Hormonal (Endocrine)

“There may be a need to evaluate possible methods for counteracting the effects of loss of sex hormones in gonadectomized dogs.”
— Dr. Benjamin Hart;  School of  Veterinary Medicine, UC Davis
(J Am Vet Med Assoc 2001; 219:51–56)

As you have probably gathered by now, the issues we have discussed regarding spay/neuter all center on hormones. Clearly the concept of spay/neuter to curb overpopulation and perhaps make dogs more manageable was undertaken without regard for, or an understanding of, potential unintended consequences.  This section of our web site will go into clinical outcomes; only some of which the veterinary community has acknowledged.  We experienced many of these clinical entities with our dog Billy, and our conclusions as to the how and why are backed up by research on canines and humans.

We want to bring you back to the schematic of the ill effects of endocrine disruptors and the three legged stool in the diseases overview.

HAHD_EDC

If we look at the Endocrine Disruptors schematic, we see the following items we have highlighted:

HAHD_Stool

Referring to the three legged stool, it follows that when a dog is spayed or neutered, the sex hormones leg is cut off, and the adrenal glands  must take on the added responsibility of sex hormone production. This could explain why some dogs are not obviously affected by spay or neuter while they are young. The adrenals are functioning at a high level and can compensate.

However, as the dog ages and/or the dog is subjected to stressful situations (surgery, injury, rehoming) the adrenals become less able to compensate and we see irregularities in the stress and immune response.

HAHD_Endocrine_Stress_Overload

Pregnenolone is the substance the adrenal glands use to make progesterone, estrogens, testosterone and cortisol.  When stress is excessive, the pregnenolone will be diverted to make cortisol instead of healthy sex hormones. Ultimately the “pregnenolone steal” in the body’s attempt to make sufficient cortisol to support the high level of chronic stress will deplete the body of adequate sex hormones.

HAHD_Endocrine_Thyroid_Adre

Proper thyroid function depends on healthy adrenal glands. The hypothalamus and pituitary glands direct both adrenal and thyroid gland hormone production. Countless studies show that chronic adrenal stress compromises hypothalamic and pituitary function, thereby suppressing thyroid function.

Hypothyroidism” (a failure of the dogs thyroid gland to produce enough thyroid hormone) has been tied directly to spay/neuter in at least one canine study. Spay/neuter in dogs was found to be correlated with a three fold increased risk of hypothyroidism compared to intact dogs.26,27

The pituitary also produces Growth Hormone, which can be compromised when the adrenal glands are excessively stressed. Lack of growth hormone can cause altered glucose metabolism, abdominal obesity, diminished muscle tone and function, and reduced vitality and energy. Clearly the hormone systems in a dog are a complex web of interdependent actions with feedback mechanisms to regulate these actions.

Disruption of the endocrine balance through spay/neuter can lead to at least three endocrine disease entities:

  1. Cushing syndrome consists of the physical and mental changes that result from having too much cortisol in the blood for a long period of time. Cortisol is a steroid hormone produced by the adrenal glands. Hyperadrenocorticism (overproduction of cortisol in the adrenal gland) is generally due to a tumor in the pituitary gland (Cushings disease) or the adrenal gland (Cushings syndrome).  “Cushing’s disease (CD) is a common endocrinological disorder in dogs with an estimated incidence of 1 to 2 cases/1,000 dogs/year. This is in contrast to humans in whom CD is rare. The clinical presentation of CD, however, is highly similar between dogs and humans, with characteristic signs, such as abdominal obesity, weight gain, fatigue, muscle atrophy and skin changes. Canine CD may therefore serve as an animal model for human CD.” 73 It is our belief the higher incidence of Cushings in the canine population has everything to do with the additional stress put on the dog’s hormonal complex (especially the adrenal and pituitary glands) and the compromise of the immune system after spay/neuter.
    1. Atypical Cushings is defined in veterinary literature as overproduction of other adrenal steroids known as “sex steroids”76   and in fact, is not Cushings at all because there is no excess cortisol. Atypical Cushings does not exist as a disease entity in humans. The closest human disease entity is Cushings with atypical presentation which is again excess cortisol from another source or patients with abnormal sensitivity to cortisol. We would suggest Atypical Cushings is a byproduct of spay/neuter, which is why it is not seen in humans.
    2. Hyperestrinism (excess estradiol) without elevated cortisol, as Billy experienced, would be an example of what veterinarians designate as Atypical Cushings in dogs. This is misleading because again Billy’s cortisol was not elevated, and the excess estradiol is not necessarily produced in the adrenal glands. Estradiol is made in many other cells of the body, e.g. fatty tissue and the brain.
    3. 3.Type 2 Diabetes is often associated with Cushings in the human environment, although this is not acknowledged by the veterinary community. A review 97 published in Trends in Endocrinology & Metabolism suggests that 36% of human patients with overt Cushing’s syndrome and 22% of patients with subclinical Cushing’s syndrome had diabetes while another 17% to 23% have impaired glucose tolerance.

