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Sexual Health & Intimacy

Postmenopausal Androgen Therapy

Glenn D. Braunstein, MD; Deborah R. Cameron, RN

In 1941, Geist and Salmon¹ reviewed the use of testosterone (T) propionate in 422 women for treatment of menopausal symptoms, menome-trorrhagia, dysmenorrhea, premenstrual tension, ovulation pain, endometriosis, and mastopathies. This early use of an androgen was not for replacement due to a deficiency, but rather for its inhibitory effect on the action of estrogen, endometrial proliferation, and reactivity of the uterine wall. In addition, Greenblatt et al² reported an improvement in libido and well-being in women treated with methyltestosterone (MT) in 1950. Since that time, the effect of a variety of androgen therapies in androgen-deficient women has been noted in controlled studies using validated psychometric tools, relatively sensitive androgen assays, and bone densitometry.

These more recent studies have demonstrated significant effects from therapy in women using T or dehydroepiandrosterone (DHEA) on sexual function,^3-16 bone health,^5,9,17,18 mood,^4,6,19 energy/fatigue,^16,19,20 and well-being.^4,6,7,20 However, these studies were of short duration (ranging from 6 weeks to 2 years), and not all of the studies reported efficacy on these parameters. Nonetheless, these studies suggest a number of possible physiologic roles for androgens in women, and there are correlations between endogenous androgen levels in women and mood, sexual gratification, desire, arousal, initiation, libido, and frequency of sexual activity.^21-28 Studies have demonstrated an increase in serum androgen levels from low baseline values after administration of androgen preparations, although only a few of these studies—primarily those that used transdermal T or oral DHEA—have avoided supraphysiologic concentrations.^4,6,7 The Table compares dosages, routes, effects, and resultant serum hormone levels reported from several trials of T therapy in women.

Low androgen concentrations may be found in women with hypo-pituitarism,²⁹ adrenal insufficiency⁷ or adrenalectomy,³⁰ surgical meno-pause,³¹ and natural menopause/ advancing age.^5,32-34 However, not all women with androgen insufficiency become symptomatic. Still, it is reasonable to consider androgen therapy (AT) in women when symptoms are present, serum androgen levels are low or below normal, or if there is a history of a surgical or medical condition affecting the ovaries or adrenal glands.³⁵ In some women, regardless of the etiology of androgen insufficiency, the quality of life may be so adversely affected that AT may deserve serious consideration.

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Table. Results of Clinical Trials of Testosterone Therapy in Women

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ANDROGEN BIOSYNTHESIS

The true androgens are T and dihydrotestosterone (DHT), which may be directly secreted or converted from the androgen precursors androstenedione (A), DHEA, and dehydroepiandrosterone sulfate (DHEAS). Most true androgens in women are derived from DHEA and DHEAS by conversion in peripheral tissues. A variety of target tissues with the requisite enzymes may be the site of local androgen conversion (eg, adipose tissue, muscle, skin). This androgen may act locally as opposed to systemically, which is termed "intracrinology." Thus, serum measurements may not accurately reflect the true androgen status of the patient. Androgen activity depends on the production rate, metabolic clearance rate, androgen receptor binding in target tissues, and regulation of gene transcription. Serum androgens may be either unbound and biologically active or bound. The amount of bioavailable or free androgen depends on the amount and characteristic affinity of the binding protein. Sex hormone-binding globulin (SHBG) has a low capacity but high affinity for T, but has a low affinity for A, DHEA, and DHEAS.³⁵ The serum SHBG level is an important factor in androgen status, as T is tightly bound by SHBG, such that only approximately 1% of T and DHT circulates freely.³⁵ The amount of bioavailable T is equal to the amount the albumin-bound T, which is able to dissociate from the protein and enter cells, plus the free T component.

