Testosterone Prevents and Treats Breast Cancer by Jeffrey Dach MD
Testosterone Prevents and Treats Breast Cancer by Jeffrey Dach MD
Peggy is a 44 year old interior designer from Idaho who arrived in my office to tell her story.
Header image: Ultrasound of Breast showing Spiculated Mass, typical for breast cancer. Courtesy of wikimedia commons .
Five years ago, Peggy felt a nodule in the right breast and brought it to medical attention. Image guided needle biopsy confirmed it was breast cancer, and Peggy underwent right lumpectomy. The pathology report showed infiltrating ductal carcinoma, an invasive cell type. Surgical margins were good, and no additional treatment was offered. Peggy did well for two years at which time she had a recurrence. The breast cancer returned with a new mass in the right breast and palpable nodes in the right axilla. In addition, CAT scan showed multiple metastatic nodules in the lungs. Her doctors offered her chemotherapy which Peggy declined. Instead she did her own research and found a doctor in Ohio, Rebecca Glaser MD, who treats breast cancer with testosterone. Peggy went to Dr. Glaser’s Clinic, and started Dr. Glaser’s protocol. A testosterone pellet was implanted, and letrozole started. Letrozole is an aromatase inhibitor drug which prevents conversion of testosterone to estrogen. Over time, the breast mass and axillary nodes gradually decreased in size and disappeared. A follow up CAT scan one year later showed the lungs were clear. Peggy was in complete remission from breast cancer using Dr. Rebecca Glaser’s testosterone/ letrozole protocol. I was impressed with this, as using testosterone for treatment of breast cancer was new to me.
In this newsletter, we will examine the medical literature on using testosterone as prevention and treatment for breast cancer, and secondly, discuss the benefits and adverse effects of testosterone for women, when combined routinely with estrogen and progesterone post-menopausal hormone replacement.
For Link to Orginal Version of this Article on my blog, CLICK HERE .
Testosterone: 39% Reduction in Breast Cancer
In 2013 and 2019, Drs. Rebecca Glaser,York and Constantine Dimitrakis studied the incidence of breast cancer in a 10-year prospective cohort study of 1,267 pre and postmenopausal women receiving at least two testosterone pellet insertions. The 10 year follow up data showed 39 percent reduction for invasive breast cancer in women treated with testosterone compared with the ‘‘age-matched’’ population. (1)
Second Study : Testosterone Prevents Breast Cancer
In 2021, Dr. Gary Donovitz conducted a retrospective observational study over 10 years of 2,377 pre- and post-menopausal women treated with Testosterone pellets, alone or combined with Estradiol. This study showed 35-50% reduction in the incidence of breast cancer for testosterone treated women, thus confirming the earlier findings of Dr. Rebecca Glaser.(1-2)
Case Reports of Treating Breast Cancer with T/AI pellets
In 2015, Drs. Rebecca Glaser, and Constantine Dimitrakakis wrote a case report of a female patient with palpable breast mass and axillary nodes. This was an infiltrating lobular, hormone receptor positive breast cancer (ER+, PR+, AR+). Baseline mammogram demonstrated the mass and axillary nodes (increased density in upper left image). Follow up mammogram (upper right image) 19 weeks after treatment with testosterone and aromatase inhibitor pellet, reveals significant reduction in tumor size and absence of previously palpable axillary lymph nodes. (regression of mammographic densities, upper right image). (4)
Above Image: Fig 3. from Glaser, R., and C. Dimitrakakis. “Testosterone and breast cancer prevention .” Maturitas 82.3 (2015): 291-295.
