Aromatase, Estrogen and Male Reproduction: a Review

Öz

The mammalian testis is both an endocrine and an exocrine gland. In addition to gonadotropins and testosterone, estrogens are found in male gonads. Estrogens regulate male gonadal functions. Estrogens perform their functions together with estrogen receptors. Estrogens participate in functions such as pubertal growth and spermatogenesis in men. The aromatase enzyme, a product of the CYP19 gene, is important in the conversion of androgens to estrogens. Aromatase is present in Leydig cells, pachytene spermatocytes, and round spermatids in the testis. Factors such as TGFβ1, TNF-α, and TH have been shown to have a negative effect on aromatase. P450 aromatase deficiency leads to disorders such as high testosterone, infertility, shrinkage and testicular weight, decreased ejaculation, and sperm motility in men. In cases such as oligospermia that develops due to the increase in serum estrogen levels, it has been observed that the level of testosterone increases by using estrogen inhibitors. In this review, changes in male gonads in aromatase deficiency and factors affecting aromatase are stated. As a result, it has been shown that aromatase expressed in the testis is important for male gonad development and spermatogenesis.

Anahtar Kelimeler

• Aromatase(CYP19),
• infertility
• estrogen
• testis

Öz

Memeli testisi hem endokrin hem ekzokrin bir bez özelliğindedir. Gonadotropinler ve testosteronun yanı sıra östrojenlerde erkek gonadlarda bulunmaktadır. Östrojenlerde erkek gonadal fonksiyonları düzenlemektedirler. Östrojenler fonksiyonlarını östrojen reseptörleriyle birlikte gösterirler. Östrojenler erkekte pubertal büyüme ve spermatogenezis gibi fonksiyonlara katılırlar. CYP19 geninin ürünü olan aromataz enzimi androjenlerin östrojenlere dönüşümünde önemlidir. Aromataz testiste Leydig hücreleri, pakiten spermatositlerde ve yuvarlak spermatidlerde mevcuttur. TGFβ1, TNF-α ve TH gibi faktörlerin aromataz üzerine negatif etkisi olduğu gösterilmiştir. P450 aromataz eksikliği erkeklerde yüksek testosteron, infertilite, testiste küçülme ve testis ağırlığında azalma, ejakulasyonda azalma ve sperm hareketliliğinde azalma gibi bozukluklara yol açmaktadır. Serum östrojen seviyesinin artmasına bağlı olarak gelişen oligospermi gibi durumlarda ise östrojen inhibitörleri kullanarak testosteron seviyesinin arttığı görülmüştür. Bu derleme ile aromataz eksikliğinde erkek gonadlarda meydana gelen değişiklikler ve aromataz üzerinde etkili olan faktörler belirtilmiştir. Sonuç olarak, testiste ifade edilen aromatazın erkek gonad gelişimi ve spermatogenezis için önemli olduğu gösterilmiştir.

Anahtar Kelimeler

• Aromataz (CYP 19)
• İnfertilite
• Östrojen
• Testis

Kaynakça

1. 1. Carreau S, Lambard S, Delalande C, Denis-Galeraud I, Bilinska B, Bourguiba S. Aromatase expression and role of estrogens in male gonad : a review. Reproductive biology and endocrinology : RB&E. 2003;1:35.
2. 2. Levallet J, Bilinska B, Mittre H, Genissel C, Fresnel J, Carreau S. Expression and Immunolocalization of Functional Cytochrome P450 Aromatase in Mature Rat Testicular Cells1. Biology of Reproduction. 1998;58(4):919-26.
3. 3. Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S. Organization of the human aromatase p450 (CYP19) gene. Seminars in reproductive medicine. 2004;22(1):5-9.
4. 4. Bulun SE, Lin ZH, Imir G, Amin S, Demura M, Yilmaz B, et al. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: From bench to treatment. Pharmacological Reviews. 2005;57(3):359-83.
5. 5. Yıldırım AB. The effects of maternal hypothyroidism on the immunoreactivity of cytochrome p450 aromatase in the postnatal rat testes. 2015;Doctoral thesis.
6. 6. Papadopoulos V CS, Szerman-Joly E, Drosdowsky MA, Dehennin L, Scholler R. . Rat testis 17β-estradiol: identification by gas chromatography-mass spectrometry and age related cellular distribution. J Steroid Biochem 1986;24:1211-6.
7. 7. Lambard S, Silandre D, Delalande C, Denis-Galeraud I, Bourguiba S, Carreau S. Aromatase in testis: expression and role in male reproduction. The Journal of steroid biochemistry and molecular biology. 2005;95(1-5):63-9.
8. 8. Yildirim AB, Ozdamar S, Kaymak E. THE EFFECTS OF MATERNAL HYPOTHYROIDISM ON THE IMMUNOREACTIVITY OF CYTOCHROME P450 AROMATASE IN THE POSTNATAL RAT TESTICLES. Acta endocrinologica (Bucharest, Romania : 2005). 2017;13(1):7-16.

