Section 2 mentions that melatonin is often used as a first treatment.
Section 8 below mentions using lignans along with ketaconazole.
Section 5 mentions using lignans in conjunction with Lysodren.
Treatment Option Considerations
Steroid Profiles in the Diagnosis of Cushing’s Disease
Clinical Endocrinology Service/College of Veterinary
Medicine/University of Tennessee
Where positive test results of increased adrenal activity are present, consider the need for:
1) Ultrasound and/or Endogenous ACTH. Procedures to rule out primary adrenal
2) Melatonin. Often used as a first treatment, especially if alopecia is present, since it
is cheap, has few side effects and is available in health food stores or via nutrient
suppliers on the Internet. Typically, a dose of 3 mg is given every 12hrs for dogs <30 lbs;
a dose of 6 mg is given every 12hrs for dogs >30 lbs. Regular melatonin is usually used
rather than rapid release or extended release products. Melatonin has anti-gonadotropic
activity (effective for ferret adrenal disease), and it inhibits aromatase enzyme in tissues
(decreases androstenedione and testosterone conversion into estradiol) and 21-
hydroxylase enzyme (effectively lowers cortisole level). Allow at least 4 months for
treatment effects to be effective. Response time is variable between dogs. Monitor
treatment effectiveness by improvement in clinical signs, biochemistries or by repeat of
3) Melatonin Implants. Available for dogs and ferrets. (WWW.MELATEK.NET). Sizes
are 8, 12 and 18 mg for <25, 25-50 and >50 lb dogs, respectively. Effects last 3-4
months. Note: Melatonin and flax hull product with lignans are used together when
estradiol is increased.
4) Lignan. Lignan has phytoestrogenic activity, and competes with estradiol for tissue
estrogen receptors, with less biological effect. Lignan also inhibits aromatase enzyme
(lowers estradiol) and 3-beta HSD enzyme (lowers cortisol). Use either FLAX HULL (SDG)
lignan, or HMRlignan. DO NOT USE flaxseed OIL as the lignan content is very low, and
the flax oil can increase triglycerides.
Suggested doses: SDG lignan; one milligram/lb B. Wt./day. HMRlignan; 10-40 mg/day for
small to large dogs.
5) Maintenance dose of LysodrenTM. Often useful in combination with melatonin and
lignan to help lower sex steroid levels other than estradiol, along with suppressive effect
on cortisol level. NOTE: MONITOR CORTISOLE LEVELS ARE FOR TYPICAL CUSHING’S
6) LysodrenTM, traditional treatment for Cushing’s disease. Very effective in lowering
cortisol, progesterone, androstenedione and 17-hydroxyprogesterone levels. NOTE:
Estradiol is not always suppressed by LysodrenTM. A baseline estradiol level 1 month
post-Lysodren will determine efficacy.
7) Trilostane. Now available in the U.S. as Vetory1TM from Dechra Veterinary Products.
NOTE: Trilostane always increases 17-hydroxyprogestone (some cross-reactivity with
pregnenolones in assays??), and frequently increases estradiol and androstenedione as
well. LysodrenTM may be preferred for Atypical Cushing’s cases. FURTHER NOTE: Care
should be used in switching from Trilostane to LysodrenTM. Allow adequate time for either
drug’s effects on the adrenals to subside before switching treatments. (E.G., one month
off drug; normal or increased stim-cortisol levels).
8) Ketoconazole. Cushing’s disease treatment. Effective for increased cortisol and
sex steroid levels. Consider 6 to 12 mg/kg, BID along with melatonin and lignan as
above. See write-up at our website (and the recent article on the ketoconazole treatment at
9) Selgiline (AniprylTM). A less used alternative Cushing’s disease treatment. See
10) Hormone cream exposure. Products may contain
estrogen/progestines/testosterone; may result in high serum levels of estradiol and
progestins, as well as nipple, vulva, and clitoris enlargement.
11) Ovarian remnant detection. hCG stim test (estrus) and measurement of
progesterone is indicated.
12) Retained testicle detection. hCG stim test and measurement of testosterone is
13) For clarification regarding test results, Contact Dr. Jack Oliver (865-974-5729;
firstname.lastname@example.org). Also Dr.’s. Kellie Fecteau or Hugo Eiler are available in Dr. Oliver’s
absence. (865-974-5638). Note: Several patterns of hormone increase occur, so doing
the complete adrenal panel is advised.
14) For further information on our Service (e.g., submission, shipping, protocols,
treatment, review articles) see our website (www.vet.utk.edu/diagnostic/endocrinology).
Revised 05-01-10 (JWO).
Currently, there are two types of lignans on the market:
1) Flax hull (SDG) lignans derived from the hulls of flax seed; and lignan that is derived
from the Norwegian Spruce tree (HMRlignan). Extensive discourse on these two product
types can be found by Googling the Internet.
SDG flax hull lignan. The major active ingredient of flax hull (SDG) lignan is
secoisolariciresinol diglucoside (thus, SDG). SDG flax hull lignan is metabolized by
intestinal bacteria to enterolactone (the major active mammalian lignan that is found in
body tissues), and also enterodiol (also a mammalian lignan). Both enterolactone and
enterodiol are formed in the gastrointestinal tract by bacterial breakdown of the consumed
SDG lignan. The process involved with SDG lignan is a two-step procedure that delays
absorption time (www.organic-herb.com). But the usual doses used appear to give
adequate levels of enterolactone for 24 hours on a once-daily-dosing basis.
HMRlignan. The active ingredient of HMRlignan is different from that of SDG flax hull
lignan and is 7-hyroxymatairesinol (thus, HMR). HMRlignan is extracted from the
Norwegian Spruce tree, and yields high amounts of HMRlignan. Once ingested, it is
directly converted by gastrointestinal bacteria into the major-endogenous-mammalian
lignan (enterolactone). HMRlignan forms more enterolactone than SDG flax hull lignan,
since another endogenous-mammalian lignan called enterodiol, is formed by SDG lignan,
and is less bioactive in systemic tissues compared to enterolactone. Cleavage of sugar
chains must occur for SDG flax hull lignan, by the intestinal bacteria, before the
mammalian lignans are formed. This may or may not offer efficacy advantages to
HMRlignan (further research will be needed to prove or disprove this). Blood levels of
HMRlignan remain adequate for 24 hours on once-daily-dosing. HMRlignan reportedly is
readily and completely absorbed from the gastrointestinal tract (SDG lignan is not
completely absorbed, although adequate blood levels do occur from dosages used).
Thus, better bioavailability and more rapid uptake occurs for enterolactone formed from
HMRlignan. Since HMRlignan’s bioavailability to the body is better than SDG flax hull
lignan, this allows reduced doses to be used.
SDG lignan, having fiber as a component, can cause increase in stool frequency (and
occasionally diarrhea). HMRlignan contains very little (if any) fiber, so this side effect
should not be seen with HMRlignan.
No adverse side effects to the use of SDG flax hull lignan have been reported to our lab,
based on suggested doses to use (one mg/lb of body weight daily). We only have limited
feedback (at this time) on the use of HMRlignan. In human studies with HMRlignan, single
doses of 1,200 mg did not have any side effects (www.hmrlignan.com). And in a chronic
(13 week) study in rodents, 2,600 mg/kg of HMRlignan did not cause any toxic effects
SDG flax hull lignan. See the article from the Lunus Pauling institute at Oregon State (www.