Androgen deficiency in women of different ages: diagnosis and treatment

1. Bachmann G., Bancroft J., Braunstein G., Burger H., Davis S., Dennerstein L. et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil. Steril. 2002; 77(4): 660-5. https://dx.doi.org/10.1016/s0015-0282(02)02969-2.
2. Abraham G.E. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J. Clin. Endocrinol. Metab. 1974; 39(2): 340-6.
3. Longcope C. Adrenal and gonadal androgen secretion in normal females. Clin. Endocrinol. Metab. 1986; 15(2): 213-28. https://dx.doi.org/10.1016/s0300-595x(86)80021-4.
4. Burger H.G. Androgen production in women. Fertil. Steril. 2002; 77(Suppl. 4): S3-5. https://dx.doi.org/10.1016/s0015-0282(02)02985-0.
5. Simpson E.R. Aromatization of androgens in women: current concepts and findings. Fertil. Steril. 2002; 77(Suppl. 4): S6-10. https://dx.doi.org/10.1016/s0015-0282(02)02984-9.
6. Luu-The V., Dufort I., Pelletier G., Labrie F. Type 5 17beta-hydroxysteroid dehydrogenase: its role in the formation of androgens in women. Mol. Cell. Endocrinol. 2001; 171(1-2): 77-82. https://dx.doi.org/10.1016/s0015-0282(02)02984-9.
7. Labrie F., Diamond P., Cusan L., Gomez J.L., Bélanger A., Candas B. Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. J. Clin. Endocrinol. Metab. 1997; 82(10): 3498-505. https://dx.doi.org/10.1210/jcem.82.10.4306.
8. Bachmann G., Oza D. Female androgen insufficiency. Obstet. Gynecol. Clin. North Am. 2006; 33(4): 589-98. https://dx.doi.org/10.1016/j.ogc.2006.09.001.
9. Davis S.R., Davison S.L., Donath S., Bell R.J. Circulating androgen levels and self-reported sexual function in women. JAMA. 2005; 294(1):91–6.
10. Wåhlin-Jacobsen S., Pedersen A.T., Kristensen E., Laessøe N.C., Lundqvist M., Cohen A.S. et al. Is there a correlation between androgens and sexual desire in women? J. Sex. Med. 2015; 12(2): 358-73. https://dx.doi.org/10.1111/jsm.12774.
11. Montoya-Botero P., Rodriguez-Purata J., Polyzos N.P. Androgen supplementation in assisted reproduction: where are we in 2019? Curr. Opin. Obstet. Gynecol. 2019; 31(3): 188-94. https://dx.doi.org/10.1097/GCO.0000000000000532.
12. Walters K.A., Rodriguez Paris V., Aflatounian A., Handelsman D.J. Androgens and ovarian function: translation from basic discovery research to clinical impact. J. Endocrinol. 2019; 242(2): R23-50. https://dx.doi.org/10.1530/JOE-19-0096.
13. Liu Y., Hu L., Fan L., Wang F. Efficacy of dehydroepiandrosterone (DHEA) supplementation for in vitro fertilization and embryo transfer cycles: a systematic review and meta-analysis. Gynecol. Endocrinol. 2018; 34(3): 178-83. https://dx.doi.org/10.1080/09513590.2017.1391202.
14. Zhang M., Niu W., Wang Y., Xu J., Bao X., Wang L. et al. Dehydroepiandrosterone treatment in women with poor ovarian response undergoing IVF or ICSI: a systematic review and meta-analysis. J. Assist. Reprod. Genet. 2016; 33(8): 981-91. https://dx.doi.org/10.1007/s10815-016-0713-5.
15. Nagels H.E., Rishworth J.R., Siristatidis C.S., Kroon B. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database Syst. Rev. 2015; (11): CD009749. https://dx.doi.org/10.1002/14651858.CD009749.pub2.
16. Longcope C. 1 Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab. 1986; 15(2):213–28.
17. Erickson G.F., Magoffin D.A., Dyer C.A., Hofeditz C. The ovarian androgen producing cells: a review of structure/function relationships. Endocr. Rev. 1985 Summer; 6(3): 371-99. https://dx.doi.org/10.1210/edrv-6-3-371.
18. Walters K.A., Handelsman D.J. Role of androgens in the ovary. Mol. Cell. Endocrinol. 2018; 465: 36-47. https://dx.doi.org/10.1016/j.mce.2017.06.026.
