Effects of testosterone treatment on clitoral haemodynamics in women with sexual dysfunction

S Cipriani, E Maseroli, V Di Stasi, I Scavello, T Todisco, G Rastrelli, M Fambrini, F Sorbi, F Petraglia, E A Jannini, M Maggi, L Vignozzi, S Cipriani, E Maseroli, V Di Stasi, I Scavello, T Todisco, G Rastrelli, M Fambrini, F Sorbi, F Petraglia, E A Jannini, M Maggi, L Vignozzi

Abstract

Purpose: To explore the effects of 6-month systemic testosterone (T) administration on clitoral color Doppler ultrasound (CDU) parameters in women with female sexual dysfunction (FSD).

Methods: 81 women with FSD were retrospectively recruited. Data on CDU parameters at baseline and after 6 months with four different treatments were available and thus further longitudinally analyzed: local non-hormonal moisturizers (NH group), n = 37; transdermal 2% T gel 300 mcg/day (T group), n = 23; local estrogens (E group), n = 12; combined therapy (T + E group), n = 9. Patients underwent physical, laboratory, and genital CDU examinations at both visits and completed different validated questionnaires, including the Female Sexual Function Index (FSFI).

Results: At 6-month visit, T therapy significantly increased clitoral artery peak systolic velocity (PSV) when compared to both NH (p < 0.0001) and E (p < 0.0001) groups. A similar increase was found in the T + E group (p = 0.039 vs. E). In addition, T treatment was associated with significantly higher FSFI desire, pain, arousal, lubrication, orgasm, and total scores at 6-month visit vs. baseline. Similar findings were observed in the T + E group. No significant differences in the variations of total and high-density lipoprotein-cholesterol, triglycerides, fasting glycemia, insulin and glycated hemoglobin levels were found among the four groups. No adverse events were observed.

Conclusion: In women complaining for FSD, systemic T administration, either alone or combined with local estrogens, was associated with a positive effect on clitoral blood flow and a clinical improvement in sexual function, showing a good safety profile.

Trial registration number: NCT04336891; date of registration: April 7, 2020.

Keywords: Clitoris; Female sexual dysfunction; Genital blood flow; Testosterone treatment in women; Treatment for female sexual dysfunction; Ultrasound.

Conflict of interest statement

The authors have no conflicts of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Total testosterone levels according to the mean frequency of sexual events in sexually active women treated for FSD. Data are expressed as box plot, with median score and interquartile range; whiskers represent minimum and maximum values. Data were adjusted for age and years since menopause
Fig. 2
Fig. 2
Effect of different treatments for female sexual dysfunction on clitoral artery PSV. Data are derived from multilevel mixed-effects linear regression. Results are reported as estimated PSV value and 95% confidence interval at baseline and at 6-month visit in the four treatment groups. Meaning of asterisks is reported in figure as inset. PSV peak systolic velocity, Non-H non-hormonal, T testosterone, E estrogens