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ANDROGENS, ADVANCING AGE, AND NATURAL MENOPAUSE

Androgen status is affected to a greater degree by advancing age than by menopause. Dehydroepiandrosterone and DHEAS concentrations begin declining in the second decade of life, so that by 80 years of age serum levels are approximately 20% to 30% of peak levels.³³ One large, longitudinal study showed a 13% decline in mean DHEAS and a 46% decline in mean T levels between ages 42 and 50 years.³⁶ However, data are less clear with regard to androgen status during the menopausal transition. Another longitudinal study found no reduction in serum T levels from 4 years before to 2 years after the final menstrual period.³⁷ However, this study did find a decrease in SHBG levels, which resulted in an increase in the free androgen index (FAI)—ie, T/SHBG x 100.³⁷ Thus, the major determinant of FAI is SHBG. There is also increased aromatization with advancing age. Therefore, there is general agreement that low androgen levels are primarily age-related, such that a symptomatic older woman who is premenopausal or perimenopausal may require evaluation for androgen insufficiency.

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SURGICAL MENOPAUSE

Bilateral oophorectomy results in an approximate 50% decline in serum T and A concentrations.³¹ The Rancho Bernardo Study³⁴ reported that elderly postmenopausal women without their ovaries had total and bioavailable T levels that were more than 40% lower than those of their counterparts with intact ovaries. In addition, both surgically and naturally menopausal women may have an exacerbated androgen insufficiency if estrogen is administered orally and/or at high dosages, resulting in elevation of SHBG levels and subsequent increased binding of T.

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ESTROGEN THERAPY

Oral and excessive estrogen therapy (ET) increases SHBG levels, increasing binding of T and decreasing the amount of bioavailable T. A daily oral dose of 0.15 mg of conjugated equine estrogen may be sufficient to significantly increase serum SHBG values. An increase in SHBG has also been reported as an effect of advancing age.³⁴ Therefore, careful consideration should be given to the dose of estrogen and the use of transdermal estrogen, which does not raise serum SHBG levels.

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ANDROGEN INSUFFICIENCY

The signs of androgen insufficiency include loss of pubic hair, decreased lean body mass, and osteopenia or osteoporosis.³⁸ Symptoms of androgen insufficiency include fatigue, low libido, and decreased well-being.³⁸ Affected women may fulfill the criteria for hypoactive sexual desire disorder (HSDD), which is defined as a change in sexual function—ie, persistent or recurring deficiency (or absence) of sexual fantasies, thoughts, desire, and/or receptivity that causes personal distress.³⁹ A consensus conference concluded that it is reasonable to consider a menopausal woman to have androgen insufficiency if she has these signs and symptoms, and has free T levels or an FAI in the lowest quartile of the normal range or below the normal range for reproductive-aged women.⁴⁰

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Evaluation

Dehydroepiandrosterone and DHEAS values can be measured precisely. However, measurement and analysis of serum T levels in women is problematic due to the lack of assays with adequate sensitivity to the low T levels seen in women, lack of established normal ranges of T in women, and the influence of SHBG.^41,42 Evaluation of androgen status is further complicated by peripheral androgen biosynthesis/ intracrinology, which allows for androgen production, metabolism, and effect without entering the circulatory system for measurement. However, free T and bioavailable T are the best indicators of androgen status considering the potency, concentration, and clinical correlations with hyperandrogenic and hypoandrogenic states in women. Since androgen levels are low in women with hypopituitarism, adrenal insufficiency, or following oophorectomy, testosterone measurements add little additional useful information for managing women who develop a low libido following the development of one of these conditions. In such settings, one can give a therapeutic trial of testosterone without hormone measurements.

Measurement of serum SHBG levels to evaluate the possible effect of ET is important, especially with oral estrogen administration. If SHBG levels are elevated, consideration should be given to using trans-dermal ET to lower SHBG concentrations.⁶ However, adequate estrogenization is necessary to increase vaginal secretions and eliminate dyspareunia that may result in avoidance of sexual activity. Finally, SHBG levels may be increased and free T levels decreased in women with hyperthyroidism or cirrhosis, and in patients using certain anti-epileptic medications.^35,41

Other possible causes of hypoandrogenic symptoms such as depression, iron deficiency, hypothyroidism, anemia, and medication use (especially glucocorticoids) should be considered and evaluated. A therapeutic trial of AT should be considered for symptomatic androgen insufficiency in women after evaluation of free T, SHBG, ET, medications, alleviation of dyspareunia (if present), and other potential causes of symptoms.

