Canine Cushing’s Disease and Lignans for Dogs
When Cushing’s or atypical Cushing’s disease is present, veterinarians and universities suggest considering Flaxseed Hulls (SDG Lignans) or HMR Lignans as possible Cushing’s treatment. Lignans For Life offers flaxseed lignans in capsule and in bulk powder form. We also offer HMR lignans and melatonin.
How Lignans Can Help in Cushing’s Disease Treatment for Dogs
- Helps the return of normal skin and coat
- Helps restore normal thirst and urination
- Aids in the return of dog’s normal weight and appetite
- Helps restore dog’s energy
- Inhibits 3-beta HSD Enzyme, which effectively reduces Cortisol levels
What is Cushing’s Disease?
Cushing’s syndrome, aka hyperadrenocorticism, is a hormone disorder involving an increase in cortisol levels. This could be a result of tumors or of taking certain glucocorticoid drugs. In the case of tumors, surgery has been very effective in humans, but is not advisable for dogs.
Cushing’s is common in humans, dogs and horses. It is a middle aged to old aged disease that affects the pituitary gland in 80% of cases. Less commonly, Cushings affects the adrenal gland. Regardless of the tumor’s location, the result is an imbalance of Cortisol, a stress hormone produced by the adrenal glands. Abnormal levels of Cortisol are implicated in the diagnosis of Cushing’s disease.
Atypical Cushings Disease is slightly different. Atypical Cushings in dogs still exhibit the same symptoms as dogs with regular Cushing’s Disease, but rather than an overproduction of Cortisol, they experience heightened levels of sex steroids (estradiol, progesterone, aldosterone, etc.). Lignans and melatonin can be an effective Atypical Cushings Disease treatment for dogs as they can both inhibit aromatase enzyme, which effectively lowers estradiol, the sex steroid responsible for many atypical Cushings symptoms.
Normal Endocrine Function
In normal people or dogs, the pituitary gland produces ACTH, which stimulates the adrenal glands and instructs them to produce cortisol. Cortisol is a vital hormone in the body that affects numerous bodily functions. In Cushingoid dogs, the overproduction of Cortisol can lead to problematic symptoms.
Cortisol Reduction and Treatment Options
Dr. Jack Oliver Canine Cushing’s Treatment Options
Full Report on Adrenal Disorders
Lignans for Life Survey Results
Causes of Canine Cushing’s Disease
Cushings in dogs is caused by one of 3 sources:
1) Adrenal tumors: 15% of the time.
2) Pituitary tumors: 80% of the time
3) The administering of too many corticosteroids, which veterinarians usually give dogs for allergy treatments.
Canine Cushing’s Symptoms
- Increased appetite
- High blood pressure
- Increased thirst
- Thinning of the hair
- Excessive urination (including accidents in the house)
- Thinner skin
- Increased panting
- Increased tendency for diabetes; cardiovascular, muscular, and nervous system problems
- Skin lesions
- Weakening of the immune system
- Pot belly or drooping stomach. Although it may appear as if your dog has gained weight, it is usually more of a weight redistribution as opposed to weight gain.
Canine Cushing’s Treatments and Remedies
Surgery. In the case of tumors, surgery has been very effective in humans, but is not advisable in dogs. With Cushings in dogs, the majority of tumors are located on the pituitary glands and it’s not recommended to perform surgery on these tumors at all. Surgery may be performed on adrenal gland tumors, but even then it is rare because of the high risk and high cost.
Chemotherapy. Historical Cushing’s Disease treatments for dogs include medicine such as Lysodren and Trilostane, which can be extreme since they are chemotherapy drugs.
Lysodren actually destroys the outer cortex of the adrenal glands. The goal with Lysodren is to damage the adrenal cortex just enough to slow down the production of glucocorticoid hormones. If too much is given, the adrenal gland can be permanently damaged and the drugs can quickly cause the opposite of Cushings—Addison’s Disease, in which no cortisol is produced. If Addison’s disease occurs, another set of drugs will be required for the rest of the dog’s life.
Addisons only occurs in about 5% of Lysodren patients. More frequently (in about 1/3 of Lysodren patients), the dog will overreact to the Lysodren by producing extremely low levels of cortisol, causing loss of appetite, vomiting, diarrhea, muscle weakness or even death. Death occurs from Lysodren in about 1% of Cushing’s disease cases.
Ketoconazole. This is an antifungal that can treat certain symptoms of Cushings in dogs. It is deemed by many veterinarians to be a safer method of treatment than Lysodren; however, it is very expensive and has no effect at all in 20% of cases.
New Holistic Treatment for Cushing’s Disease. A report published by Dr. Jack Oliver DVM, PhD, from the college of veterinary medicine at a major US University recommends flaxseed lignans and melatonin as Cushings Disease treatment for dogs. Many veterinarians recommend starting with lignans before starting a medicinal treatment, but this UofT report says it is okay to take Flax seed lignans if your dog is already taking Trilostane or Lysodren.