19. Ghayee H.K., Auchus R.J. Basic concepts and recent developments in human steroid hormone biosynthesis. Rev. Endocr. Metab. Disord. 2007; 8(4): 289-300. https://dx.doi.org/10.1007/s11154-007-9052-2.
20. Burger H.G. Androgen production in women. Fertil Steril. 2002; 77:3–5.
21. Quigley C.A., De Bellis A., Marschke K.B., El-Awady M.K., Wilson E.M., French F.S. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr. Rev. 1995; 16(3): 271-321. https://dx.doi.org/10.1210/edrv-16-3-271.
22. Lubahn D.B., Joseph D.R., Sullivan P.M., Willard H.F., French F.S., Wilson E.M. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science. 1988; 240(4850): 327-30. https://dx.doi.org/10.1126/science.3353727.
23. Antonarakis E.S., Lu C., Wang H., Luber B., Nakazawa M., Roeser J.C. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 2014; 371(11): 1028-38. https://dx.doi.org/10.1056/NEJMoa1315815.
24. Wang F., Pan J., Liu Y., Meng Q., Lv P., Qu F. et al. Alternative splicing of the androgen receptor in polycystic ovary syndrome. Proc. Natl. Acad. Sci. USA. 2015; 112(15): 4743-8. https://dx.doi.org/10.1073/pnas.1418216112.
25. Walters K., Handelsman D. Androgen receptor splice variants and polycystic ovary syndrome: cause or effect? Asian J. Androl. 2016; 18(3): 442. https://dx.doi.org/10.4103/1008-682X.161600.
26. Suzuki T., Sasano H., Kimura N., Tamura M., Fukaya T., Yajima A. et al. Physiology: Immunohistochemical distribution of progesterone, androgen and oestrogen receptors in the human ovary during the menstrual cycle: relationship to expression of steroidogenic enzymes. Hum. Reprod. 1994; 9(9): 1589-95. https://dx.doi.org/10.1093/oxfordjournals.humrep.a138757.
27. Nielsen M.E., Rasmussen I.A., Kristensen S.G., Christensen S.T., Mollgard K., Wreford Andersen E. et al. In human granulosa cells from small antral follicles, androgen receptor mRNA and androgen levels in follicular fluid correlate with FSH receptor mRNA. Mol. Hum. Reprod. 2011; 17(1): 63-70. https://dx.doi.org/10.1093/molehr/gaq073.
28. Rice S., Ojha K., Whitehead S., Mason H. Stage-specific expression of androgen receptor, follicle-stimulating hormone receptor, and Anti-Müllerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries. https://dx.doi.org/10.1210/jc.2006-1697.
29. Vendola K., Zhou J., Wang J., Famuyiwa O.A., Bievre M., Bondy C.A. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol. Reprod. 1999; 61(2): 353-7. https://dx.doi.org/10.1095/biolreprod61.2.353.
30. Murray A.A., Gosden R.G., Allison V., Spears N. Effect of androgens on the development of mouse follicles growing in vitro. J. Reprod. Fertil. 1998; 113(1): 27-33. https://dx.doi.org/10.1530/jrf.0.1130027.
31. Wang H., Andoh K., Hagiwara H., Xiaowei L., Kikuchi N., Abe Y. et al. Effect of adrenal and ovarian androgens on type 4 follicles unresponsive to FSH in immature mice. Endocrinology. 2001; 142(11): 4930-6. https://dx.doi.org/10.1210/endo.142.11.8482.
32. Vendola K.A., Zhou J., Adesanya O.O., Weil S.J., Bondy C.A. Androgens stimulate early stages of follicular growth in the primate ovary. J. Clin. Invest. 1998; 101(12): 2622-9. https://dx.doi.org/10.1172/JCI2081.
33. Ware V.C. The role of androgens in follicular development in the ovary. I. A quantitative analysis of oocyte ovulation. J. Exp. Zool. 1982; 222(2): 155-67. https://dx.doi.org/10.1002/jez.1402220207.
34. Alder E.M., Cook A., Davidson D., West C., Bancroft J. Hormones, mood and sexuality in lactating women. Br. J. Psychiatry. 1986; 148: 74-9. https://dx.doi.org/10.1192/bjp.148.1.74.
35. Appelt H., Strauss B. The psychoendocrinology of female sexuality. A research project. Ger. J. Psychol. 1986; 10: 143.
