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What is physiologic hormone replacement therapy (P-HRT)?

P-HRT and Estradiol Deficiency
If you have POI, P-HRT can help.

A prolonged deficiency of estradiol has potentially deadly consequences for women. The evidence supports replacing the missing estradiol in a physiologic manner, which means mimicking how the ovaries naturally provide this hormone. One way to restore the normal ovarian hormone levels is physiologic hormone replacement therapy (P-HRT). As with any treatment, it’s important to understand both the benefits and risks, and that the relationship between POI and P-HRT is sometimes misunderstood. 

It should be noted that cardiovascular disease (CVD) is the leading cause of death in women. Both age and estradiol deficiency with the menopausal transition independently increase a woman’s risk of CVD. Also of note is that women with early menopause (before the age of 45) have an increased risk for death from coronary heart disease, as well as a 12 percent higher risk of all-cause mortality compared with women who experience menopause after age 45.

In particular, women with primary ovarian insufficiency (POI) are at increased risk of several long-term health complications, including osteoporosis, fractures, depression, anxiety, and cognitive decline. Additionally, women with POI are at increased risk of developing ischemic heart disease (hazard ratio 1.69) and total CVD (hazard ratio 1.61) compared with healthy control women.  

That said, the elevated CVD risk among women with POI is primarily due to estradiol (E) deficiency. In naturally menopausal women and surgically induced menopause, hormone therapy with estrogen reduces the risk of CVD.

Click here to found out more about POI.

Understanding Ovarian Hormones

The major hormones produced by the ovary are:

  • Estradiol (an estrogen) 
  • Progesterone (a progestin) 
  • Testosterone (an androgen)

The National Institutes of Health (NIH) study of P-HRT in primary ovarian insufficiency (POI) used transdermal estradiol (100 ug/day) as the estrogen and oral medroxyprogesterone acetate (10mg/day for 12 days/month) as the progestin. The weight of the published evidence to date suggests this should be the first line approach to P-HRT in women with POI. 

  • Progestogens are hormones that have an effect similar to the hormone progesterone. Progesterone is produced by the ovary after ovulation has taken place, which most commonly happens on day 14 of a normal 28-day menstrual cycle.  
  • Progesterone’s role is to signal the lining of the womb (endometrium) to prepare to nourish a newly established pregnancy. The endometrium changes so it will be able to secrete nutrients for the embryo. (In fact, progesterone literally means “for pregnancy.”) 
  • The ovary produces significant amounts of progesterone for only 14 days of each 28-day menstrual cycle. If a pregnancy occurs, the ovary continues to produce progesterone until the placenta takes over this role. If no pregnancy occurs, the ovary stops making progesterone and this causes menstrual bleeding to start on day 28. Then the cycle begins over again.

The Research

To date, an NIH Intramural Research Program study provides the only long-term controlled data published regarding P-HRT for young women with POI. Most women with POI have an intact uterus, thus the recommended hormone replacement is both estrogen and progestogen. Cyclical progestogen is recommended to prevent the endometrium from developing cancer. 

The NIH study of P-HRT in POI used transdermal estradiol (100 ug/day) as the estrogen and oral medroxyprogesterone acetate (10mg/day for 12 days/month) as the progestogen. This regimen was highly effective and tolerated well. Medroxyprogesterone acetate is the only progestogen for which the available evidence demonstrates capability to fully change to secretory endometrium in conjunction with a full replacement dose of estrogen. The progestogen should be taken for 12 days each month.  

Cycling progestogen courses given less frequently than monthly (termed “long-cycle HRT”) is not recommended. This is not the manner in which the ovary supplies progestogen. A long-cycle HRT approach increases the risk of endometrial overgrowth and potentially of endometrial cancer. Medroxyprogesterone acetate is a  “pure” progestogen. Some progestogens are produced from testosterone and, as compared with medroxyprogesterone acetate, have associated male hormone effects.

The NIH study on P-HRT in POI employed medroxyprogesterone acetate as the progestin. This choice was due to concerns regarding the lack of evidence for effectiveness of oral micronized progesterone.  Oral micronized progesterone may not protect the endometrium adequately when used in conjunction with full replacement doses of estradiol. Most of the oral micronized progesterone taken by mouth is broken down by the liver. This is why such a high dose must be given.  

There are also concerns regarding the effectiveness of oral micronized progesterone in maintaining normal levels of progesterone in the blood. Evidence suggests that with the use of oral micronized progesterone, the progesterone effect on the endometrium would be inadequate. Some young women with POI will take hormone replacement therapy for decades. More supporting evidence regarding the effects of oral micronized progesterone at the level of the endometrium is needed before this can be recommended as the first-line progestogen for this clinical situation. 

There is insufficient evidence to determine if medroxyprogesterone acetate and micronized progesterone therapy differ significantly with regard to association with the development of breast cancer. 

With regard to effect on cardiovascular risk, in combination with estradiol, medroxyprogesterone acetate improves cardiovascular risk markers, including serum HDL and LDL levels, blood pressure, and blood-clotting factor levels.

Typical P-HRT Treatment Regimen

Here is a summary of the NIH P-HRT regimen: 

1) Use the 0.10 mg estradiol patch continuously. 

2) Take 10 mg of MPA (medroxyprogesterone acetate) by mouth each day from the first day of the calendar month through the 12th. 

3) Keep a menstrual calendar. 

4) Get a pregnancy test if your period is late. 

5) Stop the P-HRT if you are pregnant.

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