Flaxseed lignans are also recommended because they cannot cause Addison’s disease. Although vets often disagree on treatment programs, there can be multiple options that are effective. Some vets have recommended HMR lignans- which is short for hydroxymatairesinol -from the Norwegian Spruce tree, and other vets have recommended flaxseed lignans, which contain both HMR lignans, SDG lignans, and several other types of lignans. All lignans produce the desired effect of increasing enterolactone and enterodial in the body and ultimately reducing cortisol levels, but the flaxseed lignans have more antioxidants, as well as fiber, compared to HMR lignans. Click here to view all of Dr. Oliver’s treatment option considerations.
According to an excerpt from Dr. Oliver’s report, “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 HMR lignan. DO NOT USE flax seed oil as the lignan content is very low, and the flax oil can increase triglycerides. Lignans are safe, so doses don’t have to be exact. Suggested Doses: SDG lignan; one milligram/lb B. Wt./day. HMR lignan; 10-40 mg/day for small to large dogs.”
He also went on to reference that, “Melatonin plus phytoestrogens (such as those from Flax seed lignans) are known to inhibit 3-beta hydroxysteroid dehydrogenase. Lignans and genistein are also known to decrease the activity of aromatase enzymes in MCF-7 cells in vitro.** Therefore, combinations of melatonin and phytoestrogens may have efficacy in treating hyperestrinism conditions.” Phytoestrogens are prevalent in Lignans. Click here for the complete study
Other reasons to consider lignans and melatonin as Cushing’s Disease treatment for dogs:
- They are gentle on aging dogs
- They can be used if Cushing’s is only suspected
- There are no negative side effects
- Unlike harsh chemotherapy drugs, they cannot cause Addison’s Disease
- They are effective in reducing heightened Cortisol levels in Cushingoid Dogs
- No ongoing testing of the dog is required as with conventional treatments
What type of lignan should I choose and how much lignan should I give my dog?
Dr. Jack Oliver DVM and former head of endocrinology at the U of T reports that both HMR lignans (from Norwegian spruce trees) and SDG lignans (from flaxseed hulls) work equally well as Cushing’s Disease treatment for dogs. The main decision is finding the lignan dosage that is best for your dog. A second consideration is whether you want fiber or not. The flaxseed hulls are high fiber; the HMR lignans do not have fiber.
Our surveys concur with Dr. Jack Oliver’s findings and show that both the HMR lignans and flaxseed lignans work equally well. Only in about 1% of cases is there a need to switch from flaxseed lignan to HMR lignan, or vice versa. Find the lignan dosage that is closest to your dog’s weight and give 1-2 mg of lignan per day for each pound of body weight. For example, a 30 lb dog would take 30-60 mg of lignan per day. Click the following link for more detailed info on Lignans Dosage for Dogs.
There are no side effects to lignans, but you should keep it in the range of 1-2 mg of lignans per day for each pound of your dog’s weight. Flaxseed lignans in excess can cause a loosening of the stool. Lignans for Life offers lignans in dosages of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 80 mg.
For melatonin, give 3 mg of melatonin every 12 hours for dogs under 30 lbs. For dogs over 30 lbs, give a 6 mg melatonin every 12 hours. For very small dogs (10 lbs or less) or for those who want to give their dog a very small dosage of melatonin, vets may recommend 1 mg melatonin every 12 hours. Make sure you do not use a rapid release or a timed release melatonin; use regular melatonin. All melatonin under our Lignans for Life, K9 Select, and K9 Choice brands fit these criteria. We carry melatonin in dosages of 1 mg, 3 mg, 5 mg, and 6 mg.
What types of dogs are most susceptible to Cushing’s disease?
Females may be slightly more susceptible than males and dogs over 5 years old are more prone, but the average age of Cushing’s diagnosis is 10-12 years old. Even though all breeds are susceptible, the dog breeds at higher risk are Yorkshire, Boston, Bull, Scottish and Silky Terriers, Poodles, Dachshunds, German Shepherds, Staffordshires, Jack Russels, and Beagles.
Atypical Cushings Disease
What’s the difference between Cushing’s disease and atypical Cushings disease? Atypical Cushings disease is caused by an adrenal gland tumor (as with normal Cushings), but with atypical Cushings disease, there is no overproduction of cortisol. Instead, dogs with atypical Cushings have heightened levels of sex steroids – like estradiol – which causes most of the symptoms.
A dog with atypical Cushings will still demonstrate normal Cushing’s syndrome symptoms, but the goal in managing these symptoms is to reduce estradiol. In cases of atypical Cushings disease, an effective treatment is a flaxseed lignan and melatonin combination, as both supplements can inhibit aromotase enzyme, thus effectively lowering estradiol and controlling atypical Cushings symptoms.