Second Case Report
In 2021, Dr. Rebecca Glaser wrote a case report of a 67 year old female with a large breast mas presenting with acute respiratory failure. CAT scan of the chest showed multiple metastatic nodules. Core biopsy showed the mass was invasive ductal carcinoma (ER+, estrogen receptor positive). The patient declined conventional treatment, surgery and chemotherapy. Instead she agreed to treatment with testosterone pellet with letrozole (aromatase inhibitor), which, fortunately, induced a favorable response with regression of disease. Dr. Rebecca Glaser writes:
The patient refused conventional therapy and was treated with T+letrozole pellet implants (320 mg T + 24 mg letrozole every 9 weeks). She also began a ‘‘whole food’’ low glycemic diet. One year later, CT scan …showed considerable improvement in the size and number of nodules throughout the lungs. The patient lost 13.6 kg… remains asymptomatic, and ‘‘feels amazing.’’ The large 8-cm breast mass has markedly decreased in size and axillary nodes are no longer palpable. (3)
Third Case Report
In 2021, Dr. Rebecca Glaser provided another case report of a 58 year old female with a large breast cancer mass fixed to the sternum. The patient declined conventional therapy with surgery or chemotherapy, and instead was treated with Testosterone and Letrozole combination pellets, with complete remission. After 14 weeks, the mass no longer palpable. Dr. Glaser writes:
FIG. 7. [shows a] Fifty-eight-year-old patient referred with large immobile breast cancer fixed to sternum. [The patient] refused conventional therapy. She was treated with Testosterone 180–240 mg +12 mg letrozole combination pellet implants at baseline, weeks 6, 14, and 26. She also implemented dietary changes…baseline [exam and clinical photograph], 6-cm tumor fixed to chest wall (sternum) UIQ R [Upper Inner Quadrant Right] breast, skin discoloration… Baseline ultrasound, tumor invading periosteum (sternum) and skin—[tumor is] too large to be measured (extends off screen)…[Follow Up Exam and Clinical Photograph] week 14, complete clinical response, mass no longer palpable… [Follow Up Ultrasound] week 26, complete response confirmed on ultrasound. Patient continues on T + A pellets and remains healthy and disease free at 2 years. (3) Fig 7.
Testosterone/AI pellet with Chemotherapy for Breast Cancer
In 2017, Dr. Rebecca Glaser reported a 51 year old female who developed breast cancer (ER +) while on testosterone pellet/AI?therapy. This is the first case report of concurrent use of testosterone/aromatase inhibitor during chemotherapy. Dr. Glaser writes:
JR is a 51-year-old postmenopausal patient, with a 30-year smoking history (1978-2008) followed on a prospective IRB trial examining the incidence of breast cancer in women treated with subcutaneous T implants. She began treatment with T implants in October of 2008 for symptoms of hormone deficiency. Since February of 2013, she occasionally received T in combination with a low dose (ie, 4 mg) of anastrozole combined in the implant for symptoms of excess estrogen including irritability, fluid retention, and weight gain….Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet…Ultrasound measurements demonstrated a 43% reduction in tumor volume (12.28 vs 6.96 cc) 41 days after the patient’s initial 180 mg Testosterone + 12 mg Letrozole subcutaneous implant therapy and dietary changes… This significant reduction in tumor volume occurred before the initiation of chemotherapy…after five cycles of chemotherapy, the tumor was no longer palpable on clinical examination and unable to be identified on ultrasound, that is, complete clinical response. Most significant, there was no residual invasive cancer at the time of definitive surgery, that is, complete pathologic response… (5) end quote
Note: AI=aromatase inhibitor drugs such as anastrozole, letrazole, exemestane, etc. This family of drugs inhibit the aromatase enzyme responsible for conversion of testosterone to estradiol. Breast fibroblast cells in vicinity of a breast cancer mass express high levels of aromatase which feeds estradiol into the cancer cells, serving as a growth factor for the cancer. Blocking the conversion of testosterone to estradiol with an AI (aromatase inhibitor) essentially turns off estrogen as a cancer growth factor and causes regression of the cancr mass.(11-17)
Innovative Treatment for Breast Cancer: Placement of Multiple Testosterone Implants at Tumor Site.
In 2014, Dr. Glaser writes a case report of a 90 year old female with a left breast mass discovered incidentally on CAT scan. Subsequent mammogram and ultrasound showed a deep 2.3 centimeter mass. Ultrasound guided core biopsy revealed infiltrating ductal carcinoma (estrogen receptor [ER]–positive, progesterone receptor [PR]–positive, AR-positive, and HER2-negative). The patient refused lumpectomy, and instead took 20 mg tamoxifen daily. After 4 months of tamoxifen a follow up ultrasound showed no change in the mass, still measuring 2.3 cm. The patient was then treated with three Testosterone/ Anastrazole(aromatase inhibitor) implants directly at the tumor site. Dr Glaser writes:
Through a 5-mm lateral incision, three compounded 60 mg T [testosterone] + 4 mg A [anastrozole] pellets were implanted into the breast tissue surrounding the tumor approximately 1 cm superior to, 1 cm inferior to, and anterior to the subareolar tumor through a disposable trocar (Fig. (Fig.1).1 ). Tamoxifen was discontinued…Follow-up examination of the left breast 2 weeks after intramammary T + A pellet implantation revealed a marked decrease in tumor size on physical examination and office US. The periareolar “thickening” was no longer palpable. By week 4, the patient’s (previously unreported) left breast pain had subsided… 46 days after intramammary T + A therapy, follow-up left breast mammogram and US…the tumor measured 1.6 × 1.1 × 0.8 cm… indicating a sevenfold reduction in tumor volume compared with 5.12 mL [at baseline]…Three additional implants (ie, total dose of 180 mg T + 12 mg A) were again placed peritumorally in the left breast on [day 48]…Follow-up mammogram …on week 13, …revealed that the size of the carcinoma had continued to decrease, measuring 1.5 × 0.8 × 0.6 cm on US,…[a] 12-fold reduction in tumor volume from the original measurement… In the future, this combination [Testosterone/AI] may have the potential for both systemic and local therapies for breast cancer in subgroups of patients, possibly eliminating surgical operation, radiation therapy, and adverse effects of oral medication.(8) end quote
see mammogram Fig 2.
