Comparison of ingredients: Premarin and Cenestin/Enjuvia

There's a lot of confusion about these three HRTs, and how they differ. All three loosely fall into the category of oral synthetic estrogen hrts that deliver primarily estrone, but they are not entirely identical even though as a class they are referred to as CEEs or "conjugated equine estrogens". While Premarin is animal-derived and Cenestin/Enjuvia plant-derived, they are also not exactly equivalent in constituents.

The lists below are partly derived from information provided during 2000 on the Cenestin website and updated with information from Enjuvia's prescribing information sheet as well as some current references. Not only is it no longer posted there, but Cenestin no longer has an active website. Duramed/Barr, the original Cenestin manufacturer, has sometime since 2000 been acquired or somehow transformed into Teva Pharmaceutical Industries which, from its website, is a generic manufacturer. Their site provides no information on Cenestin as it exists today.

Cenestin


While Cenestin was originally developed as a generic for Premarin, the FDA was unable to authorize that designation because Wyeth, the manufacturer for Premarin, has not provided it an exact list of Premarin's specific ingredients. Cenestin is now listed by the US FDA as a generic for "conjugated synthetic estrogens" in their Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (sorry—the search is dynamically generated so there's no way to link directly to a specific product). Premarin is listed, in contrast, as "conjugated estrogens."

RxList, a drug directory owned and operated by WebMD, provides the best listing we can find on Cenestin, where it details the list of nine estrogenic substances for this hrt that are shown below.

Enjuvia


Enjuvia is also listed as a generic for "synthetic conjugated estrogens" by RxList and the FDA Orange Book. The RxList entry for this hrt lists the ten estrogenic substances which are shown below.

Premarin


This is the greatgrandmother of HRTs, either the gold standard or the great boogeymama, depending upon where you fall in your opinions. Although the manufacturer, makes a great deal over the ingredients being "natural" in origin, many women take issue with that use of the term for something that is produced by horses and thus not exactly natural to women.

We can't vouch for whether or not, or to what degree, the list below is an accurate representation of Premarin's constituents. It was copied from that old Cenestin website and we've never found it anyplace else. RxList has this content statement for Premarin:
a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17alpha-dihydroequilin, 17alpha- estradiol, and 17beta-dihydroequilin.
The FDA, as recently as 2005, felt that the various components of this hrt contributed significantly to its characteristics as an hrt (source):
Highly illustrative of the need for further characterization of Premarin are the recent findings regarding the estrogen compound delta (8,9) dehydroestrone sulfate (DHES). This compound, first detected in Premarin in 1975, represents only a small percentage (4.4%) of the estrogenic compounds present in the product. Recent pharmacokinetic studies demonstrate that, after single or repeated oral dosing of Premarin in women, the plasma concentration of the metabolite of DHES is approximately 34% of the combined concentration of the metabolites of the active ingredients estrone and equilin or 26% of the metabolites from the three estrogens. These pharmacokinetic data do not themselves prove that the DHES in Premarin makes a clinically meaningful contribution to the therapeutic effect of Premarin. However, preliminary clinical studies indicate that the potency of DHES may be similar to that of equilin. The finding that a low level (5%) component in the tablet would generate a significant concentration of a potentially active metabolite was completely unexpected and illustrates the longstanding inadequate characterization of Premarin.

So are they the same or not?


Further support for the functional difference between these hrts was recently tracked down by a member of our discussion list, who shared with us a very interesting research article, "Comparison of pharmacokinetics of a conjugated equine estrogen preparation (premarin) and a synthetic mixture of estrogens (C.E.S.) in postmenopausal women." Their conclusions are:
C.E.S. is not bioequivalent to Premarin. Because C.E.S. also is not pharmaceutically equivalent to Premarin, it cannot be assumed to be therapeutically equivalent. Until long-term clinical trials with C.E.S. demonstrate its efficacy, extrapolation of the long-term benefits described for Premarin to C.E.S. would be risky and questionable.
Does this mean they cannot be considered "roughly" in the same category? No. Much as the Vivelle Dot and Climara patches function very differently for some women even though their hormonal ingredient is the same, so we can consider these hrts part of the conjugated estrone family but having individual characteristics that may or may not affect how they actually function for any single given women.