36. Randolph J.F., Zheng H., Avis N.E., Greendale G.A., Harlow S.D. Masturbation frequency and sexual function domains are associated with serum reproductive hormone levels across the menopausal transition. J. Clin. Endocrinol. Metab. 2015; 100(1): 258-66. https://dx.doi.org/10.1210/jc.2014-1725.
37. Archer J.S., Love-Geffen T.E., Herbst-Damm K.L., Swinney D.A., Chang J.R. Effect of estradiol versus estradiol and testosterone on brain-activation patterns in postmenopausal women. Menopause. 2006; 13(3): 528-37. https://dx.doi.org/10.1097/01.gme.0000188737.46746.cd.
38. Sarrel P.M. Androgen deficiency: menopause and estrogen-related factors. Fertil. Steril. 2002; 77(Suppl. 4): S63-7. https://dx.doi.org/10.1016/s0015-0282(02)02967-9.
39. Simon J.A. Estrogen replacement therapy: effects on the endogenous androgen milieu. Fertil. Steril. 2002; 77(Suppl. 4): S77-82. https://dx.doi.org/10.1016/s0015-0282(02)02986-2.
40. Qin J.C., Fan L., Qin A.P. The effect of dehydroepiandrosterone (DHEA) supplementation on women with diminished ovarian reserve (DOR) in IVF cycle: Evidence from a meta-analysis. J Gynecol Obstet Hum Reprod. 2017; 46(1):1–7.
41. González-Comadran M., Durán M., Solà I., Fábregues F., Carreras R., Checa M.A. Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and meta-analysis. Reprod. Biomed. Online. 2012; 25(5): 450-9. https://dx.doi.org/10.1016/j.rbmo.2012.07.011.
42. Arlt W., Callies F., van Vlijmen J.C., Koehler I., Reincke M., Bidlingmaier M. et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N. Engl. J. Med. 1999; 341(14): 1013-20. https://dx.doi.org/10.1056/NEJM199909303411401.
43. Alkatib A.A., Cosma M., Elamin M.B., Erickson D., Swiglo B.A., Erwin P.J. et al. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. J. Clin. Endocrinol. Metab. 2009; 94(10): 3676-81. https://dx.doi.org/10.1210/jc.20090672.
44. Peixoto C., Devicari Cheda J.N., Nardi A.E., Veras A.B., Cardoso A. The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review. Curr. Drug Targets. 2014; 15(9): 901-14. https://dx.doi.org/10.2174/1389450115666140717111116.
45. Castinetti F., Guignat L., Bouvattier C., Samara-Boustani D., Reznik Y. Group 4: Replacement therapy for adrenal insufficiency. Ann. Endocrinol. (Paris). 2017; 78(6): 525-34. https://dx.doi.org/10.1016/j.ando.2017.10.007.
46. North American Menopause Society. The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society. Menopause. 2005; 12(5): 496-511; quiz 649. https://dx.doi.org/10.1097/01.gme.0000177709.65944.b0.
47. Jayasena C.N., Alkaabi F.M., Liebers C.S., Handley T., Franks S., Dhillo W.S. A systematic review of randomized controlled trials investigating the efficacy and safety of testosterone therapy for female sexual dysfunction in postmenopausal women. Clin. Endocrinol. (Oxf). 2019; 90(3): 391-414. https://dx.doi.org/10.1111/cen.13906.
48. Buster J.E., Kingsberg S.A., Aguirre O., Brown C., Breaux J.G., Buch A. et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet. Gynecol. 2005; 105(5, Pt 1): 944-52. https://dx.doi.org/10.1097/01.AOG.0000158103.27672.0d.
49. Simon J., Braunstein G., Nachtigall L., Utian W., Katz M., Miller S. et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J. Clin. Endocrinol. Metab. 2005; 90(9): 5226-33. https://dx.doi.org/10.1210/jc.2004-1747.
50. Braunstein G.D., Sundwall D.A., Katz M., Shifren J.L., Buster J.E., Simon J.A. et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch. Intern. Med. 2005; 165(14): 1582-9. https://dx.doi.org/10.1001/archinte.165.14.1582.
51. Panay N., Al-Azzawi F., Bouchard C., Davis S.R., Eden J., Lodhi I. et al. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric. 2010; 13(2): 121-31. https://dx.doi.org/10.3109/13697131003675922.
52. Wierman M.E., Basson R., Davis S.R., Khosla S., Miller K.K., Rosner W. et al. Androgen therapy in women: an Endocrine Society Clinical Practice guideline. J. Clin. Endocrinol. Metab. 2006; 91(10): 3697-710. https://dx.doi.org/10.1210/jc.2006-1121.