References

    1. Clayton AH, Goldstein I, Kim NN, et al. The international Society for the Study of Women's Sexual Health process of care for management of hypoactive sexual desire disorder in women. Mayo Clin Proc. 2018;93(4):467–487.
    1. Simon JA, Goldstein I, Kim NN, et al. The role of androgens in the treatment of genitourinary syndrome of menopause (GSM): International Society for the Study of Women's Sexual Health (ISSWSH) expert consensus panel review. Menopause. 2018;25(7):837–847.
    1. Goldstein I, Kim NN, Clayton AH, et al. Hypoactive sexual desire disorder: International Society for the Study of Women's Sexual Health (ISSWSH) expert consensus panel review. Mayo Clin Proc. 2017;92(1):114–128.
    1. Portman DJ, Gass ML, Vulvovaginal Atrophy Terminology Consensus Conference Panel (2014) Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. J Sex Med 11(12):2865-72
    1. Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(10):3489–3510.
    1. Corona G, Rastrelli G, Filippi S, et al. Erectile dysfunction and central obesity: an Italian perspective. Asian J Androl. 2014;16(4):581–591.
    1. Davis S, Papalia MA, Norman RJ, et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial. Ann Intern Med. 2008;148(8):569–577.
    1. Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for peri and postmenopausal women. Cochrane Database Syst Rev. 2005;4:CD004509.
    1. Heard-Davison A, Heiman JR, 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;4:209–217.
    1. Tuiten A, Van Honk J, Koppeschaar H, et al. Time course of effects of testosterone administration on sexual arousal in women. Arch Gen Psychiatry. 2000;57:149–153.
    1. Shufelt C, Bretsky P, Almeida C, et al. DHEA-S levels and cardiovascular disease mortality in postmenopausal women: results from the National Institutes of Health-National Heart, Lung, and Blood Institute (NHLBI)-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) J Clin Endocrinol Metab. 2010;95(11):4985–4992.
    1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
    1. Isidori AM, Buvat J, Corona G, et al. A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment-a systematic review. Eur Urol. 2014;65(1):99–112.
    1. Morelli A, Filippi S, Zhang XH, et al. Peripheral regulatory mechanisms in erection. Int J Androl. 2005;28(Suppl 2):23–27.
    1. Vignozzi L, Filippi S, Comeglio P, et al. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit. Mol Cell Endocrinol. 2014;384(1–2):143–154.
    1. Efesoy O, Çayan S, Akbay E. The effect of testosterone replacement therapy on penile hemodynamics in hypogonadal men with erectile dysfunction, having veno-occlusive dysfunction. Am J Mens Health. 2018;12(3):634–638.
    1. Aversa A, Isidori AM, Spera G, et al. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf) 2003;58(5):632–638.
    1. Jones SL, Ismail N, Pfaus JG. Facilitation of sexual behavior in ovariectomized rats by estradiol and testosterone: a preclinical model of androgen effects on female sexual desire. Psychoneuroendocrinology. 2017;79:122–133.
    1. Maseroli E, Santangelo A, Lara-Fontes B, et al. The non-aromatizable androgen dihydrotestosterone (DHT) facilitates sexual behavior in ovariectomized female rats primed with estradiol. Psychoneuroendocrinology. 2020;115:104606.
    1. Comeglio P, Cellai I, Filippi S, et al. Differential effects of testosterone and estradiol on clitoral function: an experimental study in rats. J Sex Med. 2016;13(12):1858–1871.
    1. Parish SJ, Goldstein AT, Goldstein SW, et al. Toward a more evidence-based nosology and nomenclature for female sexual dysfunctions-Part II. J Sex Med. 2016;13(12):1888–1906.
    1. Maseroli E, Fanni E, Cipriani S, et al. Cardiometabolic risk and female sexuality: focus on clitoral vascular resistance. J Sex Med. 2016;13(11):1651–1661.
    1. Battaglia C, Battaglia B, Mancini F, et al. Sexual behavior and oral contraception: a pilot study. J Sex Med. 2012;9(2):550–557.