In other words, the value in this knowledge covers several key points:
  1. If a woman responds one way to one of this family and then switches for, say, a financial reason, to another of the family and experiences different effects, she can at least know that she's not crazy;
  2. If a woman wants to switch from Premarin to something equivalent that is non-animal or that does not carry Premarin's ethical concerns, she should know that she might not find them identical but can go into the process with an open mind as to just how much change might ensue;
  3. If a woman finds herself in a position where her doctor will only prescribe Premarin and she desperately wants to change hrts because it does not suit her, she might be able to talk him into a "vegetarian version" and hope that its effects might be slightly different, thus helping alleviate the problem in the interim while she's shopping for a more responsive doctor; and
  4. For women who are having to do a lot of work to identify the best possible hrt and are down to the fine tweaking, this is one more variable that can be tested out when we reach "close but not 100%."


The lists


Cenestin estrogenic ingredients (from RxList):
  • sodium estrone sulfate
  • sodium equilin sulfate
  • sodium 17 alpha-dihydroequilin sulfate
  • sodium 17 alpha estradiol sulfate
  • sodium 17 beta-dihydroequilin sulfate
  • sodium 17 alpha-dihydroequilenin sulfate
  • sodium 17 beta-hydroequilenin sulfate
  • sodium equilenin sulfate
  • sodium 17 beta-estradiol sulfate
Enjuvia estrogenic ingredients (from RxList):
  • sodium estrone sulfate
  • sodium equilin sulfate
  • sodium 17 alpha-dihydroequilin sulfate
  • sodium 17 alpha estradiol sulfate
  • sodium 17 beta-dihydroequilin sulfate
  • sodium 17 alpha-dihydroequilenin sulfate
  • sodium 17 beta-hydroequilenin sulfate
  • sodium equilenin sulfate
  • sodium 17 beta-estradiol sulfate
  • sodium D8,9-dehydroestrone sulfate
Premarin estrogenic ingredients (from old Cenestin website):
  • sodium estrone sulfate
  • sodium equilin sulfate
  • sodium 17 alpha-dihydroequilin sulfate
  • sodium 17 alpha estradiol sulfate
  • sodium 17 beta-dihydroequilin sulfate
  • sodium 17 alpha-dihydroequilenin sulfate
  • sodium 17 beta-hydroequilenin sulfate
  • sodium equilenin sulfate
  • sodium 17 beta-estradiol sulfate
  • sodium delta 8,9-dehydroestrone sulfate
Premarin other substances:
  • 5,7,9 (10) estratrien-3beta, 17-beta-diol
  • 17 alpha-dihydro-delta 8,9-dehydroestrone
  • 17 beta-dihydro-delta 8,9-dehydroestrone
  • 5,7,9, (10) estratrien-3 betal-ol-17-one
  • 2-hydroxy-estrone
  • 2-methoxy-estrone
Premarin progestins:
  • 5 alpha pregnane-3 beta, so beta-diol
  • 5 alpha-pregnane-3 beta, 16 alpha, 20 beta-triol
  • 5 alpha-preg-16-ene-3 beta-ol-20-one
  • 5 alpha-pregnane-3 beta-ol-20-one
  • sodium 4 pregen-20-ol-3-one sulfate
  • 3 beta-hydroxy-5(10), 7 estradiene 17-one-3-sulfate
Premarin androgens:
  • 5 alpha-androstan-3 beta, 17 alpha-diol
  • 5 alpha-androstan-3 beta, 16 beta-diol
  • 5 alpha-androstan-3 beta, 16 alpha-diol
  • 5 alpha-androstan-3 beta-ol, 16-one