When sex hormones are tested in women either in saliva or blood spot, ZRT test reports give a ratio of progesterone (Pg) to estradiol (E2). The ratio is helpful in clinical practice when both E2 and Pg are within range, yet the patient continues to have symptoms. It is not expected to be normal or used clinically when either E2 and/or Pg are outside of their expected ranges or if the patient does not have clinical symptoms.
A low ratio occurs when Pg is low relative to E2. This describes the classic situation of estrogen dominance. In general, either decreasing estrogen and/or increasing progesterone are appropriate. Women who are postmenopausal are generally in this group.
A high ratio occurs when Pg is high relative to E2. This is most common with supplementation and describes progesterone dominance. When this occurs, a patient may complain of symptoms of estrogen deficiency resuming after previous successful treatment as estrogen receptors are down-regulated by excessive progesterone. In general, either increasing estradiol and/or decreasing progesterone are appropriate. This commonly occurs in menopause after a woman has been using progesterone successfully in perimenopause and her estrogen levels finally start to decrease as menopause is reached.
How is the ratio calculated?
We report an “optimal” ratio of 100-500, however this is only valid when E2 is within a normal luteal phase range; i.e., when E2 is 1.3-3.3 pg/mL in saliva, and 43-180 pg/mL in blood spot. The ratio is calculated from the Pg value in pg/mL divided by the E2 value in pg/mL.
Saliva test example: a patient has E2 = 1.5 pg/mL and Pg = 300 pg/mL. The units are the same (pg/mL), so the ratio is 300 divided by 1.5:
Blood spot or serum example: a patient has E2 = 100 pg/mL and Pg = 20 ng/mL. The Pg units are first converted to pg/mL before calculating the ratio: 1 ng/mL is equivalent to 1000 pg/mL. Therefore, the ratio is 20 ng/mL x 1000 = 20,000 pg/mL Pg, divided by 100 pg/mL E2:
Both of these examples represent normal endogenous luteal phase levels of E2 and Pg.
Is the ratio relevant in women using hormone therapy?
With some types of hormone therapy such as topical progesterone, Pg levels in saliva are much higher than endogenous luteal phase levels, ranging from 200-3000 pg/mL at 12-24 hours after dosing, and so the ratio can appear high. However, because symptoms of both estrogen dominance and progesterone dominance can look the same, testing and assessing the ratio along with clinical symptoms can help determine the next step for treatment.
Mary complains of hot flashes and night sweats. She’s a 50-year–old, newly postmenopausal woman who has never been on hormones. Her BMI is normal and she has no other health issues. A saliva test finds an E2 of 1.1 pg/mL (reported as “OK”), but a Pg level of 15 pg/mL (also “OK” for a postmenopausal woman), giving a ratio of 13.6 which is low. Based on her symptoms and a low ratio you start her on topical progesterone, which immediately helps the patient symptomatically. A few months later, you test her hormone levels again in saliva. Her E2 is 1.3 pg/mL and her Pg level is now 2500 pg/mL (within range for topical treatment). Her ratio is now 1923, reported as “high”. What do you do? The patient has no symptoms, feels great and her E2 and Pg levels are within appropriate ranges – no adjustments in treatment are needed.
A year later Mary comes back reporting hot flashes and night sweats. She was doing well until about 3 months ago. She had done a detox diet and had lost about 5 lbs. A saliva test shows that her E2 has dropped to 0.5 pg/mL: still “OK”, but much lower than last year; her Pg is still within the supplementation range at 2350 pg/mL. Her ratio is now 4700, which is still high. Unlike the last visit, however, Mary is now symptomatic. You have 3 choices: add estrogen therapy, reduce progesterone therapy, or both. Why is her higher Pg making things worse? Excessive Pg when E2 is low can down-regulate estrogen receptors and worsen estrogen deficiency symptoms. If Mary chose not to start estrogen therapy, just reducing the progesterone dosage would likely normalize her symptoms.
This case example highlights a misunderstanding that topical progesterone therapy only works for a limited period. It’s not that the progesterone stops working, it’s that the patient’s E2 level has declined further and the Pg/E2 ratio is now too high.