S P E C I A L R E P O R T
March 17, 2014
So let’s get started.
Be warned ahead of time that this estimate is very rudimentary and relies heavily on averages and interpolation of information collected from various sources.
There are three main estrogens (along with other minor estrogen analogues), collectively referred to as CEEs [conjugated equine estrogens], found in Premarin® and its daughter products such as Prempro®, Premphase® and the new osteo-menopausal combination drug Duavee®:
(1) estrone sulfate;
(2) sodium equilin sulfate and;
(3) 17α-dihydroequilenin sulfate.
CEEs are isolated from urine via a solid phase extraction process followed by either HPLC (high-performance liquid chromatography) or TLC (thin layer chromatography) on silica gel – both methods give good results with over 97% recoveries.
Ranges of the concentrations measured during the collection period were given as:
Estrone sulfate: 0.8 – 6.4 mg/L
Sodium equilin sulfate: 0.4 – 3.2 mg/L
17α-dihydroequilenin sulfate: 0.3 – 2.4 mg/L
This gives a total CEE concentration range of 1.5 – 12 mg/L all of which contribute to the total of CEEs in Premarin®-derived drugs. In order to use this information judiciously it is helpful to understand the fluctuations of CEEs in the mares’ urine over the course of gestation. A thesis paper entitled “Urinary Estrogens and Progestins in Pregnant Pony Mares” authored by Mohamed Tarek Riad gives a frame of reference that can be used to construct a simple chart based on the CCE levels during the gestation phases and normalizing (standardizing) the peak value given in the paper with the peak maximum value of 12 mg/L given above.
“Total urinary estrogen concentrations elevate in the third or fourth month (about 100 µg/24 hr) and peaks approximately the sixth to seventh month of gestation (780 µg/24 hr). This peak is followed by a rapid decline, then a more gradual decline toward parturition and a decrease to the baseline at d 1 postpartum (Raeside and Liptrap, 1975)”. 
This cycle is further corroborated in a 1991 paper “Monitoring ovarian function and pregnancy by evaluating excretion of urinary oestrogen conjugates in semi-free-ranging Przewalski's horses (Equus Przewalskii)” authored by Monfort, SL, Arthur, NP and Wildt, DE. 
According to NAERIC urine collection begins in the fall and runs through late winter which roughly translates to 6 months on the pee line. 
Breeding season occurs during the summer months such that when the mares are consigned to the barn approximately three months will have elapsed which is in concert with the 3 to 4-month elevation of the CEEs in the urine. For example, a mare might conceive in late June or early July with urine collection starting in October and lasting until the end of March.
The following chart was constructed based on these assumptions where the CEE concentration begins to rise in the third month (~ 1.5 mg/L), peaking between the sixth and seventh month (12 mg/L) with a sharp decline in the seventh month then gradually decreasing to a baseline level at 11 months (normal gestation cycle). This is merely an interpretation and not meant to be acutely factual.
The collection phase between the third and ninth month of gestation has been sectioned off into half month intervals in an attempt to estimate the average concentration of CEEs collected per day for that time interval. The average CEE concentration for any given interval is given by interpolating the midpoint on the curve between the area where the curve intersects the beginning and end of the interval and denoted by the asterisk.
This value represents the concentration of CEEs in milligrams (mg) per liter (L) of urine. In order to calculate the actual amount of CEEs in milligrams (mg) a mare excretes in a day the volume of urine output per day is required. According to the Merck Veterinary Manual the urine volume for a horse ranges from 3 – 18 ml/kg body weight/day or on average 10.5 ml/kg body weight/day. 
The NAERIC site provides a breakdown of the horse breeds involved in the PMU ranching as well as stall sizes according to the weight of the horse which gives an estimate for the average weight of a PMU horse. Horses found on NAERIC-member equine ranches fall under three distinct types:
NAERIC Light Horses: Quarter Horses, Paints, Appaloosas and Standardbreds
NAERIC CanAm Sport Horses: Thoroughbred stallion X draft-cross mares and draft horses X light horses (e.g. Quarter Horses or Paints)
NAERIC Draft Horses: Percherons, Belgians, Clydesdales and Spotted Drafts
Predominantly these horses tend to be at the high weight range for their breed due to increased bladder size which helps to maximize output. For the sake of simplicity the estimated average weight of a PMU mare taken from the stall size information would fall between 1,300 and 1,700 lb. - roughly 1,500 lb. or 680 kg.
Therefore the average daily urine output based on the average weight of a PMU mare is given as: 10.5 ml/kg body weight/day x 680 kg = 7,140 ml or approximately 7 L of urine per day. This correlates well with data from other sources (e.g. http://panutrientmgmt.cas.psu.edu/pdf/G97.pdf).
