VIMS Journal: December 2015

Review Article

Aromatase Inhibitors in Current Gynecological Practice: An Overview

Dr. Krishnendu Gupta , Dr. Bijit Chowdhury , Dr. Arunava Das

Introduction :
For several years now, the pharmacological manipulation of hormone levels has been used very successfully in the treatment of estrogen- dependent disease processes such as uterine leiomyomas, breast cancer, and endometriosis, As a part of this continued approach, aromatase inhibitors (AIs) have been introduced for the treatment of breast cancer, and more recently, endometriosis. AIs have also been used as agents for ovulation induction (OI).

Aromatase Enzyme :
Aromatase, a cytochrome P450 complex encoded by a single gene, is widely expressed in tissues such as brain, breast, placenta, ovary, testes, endometrium, skin, bone and fat. It catalyzes three consecutive hydroxylation reactions converting C19 androgens to aromatic C18 estrogens. Upon receiving electrons from NADPH-cytochrome P450 reductase, aromatase converts androstenedione and testosterone to estrone (E1) and estradiol (E2), respectively. The aromatization of androgen is the terminal and rate-limiting step in estrogen synthesis. Thus, for tissues that express this enzyme, conversion of circulating androgens from an adrenal or ovarian source will significantly increase the in- situ estrogen concentrations and provide these tissues with a proliferative advantage. Pathologically, an abnormal overexpression of aromatase in breast tissue plays an important role in breast cancer development. [1-9] Inhibition of aromatase is a new strategy for reducing growth-stimulatory effects of estrogen in breast cancer by decreasing circulating levels of estrogen.

Aromatase Inhibitors: Classification and Properties :
The effective aromatase inhibitors (AIs) developed as therapeutic agents are commonly described as first-, second-, and third-generation inhibitors according to the order of their clinical development.

The first-generation inhibitor refers to the non- steroidal inhibitor aminoglutethimide (AG), which was the first AI to be studied in patients, [10] but the reports of adrenal insufficiency led to withdrawal from clinical use. AG is less specific and inhibits other CYP450 enzymes involved in cortisol and aldosterone biosynthesis, which results in toxicity. Its efficacy in inhibiting aromatase activity stimulated the development of various new inhibitors during the 1980s and 1990s.

The second-generation inhibitors include the imidazole derivative fadrozole [11] and steroid analogue formestane (4-hydroxyandro- stenedione). [12,13] Fadrozole is more selective and potent than AG, but it still has inhibitory effects on aldosterone, progesterone, and corticosterone biosynthesis. Formestane was the first selective AI to be used clinically and was effective and well tolerated. [14] However, the fact of its requirement of intramuscular administration limited its clinical use.

The third-generation inhibitors, developed in the early 1990s, including two triazole derivatives anastrozole [15] and letrozole [16] and one steroid analogue exemestane [17] are widely used as the first-line drugs in the endocrine treatment of hormone-dependent breast cancer in postmenopausal women.

Anastrozole, letrozole and exemestane are administered orally with 1 mg, 2.5 mg, and 25 mg once daily, respectively. Compared to the first- and second-generation inhibitors, the third- generation inhibitors produce greater clinical benefit with near-complete specificity at clinical use. These AIs were also better tolerated than tamoxifen and were associated with lower incidences of endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flashes. [18,19] In addition, the incidence of contralateral breast cancer occurrence was found to be significantly lower in the AI group than the tamoxifen group. [18,20,21] However, the long- term effects of these drugs on skeletal problems, cardiovascular disease, and Alzheimer's disease need to be carefully followed up.

Anastrozole and letrozole are non-steroidal derivatives that have the triazole functional which interacts with the heme prosthetic group of aromatase, and they act as competitive inhibitors with respect to the androgen substrates. Exemestane is a steroidal and mechanism-based inhibitor that is catalytically converted into a chemically reactive species, leading to irreversible inactivation of aromatase. All three AIs appear to have similar clinical efficacy despite these differences in pharmacological properties.