9. 9. Hess RA. Oestrogen in fluid transport in efferent ducts of the male reproductive tract. Reviews of reproduction. 2000;5(2):84-92.
10. 10. Grumbach MM, Auchus RJ. Commentary - Estrogen consequences and implications of human mutations in synthesis and action. Journal of Clinical Endocrinology & Metabolism. 1999;84(12):4677-94.
11. 11. Bourguiba S, Chater S, Delalande C, Benahmed M, Carreau S. Regulation of aromatase gene expression in purified germ cells of adult male rats: effects of transforming growth factor beta, tumor necrosis factor alpha, and cyclic adenosine 3',5'-monosphosphate. Biol Reprod. 2003;69(2):592-601.
12. 12. Bourguiba S, Lambard S, Carreau S. Steroids control the aromatase gene expression in purified germ cells from the adult male rat. Journal of molecular endocrinology. 2003;31(1):83-94.
13. 13. Mitrunen K, Hirvonen A. Molecular epidemiology of sporadic breast cancer - The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutation Research-Reviews in Mutation Research. 2003;544(1):9-41.
14. 14. Simpson ER, Davis SR. Minireview: Aromatase and the regulation of estrogen biosynthesis - Some new perspectives. Endocrinology. 2001;142(11):4589-94.
15. 15. Simpson ER, Zhao Y, Agarwal VR, Michael MD, Bulun SE, Hinshelwood MM, et al. Aromatase expression in health and disease. Recent Progress in Hormone Research, Proceedings of the 1996 Conference, Vol 52. 1997;52:185-214.
16. 16. Saunders PT, Sharpe RM, Williams K, Macpherson S, Urquart H, Irvine DS, et al. Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates. Molecular human reproduction. 2001;7(3):227-36.
17. 17. Scobie GA, Macpherson S, Millar MR, Groome NP, Romana PG, Saunders PT. Human oestrogen receptors: differential expression of ER alpha and beta and the identification of ER beta variants. Steroids. 2002;67(12):985-92.
18. 18. Chen Y, Bunick D, Bahr J, Klinefelter G, Hess R. Isolation and culture of epithelial cells from rat ductuli efferentes and initial segment epididymidis. Tissue and Cell. 1998;30(1):1-13.
19. 19. Fisher J, Millar M, Majdic G, Saunders P, Fraser H, Sharpe R. Immunolocalisation of oestrogen receptor-α within the testis and excurrent ducts of the rat and marmoset monkey from perinatal life to adulthood. Journal of Endocrinology. 1997;153(3):485-95.
20. 20. Hess RA, Gist DH, Bunick D, Lubahn DB, Farrell A, Bahr J, et al. Estrogen receptor (α and β) expression in the excurrent ducts of the adult male rat reproductive tract. Journal of andrology. 1997;18(6):602-11.
21. 21. O’donnell L, Robertson KM, Jones ME, Simpson ER. Estrogen and spermatogenesis. Endocrine reviews. 2001;22(3):289-318.
22. 22. Bulun SE. Aromatase and estrogen receptor alpha deficiency. Fertility and sterility. 2014;101(2):323-9.
23. 23. Deroo BJ, Korach KS. Estrogen receptors and human disease. The Journal of clinical investigation. 2006;116(3):561-70.
24. 24. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. The New England journal of medicine. 1994;331(16):1056-61.
25. 25. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. The New England journal of medicine. 1997;337(2):91-5.
26. 26. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. The Journal of clinical endocrinology and metabolism. 1995;80(12):3689-98.
27. 27. Grumbach MM. Aromatase deficiency and its consequences. Advances in experimental medicine and biology. 2011;707:19-22.