Lignans for Dogs
Lignans, along with melatonin, have been reported to slow the progress of and help ease the pain and symptoms of canine Cushing’s disease, atypical Cushing’s disease, and diabetes in canines. Vets also recommend flax hull lignans for canine Alopecia X. Alopecia X is baldness and is common in pets with hormone imbalances, such as those found in dogs with Cushing’s disease.
Lignans are found in the hulls of flaxseed and the knots of spruce pine trees. Lignans are an all natural way to treat Cushings in dogs and are being recommended by more and more vets as knowledge of their effectiveness spreads. In another study, lignans have been shown to actually shrink tumors.
Lignans are also a popular choice because they are cost effective and poses no risk of Addison’s. Flaxseed lignans are an all natural food product safe for canine Cushings with no known side effects
Diabetes and Canine Cushing’s
One of the natural functions of cortisol is to raise blood sugar. The overproduction of cortisol creates a continuous overproduction of blood sugar levels and thus, diabetes and Cushings often go hand in hand. Chronic canine Cushings can even cause permanent diabetes.
Lignans Dosages for Dogs
For people or pets, take 1-2 mg of lignan for each pound of body weight.
Click the following link for more detailed info on Lignans Dosage for Dogs
Vet Recommendations and Customer Testimonials:
Our company, Lignans for Life LLC (formerly Products Development, LLC) has exhibited our K9 Choice and Lignans For Life products at the Western Veterinary Conference in Las Vegas and the CVC Vet show in San Diego. Hundreds of Veterinarians visited our booth, many of whom already carried our products, and many of whom started carrying our flaxseed and HMR lignans- as well as our K9 Choice brand melatonin- after the show. Most of the other vets were excited to learn about alternative treatment options; especially a low cost Cushing’s Disease treatment for dogs that promotes general health. Veterinarians worldwide use us as a source for lignans and melatonin.
Cathy from Ohio wrote to us saying, “I am very impressed with the Lignans For Life Products…the dog that I bought them for is a 15 year old Akita/Siberian Husky mix female with atypical Cushings disease. Most of her symptoms have become more manageable (heavy breathing, excessive drinking and urination, skin lesions, stiffness in her back legs, sleeplessness at night, etc) and she is more comfortable. She has a pep in her step that she hasn’t had for years and she is now a therapy dog at a local retirement center here in Akron, OH. The products were securely packaged and the order shipped promptly.”
Hal M from Scottsdale, AZ reports, “My Maltese was diagnosed with Cushing’s disease and has been taking Trilostane for 3 years. She lost her hair and our vet suggested we start her on the Lignans. Within 2 months of giving her the flaxseed lignans, she started growing her hair back. We just sprinkle the flaxseed lignans on her food and she eats it with no problems.”
Michael D from California wrote “My dog was diagnosed with Cushing’s in June 2010; we have a great Vet who recommended the lignans. We found improvement in his energy and his weight after taking your Lignans For Life lignans. They are working so well for him that I am going to take it too.” Click here for more testimonials
We recently sent out a survey to our customers to obtain more statistics on the success of using HMR and Flaxseed SDG Lignans. We sent out a request to 100 of our customers, some gave their dogs HMR lignan and some gave their dog Flax lignans. 85% of participants said they saw positive results in an average of 2 months of taking the lignans. Most used melatonin in conjunction with the lignans. Some saw results in as little as 2 weeks and some said it was 4 months before they saw results, but an average of participants saw symptoms lessen in 60 days. Improvements included outward symptoms and blood results. Others showed improved visible symptoms, but blood work stayed the same.
Lee G writes, “She is not as hungry and she sleeps through the night. She hasn’t had any more UTI’s and the excessive thirst is gone, as well as the panting. It was a little over a month when I saw results.”
Angell B writes, “Excessive thirst has improved but what I really noticed is that her hair filled in. Her pot belly shrank too.”
Stacy M writes, “clinical signs have improved, especially less drinking and urination. I saw results in a few weeks.”
Walter L writes, “His drinking has curbed a bit. Remarkable improvement in his activity and quality of life. He runs/hops and is happy like a young dog. He has a bad back, but doesn’t appear to anymore. Remarkable in a word. We saw results in 10 days.”
Here at Lignans for Life, we get dozens of phone calls each week from customers that tell us their veterinarians have recommended our web site and the use of lignans, along with melatonin, for their dogs. Most vets recommend 1-2 mg per lb of animal weight. A general rule of thumb is to give one capsule for each 30 lbs of body weight. The capsules can be easily separated and the milled flax seed hulls can be poured onto the pet’s food. Since flax seed is a natural grain, precise dosages are not required.