Clinical Uses of Aromatase Inhibitors in Gynecological Practice :
1. Breast Cancer :
In postmenopausal women, AIs were first introduced for the treatment of advanced breast cancer. Although these drugs did not increase overall survival, they appeared to be similar or better than megestrolacetate when objective responses were the end-point. [22]

The early success of these studies led to clinical trials of AIs in breast cancer patients with resectable, estrogen positive tumors. The largest of these trials compared anastrozole with tamoxifen, alone or in combination, as adjuvant treatment in women with early breast cancer following surgical resection. The study results demonstrated a small but significantly improved 3-year disease free-survival in postmenopausal women with invasive, operable breast cancer who received anastrozole alone compared with tamoxifen (89.4% versus 87.4%, hazard ratio 0.83 [95% confidence interval, 0.71-0.96]). [18]

Subsequently, many trials have been initiated to examine the role of AIs in other breast cancer clinical scenarios including its role as a sequential therapy following tamoxifen, in the treatment of ductal carcinoma in-situ, and in the prevention of breast cancer in high-risk patients. [23] Although data from these trials are still incomplete, it can be postulated that AIs will play a significant role in the therapy of estrogen receptor-positive breast cancer.

AIs have also been used as a treatment modality for premenopausal women with early breast cancer who have chemotherapy-induced amenorrhea. This off-label use should be prescribed with caution because case series have described the resumption of ovarian function following initiation of an AI regimen. [24,25] To identify women who experience a return of ovarian function, serial monitoring of estradiol and gonadotropin levels to may be indicated. [24]

Adverse effects of AIs
The short- and long-term adverse effects of AIs in postmenopausal women are related to the lack of estrogen at aromatase-targeted tissue sites and include: hot flashes, vaginal dryness, arthralgias, decreased bone mineral densityand an increased fracture rate. [26] It is currently recommended that bone mineral density (BMD) screening be repeated annually in all patients receiving AI adjuvant therapy, and bisphosphonate therapy should be initiated when T scores are -2.5 or lower. [27] To reduce the risk of osteoporosis in high-risk patients, bisphosphonates may be co- administered to patients during long-term treatment with AIs.

2. Endometriosis :
Endometriosis, defined as the presence of endometrial tissue outside of the uterine cavity (ectopic endometrium), affects 10% of women of reproductive age and as many as 50% of women with chronic pelvic pain or infertility. The principal symptoms are chronic pelvic pain, dysmenorrhea, deep dyspareunia, infertility, and urinary and cyclic bowel alterations. The pathogenesis of endometriosis is complex and multifactorial and despite being one of the most studied diseases in gynecology, its etiology has yet to be clarified. Currently, a combination of theories that include an impaired immunologic response, a genetic predisposition, and an inflammatory component provide possible explanations as to the cause of the disease.

An overexpression of the aromatase enzyme, the main responsible factor for estrogen synthesis in ectopic endometrium, has been demonstrated in endometrial tissue. [28] Aromatase catalyzes the conversion of the steroidal precursors to estrogen, which stimulates the expression of the enzyme COX-2. The estrogens produced in the endometrial tissue through aromatase promote the growth and invasion of endometrial lesion and favour the onset of pain and prostaglandin- mediated inflammation. [29] This local production of estrogen may explain the progression of endometriosis during therapy with gonadotropin- releasing hormone analogues (GnRH-a) that act only at the level of the ovarian production of estrogen [30] ; AIs on the contrary, lead to a reduction of extra-ovarian estrogen concentration. [31] The estrogen plasma levels in women taking 1-5 mg of letrozole or anastrozoledaily are reduced by 97–99%. [32]

By reducing the production of extra-ovarian estrogens, AIs stimulate an increased secretion of FSH from pituitary gland, promoting an increased ovarian production of estrogens and follicular recruitment. When used in premenopausal women, it is important to associate drugs that lead to a down-regulation of ovarian activity, such as progestins, GnRH- a, or oral contraceptives, in order to counteract the potential formation of follicular cysts. [32,33,34] The combination of conventional therapy and AIs determines the block of the production of estrogens both in ovarian and extra-ovarian endometriotic foci, reducing the painful symptoms. They have been used in a pilot study evaluating 12 women with recto-vaginal endometriosis, who had pelvic pain resistant to conventional treatments: after 6 months of treatment with letrozole (2.5mg/day), norethisterone acetate (2.5mg/day), calcium citrate, and vitamin D, there has been a significant reduction in abdominal-pelvic pain and the disappearance of endometriotic lesions at second- look surgery. [35] A subsequent study, from the same group, showed that the association of letrozole with norethisterone acetate provides pelvic pain control more effectively than norethisterone acetate alone. [36] Pelvic pain, however, tends to recur after discontinuation of treatment, just as after the discontinuation of GnRH-a. [37]