Benefits and Risks of Testosterone for Post-Menopausal HRT
Breast Cancer Prevention Program
For the past 20 years in our office we use topical testosterone cream rather than implanted pellets to achieve a serum testosterone level of 80-160 ng/dl. As mentioned above, an important benefit of testosterone therapy is breast cancer prevention. However, there is more to a breast cancer prevention program.?Here are additional measures which are listed in my recently published book, Natural Thyroid Toolkit :
1) Iodine testing and iodine supplementation to optimize urinary iodine excretion (We typically use a 12.5 mg Iodoral tablet daily for all female patients on hormone replacement). (18-20)
2) DIM (Di-Indole Methane) is a breast cancer preventive agent. (21-22)
3) Optimize Vitamin D3 levels. (23)
4) Optimize selenium levels. (24-25)
5) Methyl-folate containing multivitamin to cover those patients with MTHFR mutation, and methylation defects. (26-27)
Health Benefits of Testosterone
Health benefits of testosterone for women are described in 2021 by Dr. Glaser, who writes:
T [Testosterone] has a profound effect on lean muscle mass, bone density, and confidence as well as sex drive and performance in both sexes…Adequate amounts of (local) bioavailable T [testosterone] at the AR [Androgen Receptor] are critical for overall health, immune function, and preventing inflammation, as well as cardiovascular, neurological, gastrointestinal, pulmonary, endocrine, breast, and genitourinary health…Thus, clinical indications for T therapy include many signs and symptoms caused by T deficiency (Table 1)…Unlike adipose tissue, which can contribute to the circulating pool of estrogens, E2 [estradiol] from local aromatization would not be measurable in serum. Therefore, similar to serum T levels, serum levels of E2 should be interpreted with caution and taken into context with clinical evaluation.(3) endquote
Clinical Signs and Symptoms of Androgen Deficiency
As mentioned above, rather than relying on serum hormone levels to initiate and monitor testosterone treatment. Dr. Glaser relies on clinical signs and symptoms of androgen deficiency, which are listed below. Dr. Glaser writes:
[Symptoms of androgen deficiency include] a diminished sense of well-being, Dysphoric mood, anxiety, and irritability, Fatigue, Decreased libido, sexual activity, and pleasure, Vasomotor instability, Bone loss, Decreased muscle strength, Insomnia, Changes in cognition and memory loss, Urinary symptoms and incontinence, Vaginal dryness and atrophy, Joint and muscular pain. (3) end quote
One may recognize the above list as identical for menopausal symptoms commonly associated with estrogen deficiency, all relieved by testosterone implant therapy, as discussed below.
