Monday, March 7, 2011

What ACTH Preparations Should Be Used For Stimulation Testing?

The pituitary hormone corticotropin (adrenocorticotropic hormone or ACTH) is a single-chain 39-amino-acid peptide hormone synthesized in the corticotrophs of the anterior lobe (pars distalis) of the pituitary gland). Although the amino acid sequence of ACTH varies among species, the first 24 amino acids are identical among all species studied to date. Canine ACTH differs from human ACTH by only one amino acid residue, at position 37, although the amino terminal end of the ACTH molecule (amino acids 1 to 18) is responsible for its biologic activity.

ACTH is available in two general forms as a diagnostic testing agent. Both of these forms or preparations of ACTH work by stimulating the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a few other weakly androgenic substances.

ACTH Gel Preparations

In the past, the main ACTH preparation used for adrenal function testing was ACTH gel, which is extracted from bovine and porcine pituitary glands. The ACTH in these gel preparations is composed of the entire 39-amino-acid sequence of the ACTH peptide.

Brand name ACTH gel preparations
In the USA, the only FDA-approved, brand-name ACTH gel preparation is H.P. Acthar gel Repository Injection (80 U/ml; Questcor Pharmaceuticals). The FDA has specifically labeled H.P. Acthar Gel for use in diagnostic testing of adrenal function. However, the package insert lists a variety of other diseases and disorders for which it may be used including acute multiple sclerosis, infantile spasm, rheumatoid arthritis, hemolytic anemia, allergic conjunctivitis, and ulcerative colitis (1).

In late 2007, Questcor announced a new strategy and business model for H.P. Acthar Gel Repository Injection (2). The cost of the product was increased from an average wholesale price of $2,063 per 5-ml vial to an estimated $23,000 per vial! The company explained that its price increase was crucial in order to continue manufacturing and distributing this agent to patients who needed it, as well as to fund projects that could contribute to the company’s growth.

This increase in price has led physicians to totally abandon its use for adrenal function testing, since synthetic ACTH is so much cheaper. H.P Acthar Gel is almost 29 times more expensive than either formulation of cosyntropin available in the USA (see below). Many have also questioned the therapeutic value of H.P. Acthar Gel, especially as it compares with lower-priced and potentially therapeutically equivalent alternatives, such corticosteroids.

During the late 1970’s and early 80’s, I used this H.P. Acthar gel product routinely for ACTH stimulation testing because it was very cost effective. As the price of Acthar gel started to increase and synthetic ACTH preparations became more available, however, I had completely switched to use of only synthetic ACTH preparations by the late 1980s for adrenal gland testing in dogs and cats.

Today, performing an ACTH stimulation test with H.P. Acthar gel would cost the veterinarian over $1000 per dog just for the product alone, not including the serum cortisol determinations! Obviously, it is highly unlikely that you will be using this ACTH gel preparation for use in testing dogs and cats anytime in the future.

Generic ACTH gel preparations
Generic preparations of ACTH gels (usually 40 U/ml) can be purchased from several veterinary-compounding pharmacies. The following is a partial list of compounding pharmacies that sell such generic ACTH gels: Wedgewood Pharmacy, Pet Health Pharmacy, Red Oak Drug, Meds for Vets, and Diamond Back Drugs. Many practicing veterinarians favor these compounded ACTH products because they are slightly cheaper than Cortrosyn (and certainly much less expensive than H.P. Acthar gel!)

But as someone smart once said, ”you generally get what you pay for.”

There are 4 reasons why I do NOT recommend these compounded ACTH products:
  1. Compounding pharmacies are not governed or regulated by the FDA. Therefore, we have no guarantee that the potency of these compounded formulations are what the pharmacy claims them to be. Some batches of compounded ACTH gel may be very potent and maximally stimulate cortisol secretion, whereas others batches or preparations fail to stimulate maximal cortisol secretion or may not stimulate it at all!
  2. Because of the potential for lot-to-lot variability in compounded ACTH formulations, one should consider assessing the activity of each new vial by performing an ACTH stimulation test on a normal dog to ensure that the preparation is bioactive (i.e., it will work to stimulate cortisol secretion from the adrenal cortex). Of course, that suggestion is totally impractical for the practicing veterinarians.
  3. Because of the differences in potency and absorption of these compounded products, peak ACTH-stimulated cortisol values may occur from 30 minutes to 2 hours after gel administration (3). In contrast to H.P. Acthar gel, where peak cortisol secretion occurred 2 hours after administration, the compounded ACTH preparations are not consistent.   Because of this variability in the duration of cortisol response, most authorities recommend collecting post-ACTH at both 1 and 2 hours when using a compounded gel preparation (3).
  4. The added time and need to collect and measure a third cortisol concentration offsets any cost savings gained from using a compounded ACTH product. (And remember my second point — we should validate the test with every new vial by testing a clinically normal dog!).
The bottom line: while these compounded ACTH preparations may be less expensive than other available products, they are not recommended because the potency can vary from bottle to bottle.