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Therapy

At present, no androgen preparations have been specifically approved by the US Food and Drug Administration (FDA) for the treatment of HSDD or androgen insufficiency in women. Currently, the only FDA-approved T preparation(s) on the market for women is MT combined with esterified estrogen (EE); options include EE, 0.625 mg, plus MT, 1.25 mg, and EE, 1.25 mg, plus MT, 2.5 mg. These preparations are approved for the treatment of menopausal vasomotor symptoms unresponsive to estrogen alone.⁴³ Some studies comparing EE alone with EE plus MT have demonstrated that daily oral administration of the combined hormones when the MT component is 1.25 mg³ or 2.5 mg⁸ may significantly improve sexual function. Improvements in sexual function may be reported after 4 weeks,^3,8 with continued improvement reported through 16 weeks of therapy.³ Bone mineral density¹⁷ or bone formation markers¹⁸ also significantly increased with administration of oral EE plus MT daily compared with controls when the MT component was 2.5 mg. The efficacy and safety of T cream, patches, and implanted pellets has also been reported.^4,6,9 However, T cream requires the services of a compounding pharmacy, and T patches are currently in Phase III clinical trials and are not yet available on the market. Testosterone preparations formulated for men, who have serum T levels that are 10 to 20 times higher than women, should not be used in women.

Dehydroepiandrosterone has been used for AT in women with adrenal and androgen insufficiency.^5,7,19 In studies utilizing pharmaceutical-grade DHEA, doses above 30 mg/d may improve sexual function, although results from these trials are conflicting. Because DHEA is considered a dietary supplement by the FDA, it is available in health food and grocery stores, but over-the-counter preparations may lack consistent delivery of the stated amount of DHEA. A study found that some of these supplements may contain from 0% to approximately 150% of the stated amount of DHEA.⁴⁴

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Safety

To many clinicians, AT in women carries the potential for adverse effects including hirsutism, acne, deepening of the voice, alopecia, hepatic insult, polycythemia, sleep apnea, breast stimulation, and weight gain. These concerns are partly due to the effects observed from very high doses of androgens and anabolic steroids. However, such effects have not been observed in women who receive substantially lower doses of androgens for replacement therapy. Placebo- or estrogen-controlled studies in women of 1 month to 2 years in duration suggested that implanted, ingested, and applied T preparations are well tolerated, and demonstrated no serious side effects. The most common side effects are androgenic skin effects—acne and hirsutism. Avoidance of supraphysiologic serum T levels will help to minimize these unwanted effects. Among studies that replaced androgens to physiologic serum levels while avoiding supraphysiologic values,^4,6,7,18 acne was reported in 0% to 20% of subjects after 9 weeks to 4 months of treatment, while hirsutism occurred in 0% to 17%. Most facial hair growth was reported as light to medium. It should be noted that there were no significant changes in hirsutism or acne with treatment versus placebo in trials using a transdermal route of administration.^4,6 In addition, in a 2-year clinical trial in women comparing oral estrogen alone with combined estrogen and androgen in both high and low doses, there was no difference between groups at 24 months with regard to hirsutism using a modified Feriman-Gallwey scale.¹⁷ Reduction of high-density lipoprotein cholesterol levels is another potential adverse effect of oral AT through an effect on the liver.^3,7,18,45 However, this problem has not been observed with nonoral administration.^6,9,15,16 The use of AT in women with a history of breast cancer or any estrogen-dependent neoplasia is contraindicated due to the potential for aromatization to estrogen in target tissues.

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CONCLUSION

Women with hypopituitarism, adrenal insufficiency, adrenalectomy, or oophorectomy may become androgen deficient, and consideration of AT is important for women with alteration or removal of the organs of androgen production. However, premenopausal and naturally meno-pausal women may also become symptomatic due to age-related effects on the adrenals and the ovaries. Androgen insufficiency may severely impair the quality of a woman's life and cause great personal distress. As well, women's male partners now have longer life expectancies, and the proliferation in therapies to address male sexual function also has an impact on women's lives. Women now live approximately 33% of their lives after menopause, and quality of life for many includes the capacity to maintain and to enjoy a sexual relationship. Why some women and not others become symptomatic is unclear. However, the benefit derived by symptomatic, androgen-deficient women from AT is clear.