Testosterone Implants Relieve Menopausal Symptoms
In 2011, Dr Glaser conducted a prospective study of 300 pre- and post menopausal women treated with testosterone pellet therapy for menopausal symptoms. No aromatase inhibitor was given to this cohort. Using a self reported questionairre, called the Menopause Rating scale, Dr. Glaser showed testosterone pellet therapy alone was sufficient for complete relief of menopausal symptoms. Supplemental estrogen was not needed nor administered. This is explained by Dr. Glaser writing:
Adequate levels of continuous testosterone, provided by the subcutaneous implant, most likely protect against estrogen deficiency thus explaining why testosterone alone is effective therapy in post-menopausal patients. In our clinical practice (not included in this cohort of 300 patients), an aromatase inhibitor is used in combination with testosterone when estrogen is contraindicated (i.e. breast cancer survivors). (6)
As mentioned above, for breast cancer survivors, an aromatase inhibitor (letrozole) is added to the compounded testosterone pellet formulation. This prevents conversion of testosterone to estrogen, rendering estradiol levels undetectable. A few of the oral aromatase inhibitors currently in clinical use include: Exemestane (Aromasin?), Anastrozole (Arimidex?), and Letrozole (Femara?). (15-17)
Testosterone/AI Treatment for Breast Cancer Survivors- No Breast Cancer Recurrence after 8 years of Follow Up
By 2014, Dr. Glaser had treated 1000 breast cancer survivors with Testosterone/ Aromatase Inhibitor pellet therapy. Of this group, 72 breast cancer survivors were included in a formal prospective study. This study showed no breast cancer recurrence after 8 years of follow up. (7)
Avoid Testosterone Blocker Drugs
Once it is understood that testosterone is breast cancer preventive, one then easily comes to the conclusion that interfering with the AR (androgen receptor) blocking the effect of testerone is a bad thing causing an increase in breast cancer risk. This explains the increased breast cancer with the use of MPA (medroxyprogesterone) demonstrated in the 2002 Women’s Health Initiative Study. Further studies showed that MPA (medroxyprogestreone) has anti-androgenic effects at the dose used, and interferes with the AR, androgen receptors. This explains the increased breast cancer incidence for women receiving MPA compared to placebo in the Women’s Health Initiative Study. Mortality from breast cancer was doubled in the MPA group compared to placebo.
At high dosage, MPA has androgenic effects and has actually been used to treat metastatic breast cancer with dramatic regression in some cases. At lower doses, MPA has an anti-androgen effect, blocks androgen receptors and increases the incidence of breast cancer.?(28-37)
Testosterone for Women: My Office Protocol
Inserting a testosterone pellet provides initial total testosterone serum levels of about 600 ng/dl immediately after pellet insertion, and this declines to about 100 ng/dl after 120 days (4 months) (Fig. 10)?(3)
In my office, rather than pellets, we use topical testosterone cream (12 mg per gram), providing a serum testosterone level of 80-160 ng/dl. In general, this testosterone dosage is well tolerated. Starting dosage is a quarter gram of cream which provides 3 mg of topical testosterone topically. A small amount of cream may be applied directly to the outer eyelids, and the remainder topically to the face around the eyes, rendering a cosmetic result. Testosterone application to the eyelid improves lubrication to the eye, and relieves dry eye syndrome. The eye is lubrication by oil from the meibomian glands at the base of the eye lashes in the eye lids, and these oil glands are controlled by testosterone. In 2003, this was reported by Dr. Charles Connor from the Southern College of Optometry, in Memphis Tennessee. A patent was granted in 2007. (9-10)
For more on Testosterone for Dry Eye Syndrome, see my previous newsletter on this topic .
Testosterone Excess Symptoms
Testosterone excess symptoms are fairly obvious and easy to recognize. These include acne and facial hair. If these symptoms occurs, the topical cream is stopped for 4-7 days. After about a week or so, symptoms have resolved, and the testosterone topical cream may be restarted at half dosage.
Our Complete Program
In addition to the testosterone cream, we also provide a second cream containing the Bi-Est (80% estradiol, 20% estriol) and progesterone combination cream. Starting formula is 50 mg/gram progesterone and 5 mg per gram Bi-Est. Usual starting?dosage is half gram topically twice a day. This may be titrated up for complete relief of menopausal symptoms, or titrated down for estrogen excess symptoms of breast enlargement and tenderness. A third component is a 100 mg progesterone capsule taken at bed time.
Conclusion: Thanks and credit goes to Dr. Rebecca Glaser and?Dr. Gary Donovitz for revealing the benefits of testosterone as breast cancer preventive, and for testosterone as treatment of breast cancer.?The assumption here is that topical testosterone provides the same breast cancer prevention as testosterone pellets. Although we have the two studies done by Drs. Glaser and Donovitz?with testosterone pellets showing 40-50% reduction in breast cancer, unfortunately, the same clinical studies for topical testosterone have not been done, and should be. However, in my opinion, even without this information, the benefits should be the same for topical testosterone as for the testosterone pellets.
Many of the benefits of topical testosterone can be readily observed, and the adverse effects as well. Occasionally, dosage is reduced because of adverse effects of excess testosterone. When comparing pellets to topical cream, one obvious advantage with topical cream is the ease of dosage adjustment. Simply take a few days off the topical cream, levels decline promptly, and restart after symptoms have resolved. Obviously, this can not be done with the pellets. It may take a few months for pellet levels to come back down.
Another benefit shown by Dr. Glaser’s group is that testosterone alone may provide complete relief from menopausal symptoms. This is useful in the post menopausal breast cancer survivor treated with combined testosterone and aromatase inhibitor pellet to block conversion to estrogen. Dr. Glaser’s study showed no breast cancer recurrence after 8 years of follow up when this protocol is used for breast cancer survivors.