Stick with synthetic ACTH preparations, as described below!

Synthetic ACTH Preparations

Cosyntropin is a synthetic form of ACTH, created by isolating the first 24 amino acids from the 39-amino-acid ACTH peptide. The only indication for use of cosyntropin is in diagnostic testing of adrenal function. A dose of cosyntropin 0.25 mg, which is biologically similar to a dose of 25 units of ACTH gel, maximally stimulates the adrenal cortex.

Cosyntropin has many advantages over the use of the ACTH gels for ACTH stimulation testing. First of all, the cosyntropin test takes half the time of the ACTH gel test (1 hour vs. 2 hours). Secondly, the ACTH-stimulated cortisol response to cosyntropin is more consistent and variations in potency are not an issue. Finally, cosyntropin is less immunogenic than ACTH gel. The amino acids 22 to 39 in ACTH produce most of the molecule’s antigenicity; thus, cleaving of most of these amino acids from cosyntropin molecule renders it less likely to elicit an allergic response.

In the USA, cosyntropin is either as the brand-name product Cortrosyn (Amphastar Pharmaceuticals) or a generic cosyntropin preparation (Sandoz).

In most countries outside the USA, cosyntropin is called tetracosactide (Synacthen). Despite these differences in name, the chemical structure of tetracosactide is identical to cosyntropin (both 1-24 ACTH).

The brand-name product Cortrosyn is supplied by the manufacturer as a lyophilized powder in vials containing 0.25 mg (250 µg) of ACTH. The cosyntropin powder must be reconstituted with sterile saline solution at time of injection (4).

Unlike ACTH gels, which can be given intramuscularly (IM) or subcutaneously (SQ). Cortrosyn should NOT be administered via the SQ route. However, Cortrosyn be safely given either IM or IV (4).

In dogs, it has been shown that that either IM or IV routes of administration provide equivalent serum cortisol responses. In cats, however, a more consistent and greater adrenocortical response is elicited after IV administration of cosyntropin, so IM administration is not recommended in this species.

The current cost of Cortrosyn is $72 per vial ($62 per vial if purchased in boxes of 10-vials). Nowadays, it is common practice to dilute Cortrosyn and freeze the diluted aliquots for up to 6 months. This not only extends its shelf life, but makes the use of Cortrosyn much more cost effective.

Generic cosyntropin
Sandoz’s generic cosyntropin, in contrast, is supplied as a solution for injection (0.25 mg per vial).

According to the product insert (5), the synthetic ACTH preparation should be given only intravenously. The product insert also states that cosyntropin injection is intended as a single dose injection and contains no antimicrobial preservative; any unused portion should be discarded.

To my knowledge, no research studies of this cosyntropin generic preparation have been reported in either the dog or cat. It’s safe to assume that this product would be as effective as Cortrosyn in stimulating adrenocortical secretion. However, it is not know if the IM route would be reliable.

Even more importantly, we do not know if this preparation can be diluted and stored in the refrigerator or freezer without loss of potency.

Finally, for reasons that are unclear to me, the current cost of this generic preparation ($99 per vial) is about 30% more than the cost of an identical amount of Cortosyn.

My bottom line: for all of the reasons listed above (including the cost of
product),I would stick with Cortrosyn.

Outside of the U.S., the synthetic ACTH preparation tetracosactide (Synacthen, Novartis) is supplied as a solution for injection (0.25 mg per vial). This preparation appears to be very similar to the generic cosyntropin solution made by Sandoz.

According to my expert sources in the UK and Europe, Synacthen is ‘dirt-cheap.’ So no one has studied if this synthetic ACTH preparation is stable when diluted or how long it’s potency is maintained when stored long-term.

Generally, either one-half or the entire contents of the Synacthen vial are administered per test, depending on the size of the animal.

  1. H.P. Acthar Gel, Repository Corticotropin Injection, package insert. Union City, CA: Questcor. Available at:
  2. Questcor Board approves new strategy and business model for H.P. Acthar Gel. Union City, CA: Questcor; August 2007. Available at:
  3. Kemppainen RJ, Behrend EN, Busch KA. Use of compounded adrenocorticotropic hormone (ACTH) for adrenal function testing in dogs. J Am Anim Hosp Assoc 2005;41:368-372. Abstract available at:
  4. Cortrosyn Injection, package insert. Rancho Cucamonga, CA: Amphastar. Available at:  
  5. Cosyntropin Injection (Generic), package insert. Princeton, NJ: Sandoz. Available at:

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