Lignans for Life offers pure flax seed hulls. The hulls are separated from the flax seed via mechanical means (no chemicals are used). We offer multiple dosages and each capsule contains 15, 25, 30, or 35 mg of SDG lignans. If less is desired, the capsules come apart easily and- since the lignans are ground into a powder- the desired amount can simply be poured onto the dog’s food. However, vets agree that lignans are an all natural grain product and giving “too much” is not a major concern. It is more important to ensure the dog is taking the minimum amount of lignan required (1 mg of lignan per pound of body weight). It is best to stick within the recommended dosage of 1-2 mg per pound of body weight.
Most of our customers tell us they see results and the symptoms of canine Cushings disease diminish within an average of 2 months. Some say they see the symptoms of Cushings diminish within as little as 2 weeks.
Holistic Treatment of Canine Cushing’s Disease
Cushings in dogs is usually caused by a tumor on either the adrenal glands or the pituitary gland. The University of Tennessee college of veterinary medicine does most of the testing for Cushings when veterinarians send out blood work to determine if Canine Cushings is present. The University Department of Endocrinology is on the forefront of research in Cushing’s and they have some exciting results. A report issued by Dr Jack Oliver, DVM and Head of Endocrinology said, “Melatonin in combination with Lignans may be an effective treatment for Cushing’s disease.”
The report recommends this as a first treatment consideration before considering more harsh treatments like Ketoconazole, Lysodren or Trilostane, which are all expensive forms of chemo-therapy. Instead, lignans are an all natural and holistic way to treat Cushing’s disease in dogs.
Lignans are found in many plant sources including flaxseed, sesame seeds, broccoli, and rye, but the plant source with the most lignan is flaxseed. The lignans are found in the hull of the flaxseed. The hulls have a substantially higher amount of lignan than whole flaxseed. Flaxseed also contains SDG lignan. There is another source of lignan that comes from Norway Spruce Pine tree knots called HMR lignan. The University of Tennessee says that the HMR lignans work equally well in reducing cortisol levels associated with Cushings.
For more info on holistic and natural Cushing’s Disease treatment for dogs, Click here
The flaxseed hulls are highly concentrated with lignan and since this is a natural food product, it is safe to use and has no known side effects. The flaxseed hulls are also high in fiber, which benefits canines since many dog foods are low in fiber. Many studies show that people with high flaxseed lignan diets have better colon health.
It is the high fiber content that most likely contributes to this phenomenon. Fiber soaks up toxins in the body and increases bowel movement frequency and volume. Thus the body is able to get rid of harmful waste products more efficiently.
Dr. Jack Oliver’s report says that when using melatonin and lignans, expect to see improvement of symptoms within 4 months; however, in a recent survey of pet owners who had been treating cushings with lignans, the average time was about 2 months. The minimum recommended dosage is one milligram of lignan for each pound of dog weight. I.e. a 30 lb dog would take 30 milligrams of lignan per day. It is best to stay within 1-2 mg of lignan per pound of body weight. For small dogs, Dr. Oliver recommends 3mg of melatonin every 12 hours and for large dogs, 5-6 mg of melatonin every 12 hours.
Note: for very small dogs (10 lbs or less), or for those who want to give their dogs a very small amount of melatonin, vets may recommend 1 mg every 12 hours.
At Lignans for Life LLC (formerly Products Development, LLC) we have been selling flaxseed lignans for several years. We recently did a poll with our customers. 85% of participants said that they had positive results within 4 months. The average time in which they saw results was 2 months. Some respondents said they saw hair growing back, reduced panting, or reduced water consumption within as little as 2 weeks. Another positive outcome was improved blood test results.
Cushing’s Disease Treatment For Dogs
Section 2 mentions that melatonin is often used as a first treatment.
Section 8 mentions using lignans along with ketoconazole.
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 tumor presence.
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 12 hrs for dogs <30 lbs; a dose of 6 mg is given every 12 hrs 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 cortisol 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 steroid profile.
3) Melatonin Implants. Available for use as Cushing’s Disease treatment 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 effects on cortisol levels.
NOTE: MONITOR CORTISOL LEVELS ARE FOR TYPICAL CUSHING’S TREATMENT.
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-hydroxyprogesterone (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 JAVMA, 233:1896,2008).
9) Selgiline (AniprylTM). A less used alternative Cushing’s disease treatment. See Plumb’s Formulary.
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 indicated.
13) 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
2) lignan that is derived from the Norwegian Spruce tree (HMRlignan). Extensive discourse on these two product types can be found online.
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. (www.lpi.oregonstate.edu/infocenter/phytochemical/lignans).
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 (www.cat.inist.fr).
SDG flax hull lignan. See the article Lunus Pauling Institute at Oregon State
Click here for flaxseed lignans for dogs, HMR lignans for dogs, or melatonin for dogs