28. 28. Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C. Human models of aromatase deficiency. The Journal of steroid biochemistry and molecular biology. 2008;109(3-5):212-8.
29. 29. Kotula-Balak M, Bablok L, Fracki S, Jankowska A, Bilińska B. Immunoexpression of androgen receptors and aromatase in testes of patient with Klinefelter's syndrome. Folia histochemica et cytobiologica. 2004;42(4):215-20.
30. 30. Li X, Nokkala E, Yan W, Streng T, Saarinen N, Wärri A, et al. Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase. Endocrinology. 2001;142(6):2435-42.
31. 31. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A. History of aromatase: saga of an important biological mediator and therapeutic target. Endocrine reviews. 2009;30(4):343-75.
32. 32. Wit JM, Hero M, Nunez SB. Aromatase inhibitors in pediatrics. Nature Reviews Endocrinology. 2011;8(3):135-47.
33. 33. Seifert-Klauss V, Rabe T, Krämer A, Schneeweis A. Update on Aromatase Inhibitors. Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology. 2016;12(4):353-9.
34. 34. Miller WR, Dixon JM. Endocrine and clinical endpoints of exemestane as neoadjuvant therapy. Cancer control : journal of the Moffitt Cancer Center. 2002;9(2 Suppl):9-15.
35. 35. Pavlovich CP, King P, Goldstein M, Schlegel PN. Evidence of a treatable endocrinopathy in infertile men. The Journal of urology. 2001;165(3):837-41.
36. 36. Stephens SM, Polotsky AJ. Big enough for an aromatase inhibitor? How adiposity affects male fertility. Seminars in reproductive medicine. 2013;31(4):251-7.
37. 37. Santen RJ. Feedback control of luteinizing hormone and follicle-stimulating hormone secretion by testosterone and estradiol in men: physiological and clinical implications. Clinical biochemistry. 1981;14(5):243-51.
38. 38. Carreau S, Genissel C, Bilinska B, Levallet J. Sources of oestrogen in the testis and reproductive tract of the male. International journal of andrology. 1999;22(4):211-23.
39. 39. de Jong FH, Hey AH, van der Molen HJ. Effect of gonadotrophins on the secretion of oestradiol- and testosterone by the rat testis. The Journal of endocrinology. 1973;57(2):277-84.
40. 40. Carreau S, Wolczynski S, Galeraud-Denis I. Aromatase, oestrogens and human male reproduction. Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2010;365(1546):1571-9.
41. 41. Brodie A, Inkster S. Aromatase in the human testis. The Journal of steroid biochemistry and molecular biology. 1993;44(4-6):549-55.
42. 42. Matsumoto T, Honda S, Harada N. Alteration in sex-specific behaviors in male mice lacking the aromatase gene. Neuroendocrinology. 2003;77(6):416-24.
43. 43. Robertson KM, Simpson ER, Lacham-Kaplan O, Jones ME. Characterization of the fertility of male aromatase knockout mice. Journal of andrology. 2001;22(5):825-30.
44. 44. Carani C, Rochira V, Faustini-Fustini M, Balestrieri A, Granata AR. Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency. Clinical endocrinology. 1999;51(4):517-24.
45. 45. Herrmann BL, Saller B, Janssen OE, Gocke P, Bockisch A, Sperling H, et al. Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. The Journal of clinical endocrinology and metabolism. 2002;87(12):5476-84.
46. 46. Maffei L, Murata Y, Rochira V, Tubert G, Aranda C, Vazquez M, et al. Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. The Journal of clinical endocrinology and metabolism. 2004;89(1):61-70.
47. 47. Brooks DC, Coon VJ, Ercan CM, Xu X, Dong H, Levine JE, et al. Brain Aromatase and the Regulation of Sexual Activity in Male Mice. Endocrinology. 2020;161(10).
