Mammary Gland and Endometrial Effects of Testosterone in Combination with Oral Estradiol and Progesterone

Overview

Journal Menopause

Specialty Gynecology & Obstetrics

Date 2009 Mar 7

PMID 19265727

Citations 4

Authors

Charles E Wood

Cynthia J Lees

J Mark Cline

Affiliations

Soon will be listed here.

Abstract

Objective: The goal of this pilot study was to evaluate the effects of testosterone (T) cotherapy on mammary gland and endometrial measures in a postmenopausal primate model.

Methods: Twenty-five surgically postmenopausal cynomolgus monkeys were randomized by social group to receive daily treatment with (1) placebo, (2) oral micronized 17beta-estradiol (1 mg/d equivalent in women) + progesterone (200 mg/d equivalent in women) (E + P), or (3) E + P with T administered via subcutaneous pellets for 8 weeks at a high dose (15 mg) followed by 8 weeks at a low dose (1.5 mg) (E + P + T). The main outcome measures were breast and endometrial epithelial proliferation, as measured by Ki67/MIB1 immunolabeling.

Results: Intralobular breast proliferation did not differ significantly among groups after 8 weeks of treatment but was marginally higher (P = 0.03) in the E + P + T group after 16 weeks of treatment. No significant increase in proliferation was seen for E + P alone. Comparable changes in mammary gland markers of estrogen-receptor activity were seen for the E + P and E + P + T groups. In the endometrium, the addition of T did not increase endometrial glandular proliferation or estrogen-receptor activity or result in any distinct histologic changes.

Conclusions: The findings of this study do not support the idea that T antagonizes the effects of combined hormone therapy on breast proliferation or markers of estrogen-receptor activity. Overall, the short-term effects of T cotherapy on the mammary gland and endometrium were minimal.

Citing Articles

Selective androgen receptor modulators (SARMs) have specific impacts on the mouse uterus.

Simitsidellis I, Esnal-Zuffiaure A, Kelepouri O, OFlaherty E, Gibson D, Saunders P J Endocrinol. 2019; 242(3):227-239.

PMID: 31319382 PMC: 6690265. DOI: 10.1530/JOE-19-0153.

Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model.

Ethun K, Wood C, Cline J, Register T, Appt S, Clarkson T Menopause. 2013; 20(7):777-84.

PMID: 23793168 PMC: 3893023. DOI: 10.1097/GME.0b013e31827ce57a.

Endogenous and exogenous equol are antiestrogenic in reproductive tissues of apolipoprotein e-null mice.

Dewi F, Wood C, Lampe J, Hullar M, Franke A, Golden D J Nutr. 2012; 142(10):1829-35.

PMID: 22933749 PMC: 3442795. DOI: 10.3945/jn.112.161711.

Premenopausal serum androgens and breast cancer risk: a nested case-control study.

Zeleniuch-Jacquotte A, Afanasyeva Y, Kaaks R, Rinaldi S, Scarmo S, Liu M Breast Cancer Res. 2012; 14(1):R32.

PMID: 22339988 PMC: 3496150. DOI: 10.1186/bcr3117.

References

Hofling M, Linden Hirschberg A, Skoog L, Tani E, Hagerstrom T, von Schoultz B . Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women. Menopause. 2006; 14(2):183-90. DOI: 10.1097/01.gme.0000232033.92411.51. View

Zhou J, Ng S, Anderson K, Bondy C . Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J. 2000; 14(12):1725-30. DOI: 10.1096/fj.99-0863com. View

Hankinson S, Willett W, Manson J, Colditz G, Hunter D, Spiegelman D . Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1998; 90(17):1292-9. DOI: 10.1093/jnci/90.17.1292. View

Dorgan J, Longcope C, STEPHENSON Jr H, Falk R, Miller R, Franz C . Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1996; 5(7):533-9. View

Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin S . Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. 2003; 24(2):152-82. DOI: 10.1210/er.2001-0031. View

Wood C, Register T, Franke A, Anthony M, Cline J . Dietary soy isoflavones inhibit estrogen effects in the postmenopausal breast. Cancer Res. 2006; 66(2):1241-9. DOI: 10.1158/0008-5472.CAN-05-2067. View

. The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society. Menopause. 2005; 12(5):496-511. DOI: 10.1097/01.gme.0000177709.65944.b0. View

Cline J . Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors. Birth Defects Res B Dev Reprod Toxicol. 2007; 80(2):126-46. DOI: 10.1002/bdrb.20112. View

Cline J, Register T, Clarkson T . Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys. Menopause. 2002; 9(6):422-9. DOI: 10.1097/00042192-200211000-00007. View

10.

Missmer S, Eliassen A, Barbieri R, Hankinson S . Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst. 2004; 96(24):1856-65. DOI: 10.1093/jnci/djh336. View

11.

Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R . Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst. 1996; 88(5):291-6. DOI: 10.1093/jnci/88.5.291. View

12.

Ding E, Song Y, Manson J, Rifai N, Buring J, Liu S . Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia. 2007; 50(10):2076-84. DOI: 10.1007/s00125-007-0785-y. View

13.

Shively C, Wood C, Register T, Willard S, Lees C, Chen H . Hormone therapy effects on social behavior and activity levels of surgically postmenopausal cynomolgus monkeys. Psychoneuroendocrinology. 2007; 32(8-10):981-90. DOI: 10.1016/j.psyneuen.2007.07.002. View

14.

Stute P, Wood C, Kaplan J, Cline J . Cyclic changes in the mammary gland of cynomolgus macaques. Fertil Steril. 2004; 82 Suppl 3:1160-70. DOI: 10.1016/j.fertnstert.2004.04.035. View

15.

Hankinson S, Eliassen A . Endogenous estrogen, testosterone and progesterone levels in relation to breast cancer risk. J Steroid Biochem Mol Biol. 2007; 106(1-5):24-30. PMC: 2715949. DOI: 10.1016/j.jsbmb.2007.05.012. View

16.

Wood C, Register T, Lees C, Chen H, Kimrey S, Cline J . Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2006; 101(2):125-34. DOI: 10.1007/s10549-006-9276-y. View

17.

Tamimi R, Byrne C, Colditz G, Hankinson S . Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2007; 99(15):1178-87. DOI: 10.1093/jnci/djm062. View

18.

Cline J, Wood C . Hormonal effects on the mammary gland of postmenopausal nonhuman primates. Breast Dis. 2006; 24:59-70. DOI: 10.3233/bd-2006-24105. View

19.

Simpson E . Aromatization of androgens in women: current concepts and findings. Fertil Steril. 2002; 77 Suppl 4:S6-10. DOI: 10.1016/s0015-0282(02)02984-9. View

20.

Braunstein G . Safety of testosterone treatment in postmenopausal women. Fertil Steril. 2007; 88(1):1-17. DOI: 10.1016/j.fertnstert.2007.01.118. View