Articles with related interest:
Iodine as Breast Cancer Prevention Part One
Iodine as Treatment for Breast Cancer Part Two
Jeffrey Dach MD
7450 Griffin Rd. Suite 180/190
Davie, Fl 33314
954-792-4663
Natural Thyroid Toolkit by Jeffrey Dach MD
Cracking Cancer Toolkit by Jeffrey Dach MD
Heart Book by Jeffrey Dach MD
References:
1) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study. ” BMC cancer 19 (2019): 1-10.
demonstrated reduced incidence of invasive breast cancer in T users by 39% compared with the ‘‘age-matched’’ population. Thus, the data in the contemporary literature suggest that TTh in women is unlikely associated with an increased risk of breast carcinoma. 10,12,43,71,74,78,81,84,86
2) Donovitz G., Cottoen M. Breast Cancer Incidence Reduction in Women Treated with Subcutaneous Testosterone: Testosterone Therapy and Breast Cancer Incidence Study . Eur. J. Breast Health. 2021;17:150–156.
3) Glaser, Rebecca, and Constantine Dimitrakakis. “Testosterone Implant Therapy in Women With and Without Breast Cancer: Rationale, Experience, Evidence. ” Clinical Research and Therapeutics 2.1 (2021): 94-110.
Many physicians are not aware that serum T levels are markedly (10- to more than 15-fold) higher than E2 levels throughout the female lifespan, barring pregnancy
Serum levels of T are not a valid marker of tissue exposure in women, reflecting <20% of the total androgen activity. Accordingly, serum T levels would not be expected to correlate with androgen deficiency symptoms or clinical conditions caused by androgen deficiency. 30 This concept is extremely important to comprehend. Serum T levels should not be relied on to diagnose T deficiency or manage T dosing in women.
It is well recognized that T has a profound effect on lean muscle mass, bone density, and confidence as well as sex drive and performance in both sexes.
It is important to recognize that there are active ARs located in every major organ system throughout the body.33–38 Adequate amounts of (local) bioavailable T at the AR are critical for overall health, immune function, and preventing inflammation, as well as cardiovascular, neurological, gastrointestinal, pulmonary, endocrine, breast, and genitourinary health (Supplementary Data S1). 32–42 Thus, clinical indications for T therapy include many signs and symptoms caused by T deficiency (Table 1).1,4
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Unlike adipose tissue, which can contribute to the circulating pool of estrogens, E2 from local aromatization would not be measurable in serum. 31,46,47 Therefore, similar to serum T levels, serum levels of E2 should be interpreted with caution and taken into context with clinical evaluation.
Table 1. Signs and Symptoms of Aging Related to Androgen Deficiency
A diminished sense of well-being
Dysphoric mood, anxiety, and irritability
Fatigue
Decreased libido, sexual activity, and pleasure
Vasomotor instability
Bone loss
Decreased muscle strength
Insomnia
Changes in cognition and memory loss
Urinary symptoms and incontinence
Vaginal dryness and atrophy
Joint and muscular pain
A 67-year-old female presented with acute respiratory failure. Baseline CT scan (left column) of the chest showed multiple noncalcified pulmonary nodules—bilateral and throughout the lungs—compatible with metastatic disease. Core biopsy (breast mass) revealed ER+ invasive ductal carcinoma. The patient
refused conventional therapy and was treated with T+letrozole pellet implants (320 mg T + 24 mg letrozole every 9 weeks). She also began a ‘‘whole food’’ low glycemic diet. One year later, CT scan (right column) showed considerable improvement in the size and number of nodules throughout the lungs. The patient lost 13.6 kg (note significant decrease in fatty tissue on CT), remains asymptomatic, and ‘‘feels amazing.’’ The large 8-cm breast mass has markedly decreased in size and axillary nodes are no longer palpable. CT, computed tomography; ER, estrogen receptor
4) Glaser, R., and C. Dimitrakakis. “Testosterone and breast cancer prevention. ” Maturitas 82.3 (2015): 291-295.
5) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications .” Menopause (New York, NY) 24.7 (2017): 859.
This is the first case report of the concurrent use of T combined with an AI during neoadjuvant chemotherapy.
A 51-year-old woman on testosterone replacement therapy was diagnosed with hormone receptor-positive invasive breast cancer. Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet. Clinical status was followed. Tumor response to “testosterone-letrozole” and subsequently, “testosterone-letrozole with chemotherapy” was monitored using serial ultrasounds and calculating tumor volume.