48. 48. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine reviews. 1994;15(3):342-55.
49. 49. Corbin CJ, Graham-Lorence S, McPhaul M, Mason JI, Mendelson CR, Simpson ER. Isolation of a full-length cDNA insert encoding human aromatase system cytochrome P-450 and its expression in nonsteroidogenic cells. Proceedings of the National Academy of Sciences of the United States of America. 1988;85(23):8948-52.
50. 50. Bois C, Delalande C, Nurmio M, Parvinen M, Zanatta L, Toppari J, et al. Age- and cell-related gene expression of aromatase and estrogen receptors in the rat testis. Journal of molecular endocrinology. 2010;45(3):147-59.
51. 51. Carreau S, Delalande C, Silandre D, Bourguiba S, Lambard S. Aromatase and estrogen receptors in male reproduction. Molecular and cellular endocrinology. 2006;246(1-2):65-8.
52. 52. Silandre D, Delalande C, Durand P, Carreau S. Three promoters PII, PI.f, and PI.tr direct the expression of aromatase (cyp19) gene in male rat germ cells. Journal of molecular endocrinology. 2007;39(2):169-81.
53. 53. Simpson ER, Zhao Y. Estrogen biosynthesis in adipose. Significance in breast cancer development. Annals of the New York Academy of Sciences. 1996;784:18-26.
54. 54. Haverfield JT, Ham S, Brown KA, Simpson ER, Meachem SJ. Teasing out the role of aromatase in the healthy and diseased testis. Spermatogenesis. 2011;1(3):240-9.
55. 55. Dorrington JH, Armstrong DT. Follicle-stimulating hormone stimulates estradiol-17beta synthesis in cultured Sertoli cells. Proceedings of the National Academy of Sciences of the United States of America. 1975;72(7):2677-81.
56. 56. Valladares LE, Payne AH. Induction of testicular aromatization by luteinizing hormone in mature rats. Endocrinology. 1979;105(2):431-6.
57. 57. Sirianni R, Chimento A, Malivindi R, Mazzitelli I, Andò S, Pezzi V. Insulin-like growth factor-I, regulating aromatase expression through steroidogenic factor 1, supports estrogen-dependent tumor Leydig cell proliferation. Cancer research. 2007;67(17):8368-77.
58. 58. Catalano S, Pezzi V, Chimento A, Giordano C, Carpino A, Young M, et al. Triiodothyronine Decreases the Activity of the Proximal Promoter (PII) of the Aromatase Gene in the Mouse Sertoli Cell Line, TM4. Molecular Endocrinology. 2003;17(5):923-34.
59. 59. Hatano O, Takayama K, Imai T, Waterman MR, Takakusu A, Omura T, et al. Sex-dependent expression of a transcription factor, Ad4BP, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development. Development (Cambridge, England). 1994;120(10):2787-97.
60. 60. Wang ZJ, Jeffs B, Ito M, Achermann JC, Yu RN, Hales DB, et al. Aromatase (Cyp19) Expression is up-Regulated by Targeted Disruption of Dax1. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(14):7988-93.
61. 61. Duliban M, Gorowska-Wojtowicz E. Interstitial Leydig Cell Tumorigenesis-Leptin and Adiponectin Signaling in Relation to Aromatase Expression in the Human Testis. 2020;21(10).
62. 62. Morais RD, Nóbrega RH, Gómez-González NE, Schmidt R, Bogerd J, França LR, et al. Thyroid hormone stimulates the proliferation of Sertoli cells and single type A spermatogonia in adult zebrafish (Danio rerio) testis. Endocrinology. 2013;154(11):4365-76.
63. 63. Nelson ER, Allan ER, Pang FY, Habibi HR. Thyroid hormone and reproduction: regulation of estrogen receptors in goldfish gonads. Molecular reproduction and development. 2010;77(9):784-94.