This randomized phase III trial studies testosterone to see how well it works compared to placebo in treating postmenopausal patients with arthralgia (joint pain) caused by anastrozole or letrozole. Testosterone may help relieve moderate or severe arthralgia associated with the use of aromatase inhibitors, such as anastrozole or letrozole.

This is a randomized, placebo-controlled, phase III trial evaluating subcutaneous testosterone for the alleviation of aromatase inhibitor induced arthralgia. A parallel group design will be utilized for this two-arm study: subcutaneous testosterone vs. placebo. Patients are stratified according to baseline pain score (5-6 vs. 7-10) and age (< 50 vs. 50-60 vs. > 60). The primary objective is to determine whether testosterone will reduce AI-induced arthralgia and associated joint symptoms. The secondary objective is to explore whether testosterone will have an acceptable safety and tolerability profile, with particular reference to androgenic adverse events including acne, hirsutism, and alopecia.

Patients are followed up to six months as defined in the protocol.

Inclusion Criteria:

1. Age ≥ 18 years

2. Receiving anastrozole (1mg) or letrozole (2.5 mg) orally once a day, for ≥ 21 days prior to registration and plan to continue it throughout the duration of study

3. Body Mass Index (BMI) between 18 and 35 kg/m^2

4. Women who have undergone a total mastectomy or breast conserving surgery for primary breast cancer +/-chemo, +/-radiotherapy.

5. Must have BOTH ER and PR receptor-positive tumors and BOTH must be ≥26% positive. Alternatively, if ER and PR are determined by Allred score, the score needs to be 5 or higher

6. Women who are postmenopausal by surgery, radiotherapy or presence of natural amenorrhea ≥ 12 months

7. ≥ 5/10 arthralgia (in hands, wrist, knees, or hips) while being treated with anastrozole or letrozole which is felt by the patient to be caused by their aromatase inhibitor as defined in the protocol. Note: Patients may, or may not, be taking non-opioid analgesics

8. Ability to complete questionnaire(s) by themselves or with assistance

9. ECOG Performance Status (PS) 0, 1 or 2

10. Willing to provide informed written consent

11. Willing to return to an Alliance enrolling institution for follow-up

12. Willing to provide blood samples for correlative research purposes

13. Laboratory values prior to registration as defined in the protocol:

    1. Creatinine ≤1.5 x ULN
    2. Hemoglobin > 11 g/dL
    3. WBC > 3.0
    4. Platelet Count > 100,000
    5. SGOT (AST) ≤ 1.5 x ULN

Exclusion Criteria:

1. Presence of residual or recurrent cancer (locally or metastatic)
2. Diabetes mellitus or glucose intolerance, defined as a fasting glucose >125 mg/dL
3. History of coronary artery disease (angina or myocardial infarction)
4. Patients on hormone replacement therapy (HRT) ≤ 4 weeks prior to registration. This includes the use of vaginal estrogen therapy.
5. Known hypersensitivity to any component of testosterone.
6. Prolonged systemic corticosteroid treatment, except for topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airway diseases), eye drops or local insertion (e.g. intra-articular). Note: Short duration (< 2 weeks) of systemic corticosteroids is allowed (e.g. for chronic obstructive pulmonary disease) but not within 30 days prior to registration.
7. Receiving any other investigational agent
8. History of a deep venous thrombosis or a thromboembolism
9. Concurrent use of the aromatase inhibitor exemestane, as it is structurally similar to an androgen
10. Concurrent radiation therapy or chemotherapy
11. Current or planned use of cyclosporine, anticoagulants, oxphenbutazone, insulin, oral or injectable vitamin D doses over 4,000IU/day, or tamoxifen