The Myths and Facts of Hormone Replacement Therapy in Women
May 22, 2015

by Dr. Ashok Kadambi, MD, F.A.C.E. President – Fort Wayne Endocrinology

The purpose of this article is to set the record straight and clear up any misinformation about hormone replacement therapy in menopausal women.
Soon after the publication of the Women’s Health Initiative (WHI) study more than a decade ago, the medical world was taken by storm.

“Hormones increase the risk of cancer, heart disease, strokes and dementia” screamed the headlines in newspapers across the coun- try. Women stopped taking their hormones and the sales of Pre- marin and Prempro plummeted.

Premarin is a commonly prescribed estrogen for women who have had a hysterectomy whereas Prempro is widely prescribed as es- trogen replacement therapy in women with an intact uterus to pre- vent uterine bleeding while alleviating symptoms of menopause. The above two drugs ranked among the top 5 drugs prescribed in the US prior to the release of the details of the WHI study.

The medical establishment was equally confused and offered no real alternatives to alleviate the suffering of millions of women across the country.
The few alternatives that were offered ranged from “bite on a stick and deal with it” to “here is an antidepressant.”

The reason for the turmoil was that the WHI study concluded that the use of Prempro and Premarin for treatment of menopausal symptoms was associated with certain risks. I will attempt to ex- plain the extent of this risk more clearly in the next few paragraphs:

1. Premarin:
Premarin is a mixture estrogenic compounds and metabolites pro- cessed from the urine of pregnant mares and hence the oddly cre- ative name (PREgnant MARe’s urINe). The use of Premarin was associated with a slightly increased risk of stroke in women that started the hormone replacement after the age of 65 — on average 10 years after the onset of menopause.

2. Prempro:
Prempro is a combination pill containing Premarin plus Medroxy- progesterone acetate or Provera. To be sure Provera or Medroxy- progesterone acetate is NOT progesterone. Just how different are these two hormones? Progesterone is produced naturally by the ovaries. Provera is a synthetic alteration of perfectly good proges- terone and is not found in nature. Progesterone sustains pregnancy and is often used to prevent miscarriages, but Provera can cause miscarriages and birth defects. When Provera was added to Pre- marin as in Prempro, the risk of breast cancer increased signifi- cantly (nine times!) as also the risks for stroke, heart attacks, and dementia. The problem was not the estrogens but the introduction of Provera that increased those risks.
3. The logical conclusion then would be not to use Medroxypro- gesterone (Provera) in combination with Premarin for treatment of menopausal symptoms. Do not throw the baby out with the bath water and conclude that all hormones are bad and should be stopped.


Prempro exposes the human body to unnatural estrogens and pro- gestins such as equilin, which is known to increase the tendency of blood to clot. When taken by the oral route, the drug first passes through the liver, which is commonly known as the “first pass ef- fect.” The liver then converts the drug partially into estrogen me- tabolites such as 2-hydroxyestrogens (which protect against cancer risk) and 16-hydroxyestrogens (which can increase breast cancer risk). The proportion of these two estrogen metabolites then deter- mines the net increase or decrease in breast cancer risk.

Provera and Prempro reduce the formation of 2-hydroxyestro- gens which are protective against breast cancer by accelerating the natural programmed death of breast cancer cells. This is known in medical jargon as “apoptosis.”

The 16-hydroxyestrogens are known to interact with the estrogen receptor and cause proliferation of breast cancer cells. So one can only imagine the havoc caused by altering the ratio of these me- tabolites in women with other risk factors for breast cancer such as poor diet, lack of exercise and stress.

Incidentally, estradiol given as a topical cream does not alter the 2:16 ratio and in fact may increase it and tilt the balance in reduc- ing breast cancer risk. This is counter- intuitive, as most of us have been inundated with how hormones increase cancer risk.

Vitamin D can also increase this ratio, thereby reducing breast cancer risk so it would be prudent to keep VitD levels at the high end of optimal range for women on HRT.
It is the hormone metabolites that you make and not the hormones that you take that put you at increased risk of breast cancer. Provera and Prempro are also “prothrombotic and proinflamma- tory,” which is medical speak for increased risk for blood clots and inflammatory response that could predispose an woman for heart attacks and strokes as well as dementia and not to forget the gen- eral feeling of malaise and “brain fog” often voiced by women who take these prescriptions. Incidentally, all of these problems resolve when the women are switched over to a more natural form of HRT, which I will discuss later.

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