    1. Scavello I, Maseroli E, Di Stasi V, et al. Nomegestrol acetate/17beta-estradiol does not negatively alter the vascular resistance of clitoral arteries: a prospective, exploratory study. Int J Impot Res. 2020;32(2):239–247.
    1. Buisson O, Foldes P, Paniel BJ. Sonography of the clitoris. J Sex Med. 2008;5:413–417.
    1. Buisson O, Jannini EA. Pilot echographic study of the differences in clitoral involvement following clitoral or vaginal sexual stimulation. J Sex Med. 2013;10:2734–2740.
    1. Battaglia C, Battaglia B, Mancini F, et al. Moderate alcohol intake, genital vascularization, and sexuality in young, healthy, eumenorrheic women. a pilot study. J Sex Med. 2011;8:2334–2343.
    1. Gosling RG, King DH. Arterial assessment by Doppler-shift ultrasound. Proc R Soc Med. 1974;67:447–449.
    1. Grunewald C, Kublickas M, Nisell H, Nylund L, Westgren M. The interpretation of uterine artery pulsatility index in normal and hypertensive pregnancy. Ultrasound Obstet Gynecol. 1994;4:476–479.
    1. Poon LC, Volpe N, Muto B, et al. Second-trimester uterine artery Doppler in the prediction of stillbirths. Fetal Diagn Ther. 2013;33(1):28–35.
    1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285:2486–2497
    1. Maseroli E, Fanni E, Mannucci E, et al. Which are the male factors associated with female sexual dysfunction (FSD)? Andrology. 2016;4(5):911–920.
    1. Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000;26:191–208.
    1. Filocamo MT, Serati M, Li Marzi V, et al. The Female Sexual Function Index (FSFI): linguistic validation of the Italian version. J Sex Med. 2014;11:447–453.
    1. Crown S, Crisp AH. A short clinical diagnostic self-rating scale for psychoneurotic patients. The Middlesex Hospital Questionnaire (M.H.Q.) Br J Psychiatry. 1966;112:917–923.
    1. Cuzzolaro M, Vetrone G, Marano G, et al. The Body Uneasiness Test (BUT): development and validation of a new body image assessment scale. Eat Weight Disord. 2006;11:1–13.
    1. Park K, Goldstein I, Andry C, et al. Vasculogenic female sexual dysfunction: the hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency. Int J Impot Res. 1997;9:27–37.
    1. Rosato E, Gigante A, Barbano B, et al. Clitoral blood flow in systemic sclerosis women: correlation with disease clinical variables and female sexual dysfunction. Rheumatology. 2013;52(12):2238–2242.
    1. Maseroli E, Scavello I, Vignozzi L. Cardiometabolic risk and female sexuality-part II. Understanding (and overcoming) gender differences: the key role of an adequate methodological approach. Sex Med Rev. 2018;6(4):525–534.
    1. Dorfman RI, Shipley RA. Androgens: biochemistry, physiology and clinical significance. New York: Wiley; 1956. pp. 152–217.
    1. Jannini EA, Buisson O, Rubio-Casillas A. Beyond the G-spot: clitourethrovaginal complex anatomy in female orgasm. Nat Rev Urol. 2014;11(9):531–538.
    1. Breuer H. Androgen production in the woman. In: Hammerstein J, Lachnit-Fixson U, Neumann F, Plewig G, editors. Androgenization in Women. Princeton: Excerpta Medica; 1980. pp. 21–39.
    1. Nappi RE, Detaddei S, Ferdeghini F, et al. Role of testosterone in feminine sexuality. J Endocrinol Invest. 2003;26(3 Suppl):97–101.
    1. Traish AM, Vignozzi L, Simon JA, et al. Role of androgens in female genitourinary tissue structure and function: implications in the genitourinary syndrome of menopause. Sex Med Rev. 2018;6(4):558–571.
    1. Burnett AL, Calvin DC, Silver RI, et al. Immunohistochemical description of nitric oxide synthase isoforms in human clitoris. J Urol. 1997;158:75–78.
    1. Park JK, Kim JU, Lee SO, et al. Nitric oxide-cyclic GMP signaling pathway in the regulation of rabbit clitoral cavernosum tone. Exp Biol Med. 2002;227:1022–1030.
    1. Traish AM, Kim N, Min K, et al. Role of androgens in female genital sexual arousal: receptor expression, structure, and function. Fertil Steril. 2002;77(Suppl 4):S11–S18.