With this information it is now possible to calculate the estimated total amount of CEEs collected over a 6-month period for a single mare on the pee lines (see Table 2). This calculation assumes a collection period starting in October and ending in March and uses the average CEEs (mg/L) interpolated from the chart based on estrogen changes over the gestation period. The numbers are calculated as follows (example shown):
Average CEEs (mg/L): interpolated from the chart (midpoint of interval)
October 3.0-3.5 = 2.1 mg/L
Average CEEs (mg/day): Average CEEs (mg/L) x Average Urine output/day
Avg. CEEs (mg/day) = 2.1 mg/L x 7 L/day = 14.7 mg/day
Number of Days in Interval: half of the number of days in the month
October: 31 days/2 = 15.5 days
Total CEEs in Interval (mg) = Average CEEs (mg/day) x Number of Days in Interval
Total CEEs = 14.7 mg/day x 15.5 days = 228 mg
Total CEEs collected over 6-month period = sum of Total CEEs in all Intervals
Hence a single mare will produce an estimated total of about 9,466 mg of CEEs over the 6-month collection period. With this projected mass of CEEs per mare, the number of mares required to manufacture these HRT drugs to the tune of a profit of over a billion dollars can be estimated.
To begin there are several dosages of CEEs available in the Premarin® family of products (Premarin®, Prempro®, Premarin® vaginal cream and Premphase®) nevertheless from anecdotal evidence, by far the most commonly prescribed is that at a level of 0.625 mg CEEs for each of the drugs.
The cost of a single 0.625 mg dose varies widely across the globe however since approximately 92% of the sales of these drugs are in the US (see Table 1 in Part 1 of this Report) an average cost per dose was estimated using information from US sources.
Interestingly enough the cost versus dosage is not a linear relationship such that the cost for a lower or higher dose, for example, is often similar to the cost for a 0.625 mg dose. What’s more is that any online store selling cheap “generic” Premarin® or its sister drugs is not selling Premarin® at all as there is currently no generic form of any of these drugs approved by the FDA. Accordingly these prices are not included in the estimate.
An Internet site http://www.goodrx.com/ was used to approximate the average cost of single dosages of each of the Premarin family of drugs in a number of cities across the United States at several different pharmacies including Costco .
The GoodRx site locates the lowest prices so the assumption is that the majority of women are purchasing them at the lowest cost. In fact according to the IMS Institute for Healthcare Informatics patients are increasingly relying on copay coupons and vouchers to purchase prescription medications. Table 3 outlines the average cost per 0.625 mg dose for each drug.
The next challenge was to determine the percentage of each drug sold. A 2010 survey of the top 200 drugs by sales in the US revealed the following as shown in Table 4. Indeed it is 2010 information but I was unable to locate the same kind of data for years beyond this.
Assume that the relative percentages of sales are roughly the same for 2013. If so, the sales for 2013 and the number of doses of CEEs in total for that year can be calculated. Pfizer’s total sales for 2013 = $1,092,000,000 (see Table 1)
Given the average dose is taken to be 0.625 mg then the total number of mg required to produce 275,141,693 doses = 275,141,693 dose x 0.625 mg/dose = 171,963,558 mg.
And since in any given year a single mare produces an estimated 9,466 mg of CEEs (i.e. collected over the 6-month period) a rudimentary approximation of the total number of mares on the pee lines (in the US and elsewhere) can be given.
Total # of mares
= total mg CEEs (2013) / # of mg CEES produced per mare
= 171,963,558 mg / 9466 mg/mare
= 18,166 mares
Take it or leave it – it is not intended to be immutable but rather an approximation based on myriad variables and the inherent variability in them.
So is this number – roughly 18,000 mares – reasonable, give or take a few thousand?
At peak production during the early 2000’s there were 50,000 mares or more on farms in the Canadian West and North Dakota in the US. Since this time aggressive marketing strategies, price increases and the wide availability of these drugs without prescriptions through Internet sales has boosted both profits and sales.
Moreover, as we are well aware of now, Wyeth began to relocate the PMU farms many years ago which explains the gradual downsizing of the industry here in North America and the birth of an industry in foreign lands.
Additionally, throughout the years, both Pfizer and Wyeth have invested heavily in sponsoring studies intended to showcase the “benefits” of CEEs and downplay the inherent risks that these drugs carry with them to promote their sales.
Are these studies above board?
“There’s a high scientific opportunity cost in serving the aims of the pharmaceutical industry. In addition to distorting the research agenda, there is overwhelming evidence that drug-company influence biases the research itself. Industry-supported research is far more likely to be favorable to the sponsors’ products than is NIH-supported research. There are many ways to bias studies—both consciously and unconsciously—and they are by no means always obvious.” 
Probably not, but they boost sales and reassure the medical profession that the benefits outweigh the risks.
Sadly this tactic has been (mostly) successful with academia, the medical profession and their patients – all acceding to their strategic ruse and promoting the use of these noxious products. Not to mention the “alleged M.D. pharma whores pimping out their souls for a quick buck” – physicians accepting kickbacks and bribes to push Big Pharma’s propaganda. 
With these kinds of machinations in the works and the profits they represent is it any wonder why these drugs are still marketed and sold given the brain-washing and deception associated with them?
Granted, sales are much lower than in Wyeth’s glory days prior to the damning WHI results, as are some, but not all, prescribed dosages intended to quell the fears of the insidious side-effects.
Yet these drugs are still mainstream and are prescribed on a regular basis largely without question. In view of this, the estimate of about 18,000 mares – or roughly a third of those on the pee lines at the peak of production – could potentially represent the sad reality of the PMU industry.
Whatever the case may be, given the lack of transparency afforded by the pharmaceutical industry, we may never know for certain.
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