A large team of scientists have determined that unlike synthetic progestins which increase breast cancer risks, natural progesterone has the potential to slow the growth of many breast cancer tumors or even shrink them.

   It has long been known that tumors with estrogen receptors (ER) and progesterone receptors (PR) (ER/PR double positive) have the best clinical outcome, but the interplay between the two proteins has remained elusive. Both are transcription factors, which means they are both involved in switching genes on and off. In a study published in Nature, July 2015, researchers from prestigious institutions including the Cancer Research UK Cambridge Institute; University of Adelaide, Australia; University of Texas, Southwestern Medical Center at Dallas; and University of North Carolina at Chapel Hill explain why double positive breast cancer patients have the best chance of survival. The finding could benefit up to half of all breast cancer patients.

   Scientists know that when activated by most forms of estrogen - especially estradiol and its metabolites, estrogen receptors turn on genes within cancerous cells that program those cells to multiply rapidly and stay alive rather than die off as normal, healthy cells do. When activated by progesterone, progesterone receptors attach themselves to estrogen receptors. Once this happens, estrogen receptors stop turning on genes that promote the growth of the cancer cells. Instead, they turn on genes that promote the death of cancer cells (apoptosis) and stimulate the growth of healthy, normal cells.

   Jason Carroll and colleagues of Cancer Research UK's Cambridge Research Institute grew breast cancer cells that displayed both ER and PR in the laboratory, and made sure the cells had enough estrogen and progesterone to bind to the receptors. They found that the receptor bound to different regions of DNA depending on whether progesterone was present. In other words, the PR (that had bound to progesterone) was changing the genes that the ER was switching on or off. In addition, the researchers saw that progesterone was associated with slowing cancer cell growth.

   Following in vitro testing, the researchers ran tests on breast cancer tumors in live mice. After embedding ER positive/PR positive breast tumors in a number of mice, they exposed some of the mice to estrogen only, others to both estrogen and progesterone, and others to no hormones at all. After 25 days, the team found that while the tumors in the mice that received only estrogen grew, the tumors in the mice that received both estrogen and progesterone decreased in size.

   Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumor explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. These findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

   The researchers pointed out that only natural, bio-identical progesterone slows the growth of breast cancer. Conversely, synthetic progestins (molecularly altered forms of progesterone) have been shown to increase rather than decrease breast cancer risks.

   This is exciting news for women who are diagnosed with ER/PR positive breast cancers. If such women have healthy progesterone levels, or when progesterone levels are increased through natural progesterone supplementation, treatment outcomes may improve significantly. In their book What Your Doctor May Not Tell You About Breast Cancer, John R. Lee, M.D. and David Zava, Ph.D. noted that women with progesterone levels that are low relative to estrogen levels are more likely to get breast cancer and have poorer treatment outcomes. They concluded that estrogen dominance causes estrogen receptors to activate genes such as Bcl-2 that are known to promote the rapid growth of cancer cells. They theorized that chronic states of estrogen dominance contribute to high rates of breast cancer, and their theory has been validated with this latest research.

   Hormonal imbalances have reached epidemic proportions in most developed countries over the last several decades. Due to poor diets, lack of exercise, a rise in obesity levels, the widespread use of hormone-altering chemicals, and other factors, many women suffer from chronically higher than normal estrogen levels and much lower than normal progesterone levels.

References

   Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting > 25% of adults. Oral agents are frequently used for chronic pain treatment, but their use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, and systemic side effects. Several types of topical agents have been shown to be useful in the treatment of patients with chronic pain. In patients with hand and knee osteoarthritis (OA), the American College of Rheumatology favors topical agents for patients who have pre-existing gastrointestinal risk or are aged ≥ 75 years. Topical NSAIDs have been shown to provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients with knee OA. Topical NSAIDs have been shown to have a lower incidence of gastrointestinal complaints than oral formulations. In patients with neuropathic pain, topical formulations have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain, and in relieving patient pain due to complex regional pain syndrome. Data suggest that topical therapies may offer a well-tolerated alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain.

Postgrad Med. 2013 Jul;125(4 Suppl 1):25-33.

    After demonstrating that prazosin penetrated the skin barrier when mixed in LipodermŽ cream base, application of the cream to the forearm of 10 healthy participants demonstrated functional blockade of α1-adrenoceptors. Effects of the cream on sensitivity to mechanical and thermal stimulation were investigated in 14 healthy participants and 19 patients with CRPS (eight with an apparent adrenergic component of pain). Both in patients and controls, topical application of prazosin 1% cream increased sensitivity to skin cooling but reduced hyperalgesia to sharp stimulation and allodynia to brushing. Topical therapy uses smaller doses compared to oral medications, and can help to prevent systemic side-effects.

Eur J Pain. 2015 Nov 16.