3. Ovulation Induction :
In premenopausal women, AIs reduce hypothalamic-pituitary estrogen feedback that leads to increased gonadotropin-releasing hormone (GnRH) secretion, concomitant elevations in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and increased follicular development. The gonadotropin- stimulating action of letrozole has been used off- label in the treatment of patients with ovulatory dysfunction, such as polycystic ovary syndrome (PCOS), and for increasing the number of ovarian follicles recruited for ovulation in women who are already ovulatory. [38,39]

In a meta-analysis of four published trials, including 662 women with PCOS, pregnancy rates were similar between women treated with clomiphene citrate and women treated with letrozole (relative risk, 1.02; 95% confidence interval, 0.83–1.26). [40] Some have raised concerns about this off-label use because letrozole may disrupt the normal aromatase activity in tissues during early fetal development and can be potentially teratogenic if administered inadvertently during early pregnancy. However, a large study of 911 newborns conceived using letrozole for ovulation induction (OI) showed no difference in rates of congenital malformations. [41] In addition, the half-life of letrozole (approximately 30 – 60 hours) is much shorter than that of clomiphene citrate (5 – 7 days) and, thus, should be effectively cleared from the body by the time of embryo implantation, likely preventing a teratogenic effect when used in OI. The possible advantages of letrozole over clomiphene citrate include reduced multiple pregnancies, lower estradiol levels, and an absence of anti-estrogenic adverse effect on the endometrium. However, there is no evidence currently to prove that letrozole is more effective than clomiphene citrate for OI. However, letrozole may have a role in the treatment of clomiphene-resistant patients. [42,43]

Aromatase inhibitors (AIs) have definitely gained importance in modern gynecological practice as an effective therapeutic adjuvant for early- stage and late-stage breast cancer. Their role in chemoprevention of breast cancer in high-risk patients remains to be defined. Adverse effects of AIs in postmenopausal women are due to the estrogen lowering action at the target tissues and include hot flashes, vaginal dryness, arthralgias and decreased bone mineral density. Several studies have positively indicated a molecular basis for treating endometriosis with AIs. AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin- releasing hormone analogues have been used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to recto-vaginal endometriosis refractory to other medical or surgical treatment. AIs have shown promise in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. In the reproductive-aged women, AIs stimulate gonadotropin secretion and increase follicular activity, proving a strong challenger to the time- tested clomiphene citrate as an ovulation induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. Data from recent retrospective and prospective studies support the safety of AIs for ovulation induction.

Acknowledgements :
The authors graciouslyacknowledge and record their gratitude to the ACOG Committee Opinion No. 412, August 2008 (reaffirmed in 2014), and to Dr. Gabriella Zito et al (Hindawi Publishing Corporation, BioMed Research International, Volume 2014, Article ID 191967) for reproduction of information in the above- mentioned review article.

  1. Esteban JM et al. Detection of intratumoral aromatase in breast carcinomas. An immunohistochemical study with clinicopathologic correlation. Am J Pathol 1992; 140:337-343.

  2. Bulun SE et al. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 1993;77:1622-1628.

  3. Harada N. Aberrant expression of aromatase in breast cancer tissues. J Steroid Biochem Mol Biol 1997; 61:175-184.

  4. James VH et al. Aromatase activity in normal breast and breast tumor tissues: in vivo and in vitro studies. Steroids 1987;50:269-279.

  5. Lu Q et al. Expression of aromatase protein and messenger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. Endocrinology 1996;137:3061-3068.

  6. Miller WR, O'Neill J. The importance of local synthesis of estrogen within the breast. Steroids 1987; 50:537-548.

  7. Santen RJ et al. Stromal spindle cells contain aromatase in human breast tumors. J Clin Endocrinol Metab 1994;79:627-632.

