Aromatase Inhibitors for the Treatment of Endometriosis

Capsule:
A review is presented of the role of aromatase in the pathogenesis of endometriosis, discuss the pharmacology of aromatase inhibitors, and examine clinical applications of aromatase inhibitors for endometriosis treatment.

Authors:
Mary Ellen Pavone, M.D., M.S.C.I. and Serdar E. Bulun, M.D.

Volume 98, Issue 6, Pages 1370-1379, December 2012

Abstract:

A review is presented of the role of aromatase in the pathogenesis of endometriosis, discuss the pharmacology of aromatase inhibitors, and examine clinical applications of aromatase inhibitors for endometriosis treatment.

  • andrea romano

    I want to congratulate the authors for the interesting and thorough overview.

    I would also like to share my concerns regarding some controversial issues and listen the author’s opinion about some possible future developments.

    The role of aromatase in endometriosis is supported by many studies (referred in the review). However, there are other reports that disprove some of the observations that are presented as facts in this review, including the role of aromatase. Our team in Maastricht (and others) using validated real-time PCR protocols has observed very low mRNA levels of this enzyme (barely detectable), which do not seem to be higher in endometriosis than in controls.
    In addition, although some trials have indicated that aromatase inhibitors can
    alleviate endometriosis symptoms, these studies do not clarify whether the
    aromatase inhibition takes place locally or peripherally.
    In conclusion, the local role of aromatase remains debated.

    With in my mind the idea that our efforts should be dedicated to improve the condition of endometriosis patients and to move forward the research for new treatments and better care, I would like to propose a joint effort for the future to develop standardized methods for our assays and to try as much as possible to have multi centre confirmation of our own results; including perhaps, sharing samples.

    In addition to this point, not everything may be due to technical issues but can reflect real inter-individual differences. We know that endometriosis is heterogeneous, multifactorial and we doubt whether it is the manifestation one only, or of a number of distinct pathogenic conditions.
    Hence, I believe that our perspective should change. Instead of searching for a unique mechanism, it can be valuable to identify in a patient-to-patient basis the cause of endometriosis, hence to develop personalised care: inhibition of the local aromatase-loop, inhibition of the peripherally aromatisation of androgens in women with high androgen levels, or other approaches like STS or (when available) HSD17B1 inhibitors.

    • Serdar Bulun

      I will be very candid with you. Local aromatase expression in
      endometriosis is not debatable for the following reasons. 1. Tom Price and Evan
      Simpson developed the first PCR assay to detect aromatase in 1990 and I joined
      this team in 1991 to further develop it and started publishing my findings
      since 1993. My team has been instrumental in advancing PCR techniques all the
      way to real-time PCR technology. I do not think anybody understands the
      pitfalls of this assay better than my team does. 2. I had personal
      communications with well-established endometriosis investigators or steroid
      biochemists in various regions of the US including Hugh Taylor (Yale), Linda
      Giudice (UCSF), Carole Mendelson (UTSW), each of whom used independent
      techniques and samples to confirm our original findings and published these. 3.
      Not only did we show aromatase expression in all three forms of endometriosis,
      we also described an elaborate pathway to explain the cellular and molecular
      origins of endometriosis using aromatase as the starting point (Bulun NEJM
      2009). 4. Aromatase is unique in that low levels of its expression (Ct values
      in the range of low to mid 30s) give rise to biologically meaningful estrogen
      levels (pmol quantities). This is usually not appreciated by investigators not
      familiar with this field and must be what is confusing your team. You are
      probably used to working with genes expressed at higher levels, such as HDS17B1
      or STS. 5. Just because a technique has not worked in your hands does not mean
      everybody else is wrong or the subject is now debatable. You definitely need to
      gain more expertise and experience in medical research in general and
      especially in the area of steroid biochemistry, if you are sincerely interested
      in getting to the truth. If you send one or two of your postdocs or students to
      my lab, I will be very happy to train them; I bet they will start getting
      different results once they understand the proper biology and techniques. 5.
      Aromatase inhibitor treatment definitely works to reduce pain in endometriosis.
      The lack of larger randomized studies is explicable by the lack of
      pharmaceutical support since patent protection for these inhibitors has already
      run out or about to run out. Keep in mind that the first OC trial in
      endometriosis was performed decades after the routine use of these medications
      in endometriosis for the same reason. 6. I agree with you that we still do not
      know if AIs show their effects through local or systemic aromatase inhibition;
      possibly both. There is substantial circumstantial clinical evidence that local
      expression plays a major role in mediating pelvic pain. We listed these reasons
      in the review.

      I wholeheartedly agree that new mechanisms should be uncovered. This does not
      make aromatase and the related biology irrelevant. It is what it is. I
      personally do not think HSD17B inhibition will work in endometriosis or breast
      cancer because of the redundancy issue. There are at least 10 other genes,
      which catalyze the same reaction as HSD17B1. The advantage with targeting
      aromatase is that a single gene encodes it; so its inhibition effectively kills
      almost all estrogen production. That is why AIs replaced tamoxifen to treat
      breast cancer; HSD17B or STS inhibitors have been developed since 1970s but
      never made it to phase 3 trials, possibly for this reason.

  • Sérgio Soares

    I want to congratulate the authors for the excellent review. I would like to listen to their opinion about the pharmacological management of endometriosis in women at advanced reproductive age. Considering that no prospective randomized study has been published on the issue yet, would there be enough support to the decision of prescribing an AI + progestin therapy to these patients, instead of, for example, a progestin only therapy? Wouldn’t it be more reasonable, in clinical practice, to wait for the proper studies to clarify what are the real advantages and risks of the combined therapy over any other currently used?

    • Serdar Bulun

      Aromatase inhibitor treatment definitely works to reduce pain in
      endometriosis. The lack of larger randomized studies is explicable by the lack
      of pharmaceutical support since patent protection for these inhibitors has
      already run out or about to run out. Keep in mind that the first randomized OC trial in
      endometriosis was performed decades after the routine use of these medications was started in 1970s for the same reason.

      For reproductive age patients with refractory endometriosis, I first rule out ovarian endometrioma or rectovaginal nodule both of which should be treated by surgical resection by an experienced laparoscopist. I usually start with giving continuous OC treatment for 6 months and ask the patient to keep a simple VAS pain diary. If pain levels do not decrease to a level acceptable or satisfying to the patient, I add an aromatase inhibitor such as anastrozole 1 mg/d. This usually provides pain relief in 80-90% of patients, who previously have not responded to conventional measures.

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