53. Cухих Г.Т., Сметник В.П., Ильина Л.М., Юренева С.В., Коновалова В.Н.,Балан В.Е., Зайдиева Я.З., Марченко Л.А., Мельниченко Г.А., Азизян К.М., Ткачева О.Н. Практические рекомендации по применению заместительной гормональной терапии у женщин в пери- и постменопаузе. Ярославль: Литтера; 2009. 249 с. [Sukhikh G.T., Smetnik V.P., Ilyina L.M.,Yureneva S.V., Konovalova V.N., Balan V.E., Zaidieva Ya.Z., Marchenko L.A., Melnichenko G.A., Azizyan K.M., Tkacheva O.N. Practical recommendations for the use of hormone replacement therapy in peri- and postmenopausal women. Yaroslavl: Litter; 2009. 249 p.(in Russian)].
54. Raghunandan C., Agrawal S., Dubey P., Choudhury M., Jain A. A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women. J. Sex. Med. 2010; 7(3): 1284-90. https://dx.doi.org/10.1111/j.17436109.2009.01667.x.
55. Nathorst-Böös J., Flöter A., Jarkander-Rolff M., Carlström K., von Schoultz B. Treatment with percutanous testosterone gel in postmenopausal women with decreased libido--effects on sexuality and psychological general well-being. Maturitas. 2006; 53(1): 11-8. https://dx.doi.org/10.1016/j.maturitas.2005.01.002.
56. de Paula F.J.F., Soares J.M., Haidar M.A., de Lima G.R., Baracat E.C. The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms. Maturitas. 2007; 56(1): 69-7. https://dx.doi.org/10.1016/j.maturitas.2006.06.005.
57. Flöter A., Nathorst-Böös J., Carlström K., von Schoultz B. Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being. Climacteric. 2002; 5(4): 357-65.
58. Tungmunsakulchai R., Chaikittisilpa S., Snabboon T., Panyakhamlerd K., Jaisamrarn U., Taechakraichana N. Effectiveness of a low dose testosterone undecanoate to improve sexual function in postmenopausal women. BMC Womens Health. 2015; 15: 113. https://dx.doi.org/10.1186/s12905-015-0270-6.
59. Fernandes T., Costa-Paiva L.H., Pinto-Neto A.M. Efficacy of vaginally applied estrogen, testosterone, or polyacrylic acid on sexual function in postmenopausal women: a randomized controlled trial. J. Sex. Med. 2014; 11(5): 1262-70. https://dx.doi.org/10.1111/jsm.12473.
60. Shifren J.L., Davis S.R., Moreau M., Waldbaum A., Bouchard C., DeRogatis L. et al. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 Study. Menopause. 2006; 13(5): 770-9. https://dx.doi.org/10.1097/01.gme.0000243567.32828.99.
61. Noventa M., Vitagliano A., Andrisani A., Blaganje M., Viganò P., Papaelo E. et al. Testosterone therapy for women with poor ovarian response undergoing IVF: a meta-analysis of randomized controlled trials. J. Assist. Reprod. Genet. 2019; 36(4): 673-83. https://dx.doi.org/10.1007/s10815-018-1383-2.
62. Heard-Davison A., Heiman J.R., Kuffel S. Genital and subjective measurement of the time course effects of an acute dose of testosterone vs. placebo in postmenopausal women. J. Sex. Med. 2007; 4(1): 209-7. https://dx.doi.org/10.1111/j.1743-6109.2006.00406.x.
63. Myers L.S., Dixen J., Morrissette D., Carmichael M., Davidson J.M. Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. J. Clin. Endocrinol. Metab. 1990; 70(4): 1124-31. https://dx.doi.org/10.1210/jcem-70-4-1124.
64. Triantafyllidou O., Sigalos G., Vlahos N. Dehydroepiandrosterone (DHEA) supplementation and IVF outcome in poor responders. Hum. Fertil. (Camb). 2017; 20(2): 80-7. https://dx.doi.org/10.1080/14647273.2016.1262065.
65. Sun B., Wang F., Sun J., Yu W., Sun Y. Basal serum testosterone levels correlate with ovarian response but do not predict pregnancy outcome in non-PCOS women undergoing IVF. J. Assist. Reprod. Genet. 2014; 31(7): 829-35. https://dx.doi.org/10.1007/s10815-014-0246-8.

Received 18.11.2019

Accepted 29.11.2019