  8. Sun XZ et al. Autocrine and paracrine actions of breast tumor aromatase. A three-dimensional cell culture study involving aromatase transfected MCF-7 and T- 47D cells. J Steroid Biochem Mol Biol 1997;63:29-36.

  9. Vermeulen A et al. Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol 1986;22:515-525.

  10. Santen RJ. Suppression of estrogens with aminoglutethimide and hydrocortisone (medical adrenalectomy) as treatment of advanced breast carcinoma: a review. Breast Cancer Res Treat 1981; 1:183-202.

  11. Beretta KR et al. CGS16949A, a newaromatase inhibitor in the treatmentof breast cancer-a phase I study. Ann Oncol1990;1:421-426.

  12. Dowsett M et al. Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4- hydroxyandrostenedione in postmenopausal breast cancer patients. Cancer Res1989;49:1306-1312.

  13. Brodie AM. Aromatase inhibitors in the treatment of breast cancer. J Steroid Biochem Mol Biol1994; 49:281-287.

  14. Coombes RC. et al. 4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer. Lancet 1984;2:1237-1239.

  15. Plourde PV et al. ARIMIDEX: a neworal, once-a-day aromatase inhibitor. J Steroid Biochem Mol Biol 1995;53:175-179.

  16. Lipton A et al. Letrozole (CGS 20267). A phase I study of a new potentoral aromatase inhibitor of breast cancer. Cancer 1995;75:2132-2138.

  17. Evans TR et al. Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res 1992; 52:5933-5939.

  18. Baum M et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131-2139.

  19. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med2003;348:2431-2442.

  20. Coombes R.C. et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350:1081-1092.

  21. Goss PE et al. 2003. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349:1793-1802.

  22. Buzdar AU et al. Anastrazole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Armidex Study Group. Cancer 1998; 83:1142-52.

  23. Bickenbach KA, Jaskowiak N. Aromatase inhibitors: an overview for surgeons. J Am CollSurg 2006; 203:376-389.

  24. Smith IE et al. Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhea: caution and suggested guidelines. J Clin Oncol 2006; 24:2444-2447.

  25. Burstein HJ et al. Inadvertent use of aromatase inhibitors in patients with breast cancer with residual ovarian function: cases and lessons. Clin Breast Cancer 2006;7:158-161.

  26. Howell A et al. Results of the ATAC trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60-62.

  27. Hillner BE et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042-4057.

  28. Meresman GF et al. Effects of aromatase inhibitors on proliferation and apoptosis in eutopic endometrial cell cultures from patients with endometriosis. Fertil Steril 2005;84(2):459-463.

  29. Velasco I et al. Aromatase expression in endometriotic tissues and cell cultures of patients with endometriosis. Mol Hum Reprod 2006;12(6):377-381.

  30. Bulun SE et al. Estrogen production and metabolism in endometriosis. Annals of the New York Academy of Sciences 2002;955:75-85.

  31. Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis. FertilSteril 2012; 98, (6):1370-1379.

  32. Amsterdam LL et al. Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril 2005;84(2):300-304.

  33. Ailawadi RK et al. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. FertilSteril 2004;81(2):290-296.

  34. Remorgida V et al. Letrozole and desogestrel-only contraceptive pill for the treatment of stage IV endometriosis. Aust NZ J Obstet Gynaecol 2007; 47(3):222-225.

  35. Remorgida V et al. Letrozole and norethisterone acetate in rectovaginal endometriosis. Fertil Steril 2007;88(3):724-726.

  36. Ferrero S et al. Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis. Hum Reprod 2009; 24(12):3033-3041.

  37. Abushahin F et al. Aromatase inhibition for refractory endometriosis-related chronic pelvic pain. Fertil Steril 2011;96(4):939-942, Erratum in: Fertil Steril 2012; 97:1017.

  38. Fisher SA et al. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002;78:280-285.

  39. Bedaiwy MA et al. Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation. Hum Reprod 2006;21:2838-2844.

  40. Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril 2007 June 21. DOI: 10.1016/j.fertnstert.2007.03.094.

  41. Tulandi T et al. Congenital anomalies among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006; 85:1761-1765.

  42. Badawy A et al. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fertil Steril 2007 June 18. DOI: 10.1016/j. fertnstert. 2007.02.062.

  43. Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clin Obstet Gynecol 2011; 54(4):685-695.


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