    1. D'Amati G, di Gioia CR, Bologna M, et al. Type 5 phosphodiesterase expression in the human vagina. Urology. 2002;60(1):191–195.
    1. Morelli A, Filippi S, Mancina R, et al (2004) Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa [published correction appears in Endocrinology 2004;145(7):3152] Endocrinology 145(5):2253–2263
    1. Carosa E, Rossi S, Giansante N, et al. The ontogenetic expression pattern of type 5 phosphodiesterase correlates with androgen receptor expression in rat corpora cavernosa. J Sex Med. 2009;6(2):388–396.
    1. Lawson CD, Burridge K. The on-off relationship of rho and Rac during integrin-mediated adhesion and cell migration. Small GTPases. 2014;5:27958.
    1. Tojkander S, Gateva G, Lappalainen P. Actin stress fibers–assembly, dynamics and biological roles. J Cell Sci. 2012;125(Pt 8):1855–1864.
    1. Maggi M, Filippi S, Ledda F, et al. Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. Eur J Endocrinol. 2000;143:143–154.
    1. Santoro N, Epperson CN, Mathews SB. Menopausal symptoms and their management. Endocrinol Metab Clin North Am. 2015;44(3):497–515.
    1. Martini M, Di Sante G, Collado P, et al. Androgen receptors are required for full masculinization of nitric oxide synthase system in rat limbic-hypothalamic region. Horm Behav. 2008;54(4):557–564.
    1. McCall-Hosenfeld JS, Freund KM, Legault C, et al. Sexual satisfaction and cardiovascular disease: the Women's Health Initiative. Am J Med. 2008;121(4):295–301.
    1. Tall JM, Stuesse SL, Cruce WL, Crisp T. Gender and the behavioral manifestations of neuropathic pain. Pharmacol Biochem Behav. 2001;68(1):99–104.
    1. Dina OA, Aley KO, Isenberg W, et al. Sex hormones regulate the contribution of PKCepsilon and PKA signalling in inflammatory pain in the rat. Eur J Neurosci. 2001;13:2227–2233.
    1. Calabrese D, Giatti S, Romano S, et al. Diabetic neuropathic pain: a role for testosterone metabolites. J Endocrinol. 2014;221(1):1–13.
    1. Maseroli E, Vignozzi L (2020) Testosterone and vaginal function. Sex Med Rev 17
    1. Islam RM, Bell RJ, Green S, et al. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019;S2213–8587(19):30189–30195.
    1. Daan NM, Jaspers L, Koster MP, et al. Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features. Hum Reprod. 2015;30:2376–2386.
    1. Meun C, Franco OH, Dhana K, et al. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam study. J Clin Endocrinol Metab. 2018;103(4):1622–1630.
    1. Barrett-Connor E, Goodman-Gruen D. Dehydroepiandrosterone sulfate does not predict cardiovascular death in postmenopausal women. The Rancho Bernardo Study. Circulation. 1995;91:1757–1760.
    1. Eftekhar T, Sohrabvand F, Zabandan N, et al. Sexual dysfunction in patients with polycystic ovary syndrome and its affected domains. Iran J Reprod Med. 2014;12(8):539–546.
    1. Cao ZT, Botelho JC, Rej R, Vesper H. Accuracy-based proficiency testing for testosterone measurements with immunoassays and liquid chromatography-mass spectrometry. Clin Chim Acta. 2017;469:31–36.
    1. Huhtaniemi IT, Tajar A, Lee DM, et al. Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. Eur J Endocrinol. 2012;166(6):983–991.
    1. Mollaioli D, Di Sante S, Limoncin E, et al. Validation of a Visual Analogue Scale to measure the subjective perception of orgasmic intensity in females: the Orgasmometer-F. PLoS ONE. 2018;13(8):e002076.
    1. Gravina GL, Brandetti F, Martini P, et al. Measurement of the thickness of the urethrovaginal space in women with or without vaginal orgasm. J Sex Med. 2008;5(3):610–618.
    1. Buisson O, Jannini EA. Pilot echographic study of the differences in clitoral involvement following clitoral or vaginal sexual stimulation. J Sex Med. 2013;10(11):2734–2740.
    1. Corona G, Mannucci E, Ricca V, et al. The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. Int J Androl. 2009;32(6):720–728.

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