Androgen therapy for women with symptomatic androgen insufficiency has been utilized to a greater extent in the United Kingdom and Australia. Tibolone, which has estrogenic, progestational, and androgenic effects is utilized in Europe. In Australia, women are often treated with implanted T pellets. Whatever AT is used, patients should be monitored to avoid su-praphysiologic levels of androgens and observed for beneficial and adverse effects on a frequent basis.

Studies that have investigated AT in women have been short-term and contradictory. Data are difficult to interpret due to the lack of sensitivity of T assays and the complex nature of sexual relationships. Larger, longer-term studies will be required to determine safe, effective therapies for the increasing number of women who request treatment to improve sexual function and well-being.

Based on the evidence of current studies, it is reasonable to consider AT for a symptomatic, androgen-deficient woman. Any possible iatrogenic causes for the symptoms should be investigated, and evaluation of serum SHBG levels may be necessary to determine whether oral ET is producing elevated SHBG levels. If so, switching to transdermal ET may be warranted. Second, evaluation for hypothyroidism, depression, or relationship issues should be undertaken. But if other factors have been excluded, AT should be considered for women with hypopituitarism, adrenal insufficiency, adrenalectomy, oophorectomy, and natural menopause who are experiencing sexual dysfunction and diminished well-being.

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Glenn D. Braunstein, MD, is professor and chair, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif; and vice chair, David Geffen School of Medicine, University of California-Los Angeles. Deborah R. Cameron, RN, is research nurse, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, Calif.

Financial Disclosure
Glenn D. Braunstein, MD, reports that he is a principal investigator and consultant for studies conducted by Procter & Gamble Pharmaceuticals, Inc, on a transdermal matrix delivery system for testosterone in women.