There was a 43% reduction in tumor volume 41 days after the insertion of testosterone-letrozole implants, before starting chemotherapy. After the initiation of concurrent chemotherapy, the tumor responded at an increased rate, resulting in a complete pathologic response. Chemotherapy was tolerated. Blood counts and weight remained stable. There were no neurologic or cardiac complications from the chemotherapy.
pellets containing 60 mg of T and 4 mg of letrozole (60 mg T + 4 mg L).
Ultrasound measurements demonstrated a 43% reduction in tumor volume (12.28 vs 6.96 cc) 41 days after the patient’s initial 180 mg T + 12 mg L subcutaneous implant therapy and dietary changes (Fig. (Fig.1).1 ). This significant reduction in tumor volume occurred before the initiation of chemotherapy…
after five cycles of chemotherapy, the tumor was no longer palpable on clinical examination and unable to be identified on ultrasound, that is, complete clinical response. Most significant, there was no residual invasive cancer at the time of definitive surgery, that is, complete pathologic response.
Subcutaneous T + L therapy in conjunction with a whole food, low (processed)-carbohydrate diet was beneficial in the neoadjuvant therapy of breast cancer. In addition, T + L did not interfere with chemotherapy, supporting preclinical and clinical data. The T + AI combination implant seems to be a promising therapy that has the potential to simultaneously treat breast cancer, prevent side effects of chemotherapy, and improve health and quality of life in breast cancer survivors.
6) Glaser, Rebecca, Anne E. York, and Constantine Dimitrakakis. “Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS).” Maturitas 68.4 (2011): 355-361.
7) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Efficacy of subcutaneous testosterone on menopausal symptoms in breast cancer survivors.” J Clin Oncol 32.Suppl 2 (2014): 109.
Over 1000 Testosterone + Anastrozole (T + A) pellet
insertions have been performed in breast cancer survivors
since 2006. Between April 2013 and May 2014, 72
patients had been enrolled in the study and were eligible
for analysis. T implant dosing is weight based3. Over 90% of patients were treated with 8 mg of A combined with T in the
implant. A lower dose of A (4 mg) is occasionally used in
smaller patients and/or patients with lesser or more remote
disease. A higher dose of A (12 mg) is occasionally used in
obese patients with advanced disease, or in the neo-
adjuvant setting*. Subcutaneous implants are inserted in
the gluteal or inguinal area** at 3-month intervals on
average. Therapeutic T levels were confirmed without
elevation of estradiol in any postmenopausal survivor.
There have been no cancer recurrences in up to 8 years
of therapy.
8) Glaser, Rebecca L., and Constantine Dimitrakakis. “Rapid response of breast cancer to neoadjuvant intramammary testosterone-anastrozole therapy: neoadjuvant hormone therapy in breast cancer.” Menopause (New York, NY) 21.6 (2014): 673.
9) Connor, C. G. “Treatment of dry eye with a transdermal 3% testosterone cream.” Investigative Ophthalmology & Visual Science 44.13 (2003): 2450-2450.
Patent WO2008070728A3 (Date: 2007-12-05)
Abstract The present invention comprises a composition and methods for treating eye conditions using a composition having a therapeutically effective amount of a progestagen, a therapeutically effective amount of a testosterone and pharmaceutically acceptable carrier, wherein the composition is applied to the palpebral part of the eye and/or ocular surface. Application filed by Southern College Of Optometry, Charles G Connor, Charles Haine
Aromatase in Breast Cancer Tissue
11) Bulun, S. E., et al. “Regulation of aromatase expression in breast cancer tissue.” Annals of the New York Academy of Sciences 1155.1 (2009): 121-131.
12) Kijima, Ikuko, Toru Itoh, and Shiuan Chen. “Growth inhibition of estrogen receptor-positive and aromatase-positive human breast cancer cells in monolayer and spheroid cultures by letrozole, anastrozole, and tamoxifen .” The Journal of steroid biochemistry and molecular biology 97.4 (2005): 360-368.
13) Mukhopadhyay, Keya De, et al. “Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells .” PloS one 10.4 (2015): e0121136.
In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.
14) Smith, Ian E., and Mitch Dowsett. “Aromatase inhibitors in breast cancer.” New England Journal of Medicine 348.24 (2003): 2431-2442.
15) Chumsri, Saranya, et al. “Aromatase, aromatase inhibitors, and breast cancer.” The Journal of steroid biochemistry and molecular biology 125.1-2 (2011): 13-22.
