compare those three ART treatments in a randomized controlled trial investigating the efficacy, safety and cost-effectiveness.