References

1. Geist SH, Salmon UJ. Androgen therapy in gynecology. JAMA. 1941;117: 2207-2213.
2. Greenblatt RB, Barfield WE, Garner JF, Calk GL, Harrod JP Jr. Evaluation of an estrogen, androgen, estrogen-androgen combination, and a placebo in the treatment of the menopause. J Clin Endcrinol Metab. 1950;10(12): 1547-1558.
3. Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79(6):1341-1352.
4. Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause 2003;10(5):390-398.
5. Baulieu EE, Thomas G, Legrain S, et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge study to a sociobiomedical issue. Proc Natl Acad Sci USA. 2000;97(8):4279-4284.
6. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343(10):682-688.
7. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med. 1999;341(14):1013-1020.
8. Sarrel P, Dobay B, Wiita B. Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual behavior and neuroendocrine responses. J Reprod Med. 1998; 43(10):847-856.
9. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas. 1995; 21(3):227-236.
10. Sherwin BB, Gelfand MM. The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med. 1987; 49(4):397-409.
11. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med. 1985;47(4):339-351.
12. Braunstein G, Shifren J, Simon J, Lucas J, Rodenberg C, Watts N.Testosterone patches for the treatment of low sexual desire insurgically menopausal women. Menopause. 2003;10:587. 2003;10(5):390-398.
13. Simon JA, Nachtigal LE, Davis SR, Utian W, Lucas J, Braunstein G. Transdermal testosterone patch improves sexual activity and desire in surgically menopausal women. Obstet Gynecol. 2004; 103 (suppl):64S.
14. Buster J, Dingsberg S, Aguirre O, Brown C, Wekselman K, Casson P. Large phase III study confirms that transdermal testosterone patch 300 µg/day significantly improves sexual function with minimal side effects in surgically menopausal women. In: Program and abstracts of the 86th annual meeting of the Endocrine Society. June 16-19, 2004; New Orleans, La. Abstract OR44-6.
15. Burger H, Hailes J, Nelson J. Effect of combined implants of oestradiol and testosterone on libido in post-menopausal women. Br Med J (Clin Res Ed). 1987;294(6577):936-937.
16. Burger HG, Hailes J, Menelaus M, Nelson J, Hudson B, Balazs N. The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas. 1984;6(4):351-358.
17. Barrett-Connor E, Young R, Notelovitz M, et al. A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles. J Reprod Med. 1999;44(12):1012-1020.
18. Raisz LG, Wiita B, Artis A, et al. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab. 1996;81(1):37-43.
19. Hunt PJ, Gurnell EM, Huppert FA, et al. Improvement in mood and fatigue after dehydroepiandrosterone treatment in Addison's disease in a randomized double-blind trial. J Clin Endocrinol Metab. 2000;85(12):4650-4656.
20. Sherwin BB, Gelfand MM. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol. 1985;151(12):153-160.
21. Persky H, Lief HI, Strauss D, Miller WR, O'Brien CP. Plasma testosterone levels and sexual behavior of couples. Arch Sex Behav 1978;7(3):157-173.
22. Persky H, Dreisbach L, Miller WR, et al. The relation of plasma androgen levels to sexual behaviors and attitudes of women. Psychosom Med. 1982; 44(4):305-319.
23. McCoy NL, Davidson JM. A longitudinal study of the effects of menopause on sexuality. Maturitas 1985;7(3):203-210.
24. Morris NM, Udry JD, Khan-Dawood F, Dawood MY. Marital sexual frequency and midcycle female testosterone. Arch Sex Behav. 1987;16(1): 27-37.
25. Van Goozen SHM, Wiegant VM, Endert E, Helmond FA, Van de Poll NE. Psychoendocrinological assessment of the menstrual cycle: the relationship between hormones, sexuality, and mood. Arch Sex Behav. 1997; 26(4):359-382.
26. Riley A, Riley E. Controlled studies on women presenting with sexual drive disorder. I. Endocrine status. J Sex Marital Ther. 2000;26(3):269-283.
27. Myers LS, Dixen J, Morrissette D, Carmichael M, Davidson JM. Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. J Clin Endocrinol Metab. 1990;70(4): 1124-1131.
28. Dow MG, Hart DM, Forrest CA. Hormonal treatments of sexual unresponsiveness in postmenopausal women: a comparative study. Br J Obstet Gynaecol. 1983;90(4):361-366.
29. Miller KK, Sesmilo G, Schiller A, Schoenfeld D, Burton S, Klibanski A. Androgen deficiency in women with hypopituitarism. J Clin Endocrinol Metab. 2001;86(2):561-567.
30. Waxenberg SE, Drellich MG, Sutherland AM. The role of hormones in human behavior. I. Changes in female sexuality after adrenalectomy. J Clin Endocrinol Metab. 1959;19(2):193-202.
31. Judd HL, Lucas WE, Yen SS. Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol. 1974;118(6):793-798.
32. Zumoff B, Strain GW, Miller LK, Rosner W. Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab. 1995;80(4):1429-1430.
33. Labrie F, Belanger A, Cusan L, Gomez JL, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 1997;82(8): 2396-2402.
34. Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab. 2000; 85(2):645-651.
35. Vermeulen A. Plasma androgens in women. J Reprod Med. 1998;43(8 Suppl):725-733.
36. Lasley BL, Santoro N, Randolf JF, Gold EB, Crawford S, Weiss, G, et al. The relationship of circulating dehydroepiandrosterone, testosterone, and estradiol to stages of the menopausal transition and ethnicity. J Clin Endocrinol Metab. 2002;87(8):3760-3767.
37. Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab. 2000;85(8):2832-2838. 2000;7:1-6.
38. Braunstein GD. Androgen insufficiency in women: summary of critical issues. Fertil Steril. 2002;77(Suppl 4):S94-S99.
39. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV). Washington, DC: American Psychiatric Press; 1994: 539.
40. Bachmann G, Bancroft J, Braunstein G, et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril. 2002;77(4): 660-665.
41. Guay AT. Screening for androgen deficiency in women: methodological and interpretive issues. Fertil Steril. 2002; 77(Suppl 4):S83-S88.
42. Miller KK, Rosner W, Lee H, Hier J, Sesmilo G, Schoenfeld D, et al. Measurement of free testosterone in normal women and women with androgen deficiency: comparison of methods. J Clin Endocrinol Metab. 2004;89(2):525-533.
43. Phillips E, Bauman C. Safety surveillance of esterified estrogens methyltestosterone (Estratest and Estratest HS) replacement therapy in the United States. Clin Ther. 1997;19(5):1070-1084.
44. Parasrampuria J, Schwartz K, Petesch R. Quality control of dehydroepian-drosterone dietary supplement products. JAMA. 1998;280(18): 1565.
45. Watts NB, Notelovitz M, Timmons MC, Addison WA, Wiita B, Downey LJ. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol. 1995; 85(4):529-537.

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