16) Fabian, Carol J. “The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer.” International journal of clinical practice 61.12 (2007): 2051-2063.
17) Narashimamurthy, J., A. Raghu Ram Rao, and G. Narahari Sastry. “Aromatase inhibitors: a new paradigm in breast cancer treatment.” Current Medicinal Chemistry-Anti-Cancer Agents 4.6 (2004): 523-534.
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18) Mendieta, Irasema, et al. “Molecular iodine exerts antineoplastic effects by diminishing proliferation and invasive potential and activating the immune response in mammary cancer xenografts.” BMC cancer 19.1 (2019): 1-12.
19) Moreno-Vega, Aura, et al. “Adjuvant effect of molecular iodine in conventional chemotherapy for breast cancer. randomized pilot study.” Nutrients 11.7 (2019): 1623.
20) Manjer, Jonas, Malte Sandsveden, and Signe Borgquist. “Serum Iodine and Breast Cancer Risk: A Prospective Nested Case-Control Study Stratified for Selenium Levels.” Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 29.7 (2020): 1335-1340.
21) Williams, David E. “Indoles derived from glucobrassicin: Cancer chemoprevention by indole-3-carbinol and 3, 3′-diindolylmethane.” Frontiers in Nutrition 8 (2021): 734334.
22) Amarakoon, Darshika, et al. “Indole-3-Carbinol: Occurrence, Health-Beneficial Properties, and Cellular/Molecular Mechanisms.” Annual Review of Food Science and Technology 14 (2023): 347-366.
23) Benarba, Bachir, and Adel Gouri. “Role of vitamin D in breast cancer prevention and therapy: Recent findings.” Journal of Medicine 21.1 (2020): 46.
24) Szwiec, Marek, et al. “Serum selenium level predicts 10-year survival after breast cancer.” Nutrients 13.3 (2021): 953.
25) Kim, Seung Jo, et al. “Antitumor effects of selenium.” International Journal of Molecular Sciences 22.21 (2021): 11844.
26) Li, Zhen, et al. “The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism is associated with breast cancer subtype susceptibility in southwestern China.” Plos one 16.7 (2021): e0254267.
27) Omran, Moataza H., et al. “Strong Correlation of MTHFR Gene Polymorphisms with Breast Cancer and its Prognostic Clinical Factors among Egyptian Females.” Asian Pacific Journal of Cancer Prevention: APJCP 22.2 (2021): 617.
28) Chlebowski, Rowan T., et al. “Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.” Jama 304.15 (2010): 1684-1692.
29) Birrell, Stephen N., et al. “Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer.” The FASEB Journal 21.10 (2007): 2285-2293.
There is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT.
We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.—
Medroxyprogesterone Inhibits via Androgen Receptor
30) Hackenberg, Reinhard, et al. “Medroxyprogesterone acetate inhibits the proliferation of estrogen-and progesterone-receptor negative MFM-223 human mammary cancer cells via the androgen receptor.” Breast cancer research and treatment 25 (1993): 217-224.
31) Bentel, Jacqueline M., et al. “Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells .” Molecular and cellular endocrinology 154.1-2 (1999): 11-20.
32) Dran, G., et al. “Effect of medroxyprogesterone acetate (MPA) and serum factors on cell proliferation in primary cultures of an MPA-induced mammary adenocarcinoma. ” Breast cancer research and treatment 35.2 (1995): 173-186.
33) Zaucha, R., K. Sosińska-Mielcarek, and J. Jassem. “Long-term survival of a patient with primarily chemo-resistant metastatic breast cancer treated with medroxyprogesterone acetate. ” The Breast 13.4 (2004): 321-324.
The prognosis of breast cancer patients with liver metastases is extremely poor. Here we present the case of a 66-year-old female breast cancer patient with multiple liver metastases diagnosed 2 years after a radical modified mastectomy followed by adjuvant tamoxifen. At progression, anthracycline-based chemotherapy was administered, but a CT scan following two cycles of FEC (5-fluorouracil, epirubicin, cyclophosphamide) showed progression of the liver metastases. Chemotherapy was therefore switched to medroxyprogesterone acetate (MPA). After 3 months the patient’s general status improved, and disease stabilization was observed at the next CT scan. A further 4 months of MPA treatment resulted in complete response of all liver lesions. Treatment with oral MPA was continued for 4 years. At present, 11 years after the diagnosis of metastatic liver involvement, the patient is alive, free of cancer, and fully ambulatory. Despite bulky visceral disease and chemoresistance, hormonal treatment with MPA resulted in a spectacular and long-lasting response.
