A Note from Neal- Webinar Series: Progesterone for Women Part 4- What You Must Document Before Prescribing Micronized Progesterone

by Neal Rouzier, MD

February 2024

Cancer Newsletter – University of Kansas Cancer Center 

A patient recently became concerned about an article that appeared last month in Cancer Newsletter from the University of Kansas Cancer Center that discussed the current research implicating that progesterone is associated with breast cancer. And last year a paper was published indicating that higher levels of progesterone were associated with an increase in breast cancer in menopausal women. The women were not taking progesterone, rather serum levels were tested in menopausal women not taking HRT. I found this hard to believe as once the ovaries shut down at menopause, levels of progesterone approach zero as production of progesterone (P4) ceases. If no P4 is produced by the ovaries, and the patients are not taking P4, then the levels being tested must be minuscule. Nevertheless, the paper and conclusions were worthless as it was a baseline association study which does not prove causation. However, to the casual reader or layperson, this implies that taking P4 may increase one’s risk of breast cancer.  Nothing could be further from the truth. So, now researchers are claiming that higher P4 levels are associated with increased breast cancer risk. The team of researchers from —claim that P4 is responsible for an increased risk, implying that higher levels of P4 are harmful and lower P4 levels are safer. 

Their Claim that P4 May be Responsible for an Increased Cancer Risk 

Kristi Hales, RPh. became concerned that a cancer research center is claiming and reporting that P4 may be responsible for an increased risk of cancer, so she calls them up to inquire about the research and literature to support this claim. This is of significant importance and consequences for those of us that prescribe P4 on a daily basis, as well as for the patients that take P4. What Kristi received as a reply was troublesome. The researchers could not provide any study or literature that showed P4 administration was harmful or that P4 caused cancer. What the researchers provided, not surprisingly, were baseline observation studies of women not on P4 that experienced an effect on some genes, but none were outcome studies or RCTs in women taking P4. In the last 3 webinars, I presented multiple studies and literature reviews proving a decrease in breast cancer risk and incidence with P4 administration.  

Publication – Nature Reviews Cancer 

Tinney, et. al., published in Nature Reviews Cancer the benefits of P4 in treating active breast cancer. If P4 is successfully utilized as a treatment for active breast cancer, how is it possible that some researchers claim that it causes breast cancer? How can these researchers ignore 20 years of data and research demonstrating the protective benefits of P4 in preventing breast cancer? After re-reading the newsletter and their references, their agenda finally dawned on me. What do cancer research centers do? They discover and market new drugs to protect against breast cancer. If estrogen blockers are so successful, then P4 blockers should also be beneficial. Researchers first must prove that P4 increases the risk, and that blocking the P4 receptor is beneficial.

Progesterone Receptor Blocker, Really!! 

In their newsletter, the researchers discuss the profound effect that estrogen blockers have on the treatment of breast cancer. They theorized, and hoped, that discovery and development of a new drug, a progesterone-receptor blocker, would prove effective and beneficial in treating active breast cancer, similar to AIs and tamoxifen. There is no drug (P4 receptor blocker) yet nor any outcome studies. However, we already have P4 receptor blockers called progestin’s. And we know the RR of those blockers for breast CA: MPA is 1.7 and norethindrone 2.1, whereas the RR for P4 averages 0.8. I guess those researchers don’t read cancer journals. I feel that spreading and publishing this misinformation will be misinterpreted by the lay public which will lead to patients stopping their P4, thinking that it could be harmful. Without any outcome RCTs to support their claims, this confusing and misleading misinformation should not be published.  

Association does not Prove Causation! 

As I have taught in every course, association does not prove causation, observation does not prove causation, and correlation does not prove causation. In almost all baseline studies in women, high levels of estradiol are associated with an increased risk of breast cancer, heart disease, and diabetes. However, in every RCT where estrogen (E2) is administered, there is a decrease in breast cancer, heart disease, and DM. In every baseline study in women (that probably have PCOS), higher levels of testosterone are associated with an increased risk of breast cancer, heart disease, and DM. However, when testosterone is administered, there is a decreased risk of breast cancer, heart disease, and DM. In every baseline study in men, higher levels of E2 are associated with an increased risk of CVD, cancer, and DM. However, in every study where we raise E2 with testosterone, or give E2 to men, there is a decrease in CVD, DM, and cancer.  What is observed at baseline is completely the opposite of what happens when we give the hormone. The same applies here. If a miniscule increase in P4 levels is associated with harm, we observe the opposite when P4 is administered to menopausal women. Medical literature states that there is no study proving harm upon administering P4. The average RR of breast cancer ranges from 0.8 to 1.0, depending on dosing. If baseline observation proves higher baseline levels are harmful, this observation should not be extrapolated to imply that P4 administration is harmful. Furthermore, this observation should not be extrapolated to imply that a P4 receptor blocker is indicated without substantiating evidence of benefit.   

For this webinar I will present a contrasting opinion that is evidence-based as opposed to their speculation without EBM support.  In the last several webinars on P4, I reviewed meta-analysis on P4, the many benefits, and lack of harm. Tinney’s research was reviewed demonstrating the apoptotic effect of P4 both in vitro and in vivo. In this webinar I will further discuss other outcome studies demonstrating the protective effects of P4 in addition to the mechanisms of action for cancer and CVD protection. Yes, I will forward a copy of this webinar to the cancer researchers that were the impetus for this webinar. As I am asked to review cases on a regular basis, this webinar will review the most up-to-date review of breast cancer and hormones that I use to refute any concern that P4 causes cancer.  

OBJECTIVES: 

1. Critique recent claims that P4 is causative of an increase in breast cancer incidence. 
2. Analyze the study claiming that P4 is associated with breast cancer. 
3. Discuss outcomes studies demonstrating breast cancer protection.  
4. Review the many mechanisms of action of P4 in protecting against breast cancer and CVD.  

CASE PRESENTATION:

Your 60 y/o patient requests an appointment to discuss her concern after she read a recent cancer newsletter that claimed progesterone is associated with an increase in breast cancer. The material that you had provided her in the hormone booklet states that micronized progesterone not only does not cause breast cancer but protects against breast cancer. Now she is concerned that the information you provided, as well as claims that P4 protect against breast cancer, are not true. She feels that she has been misled. It was her impression that BHRT was protective against breast cancer but that is not the viewpoint of her PMD. She feels that she has been misled and is considering stopping the hormone program out of fear of breast cancer that was further stoked by her PMD. She admits, how could a leading breast cancer research center be wrong, and you be right? 

You reassure her that BHRT does not increase the risk of breast cancer, wherein it is probably protective against breast cancer. You provide her with all the studies that have been reviewed in the webinars. You also provide her with the most current literature that contrasts the cancer-causing effects of progestins with the cancer-protective effects of P4. Now she is more confused as the medical literature definitively proves P4 protects against cancer which is the opposite claim of the cancer research center. She is content with your confidence and reassurance, particularly since you provided the scientific literature demonstrating the safety and efficacy of P4 in comparison to synthetic progestins. Although she doesn’t understand the concept that association does not prove causation, multiple studies and meta-analysis from peer reviewed journals prove the claims of these cancer center researchers wrong. In addition, your explanation and understanding of the literature and concepts help the patient better understand the controversy and misinformation. Despite what the PDR states, you provide evidence-based medical literature that refutes the risk claimed by the researchers that P4 causes cancer. The patient is pleased with the literature you provided to her, and she is content with your understanding and explanation. 

Respectfully,

Neal