34) Buchanan, Grant, et al. “Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate. ” Cancer research 65.18 (2005): 8487-8496.
35) Poulin, R., et al. “Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells .” Breast cancer research and treatment 13.2 (1989): 161-172.
Medroxyprogesterone acetate (MPA) is a synthetic progestin, currently used in the adjuvant treatment of advanced breast cancer, which induces remission rates (30-40%) comparable to those obtained with other types of endocrine therapies. Since, in addition to its progestin-like action, MPA exhibits androgen- and glucocorticoid-like activities in other tissues, the present study was designed to assess the relative contribution of the different steroid receptor systems in the direct action of MPA on breast cancer cell growth, using the ZR-75-1 human mammary carcinoma cell line as an in vitro model. Unlike pure progestins, MPA potently inhibited the proliferation of ZR-75-1 cells in a concentration-dependent manner either in the presence or in the absence of estrogens, and the addition of insulin had only marginal effects on its growth-inhibitory activity. On the other hand, both hydroxyflutamide (OHF, a non-steroidal monospecific antiandrogen) and RU486 (a potent antiglucocorticoid and antiprogestin also endowed with antiandrogenic activity) competitively reversed MPA antiproliferative effects. MPA further decreased the growth of ZR-75-1 cells co-incubated with maximally inhibitory concentrations of either 5 alpha-dihydrotestosterone (DHT) or dexamethasone (DEX), although at about 300-fold higher MPA concentrations with DHT-treated than with DEX-treated ZR-75-1 cells, thus demonstrating a highly predominant androgenic effect. However, MPA had no effect on the growth of ZR-75-1 cells co-incubated with DHT and DEX simultaneously, thus supporting the predominant role of androgen and glucocorticoid receptors in MPA action. A 12-day preincubation of ZR-75-1 cells with increasing concentrations of MPA (10(-12) to 3 x 10(-6)M) decreased the specific uptake of [3H]estradiol (E2) by intact cell monolayers to the same extent as 10 nM DHT, an effect which was competitively blocked by the addition of OHF (3 microM). MPA action on ZR-75-1 cell growth also significantly differed from that of progestins in being additive to the inhibition of E2-stimulated growth by the steroidal antiestrogen ICI164384. The present data indicate that the main action of MPA on ZR-75-1 human breast cancer cell growth is due to its androgen receptor-mediated inhibitory action, while its glucocorticoid-like activity could play an additional role at high concentrations.
Anti-Androgen Action of MPA in normal breast tissue- POST MENOPAUSAL WOMEN
36) Ochnik, Aleksandra M., et al. “Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo .” Menopause 21.1 (2014): 79-88.
Objective: Medroxyprogesterone acetate (MPA), a component of combined estrogen-progestin therapy (EPT), has been associated with increased breast cancer risk in EPT users. MPA can bind to the androgen receptor (AR), and AR signaling inhibits cell growth in breast tissues. Therefore, the aim of this study was to investigate the potential of MPA to disrupt AR signaling in an ex vivo culture model of normal human breast tissue.
Methods: Histologically normal breast tissues from women undergoing breast surgical operation were cultured in the presence or in the absence of the native AR ligand 5α-dihydrotestosterone (DHT), MPA, or the AR antagonist bicalutamide. Ki67, bromodeoxyuridine, B-cell CLL/lymphoma 2 (BCL2), AR, estrogen receptor α, and progesterone receptor were detected by immunohistochemistry.
Results: DHT inhibited the proliferation of breast epithelial cells in an AR-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. These hormonal responses were not commonly observed in cultured tissues from premenopausal women. In tissues from postmenopausal women, DHT either induced or repressed BCL2 expression, and the antiandrogenic effect of MPA on BCL2 was variable. MPA significantly opposed the positive effect of DHT on AR stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels.
Conclusions: In a subset of postmenopausal women, MPA exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT.
37) Ochnik, Aleksandra Monica. The molecular actions of medroxyprogesterone acetate on androgen receptor signalling and the promotion of breast cancer. Diss. 2012. (Doctoral dissertation).
Using the ex vivo breast explant tissue model, I have demonstrated that MPA [medroxyprogesterone] impedes DHT [dihydrotestosterone]-induced AR [androgen receptor]-signalling in post-menopausal non-malignant human breast epithelial cells. Importantly, these studies have established a potential biological link between the effects of MPA [medroxyprogesterone] promoting increased breast epithelial proliferation in post-menopausal women taking cHRT [estrogen/MPA] by the disruption of the DHT [dihydrotestosterone]-induced AR [androgen receptor]-signalling.
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