Steroid hormone profiling in veterinary medicine started at the University of Tennessee Clinical Endocrinology Service, on the premise that multiple steroid hormone analyses would increase the diagnostic accuracy of adrenal-function tests.76

Even today, their web site states, “Our Clinical Endocrinology Service is the only veterinary diagnostic laboratory in the United States to offer an adrenal steroid profile test in dogs. Our Service has gained a national and international reputation for providing adrenal steroid profile testing. The adrenal steroid profiles (also known as adrenal panels) are determined in dogs, cats, ferrets, and rabbits that are suspected of having adrenal disease. These profiles provide a more complete evaluation of adrenocortical function by assessing hormone concentrations that arise from different parts of the hormone synthesis pathway.”

However, it is clear from the scientific reviews/studies over time, that there was little or no appreciation in the veterinary community or among the “experts” at the University of Tennessee for the hormonal chaos spay/neuter was creating.  For example, in 2003, at the University of Tennessee a study 77was conducted to determine steroid hormone concentration profiles in healthy intact and neutered male and female dogs.  It states:

“Results from this study will enhance interpretation of suspected adrenal and/or gonadal disorders of dogs.  Because estradiol concentrations were similar in all groups of dogs, measuring estradiol may not be a useful diagnostic test.”

Several years later, from a  2007 presentation 76given by one of the same scientists:

Hyperestrinism in dogs may be a new and emerging disease entity. In sample submissions to the Clinical Endocrinology Service (2005) at The University of Tennessee, 40% of adrenal panels had elevated estradiol levels present (>70 pg/ml).  In hyperestrinism cases, estradiol is the estrogen that is increased…Effective treatment options for hyperestrinism in dogs is limited at the present time…Aromatase enzyme inhibiting drugs will decrease estradiol levels, but currently are infrequently used (except melatonin) in animals due to cost considerations.”

It is clear in 2005 the Tennessee veterinarians were recommending melatonin as the most practical aromatase inhibitor to counteract hyperestrinism (too much estradiol) in dogs. There was at least one other aromatase inhibitor (Arimidex – generic name anastrozole 96) available that had proven to be safe and effective in dogs by studies dating back to 1994. The cost of anastrozole was significant.

However, the viewpoint of these veterinarians was so myopic as to be dangerous. The research on melatonin, as early as 1996, found that melatonin is a hormone with such global effects in the bodies of people (and animals) that it was termed a “master hormone”, and a “candidate for universal panacea”.86

In 2005, researchers associated with UC Berkeley published a study in Science Daily which should have garnered the attention of these veterinarians. The article was entitled, “Popular Supplement Melatonin Found To Have Broader Effects In Brain Than Once Thought.” In fact, the author Dr. Bentley noted, “This is quite exciting in terms of potential effects of melatonin on the reproductive axis, that is, the link between the brain, the pituitary gland and the gonads…Melatonin has not been considered to have an effect on any neuropeptide in the brain of any vertebrate. If melatonin can do this on one neuropeptide system, it has the potential to do it on any other neuropeptide system…It is a powerful hormone, and yet people don’t realize that it’s as ‘powerful’ as any steroid. I’m sure that many people who take it wouldn’t take steroids so glibly. It could have a multitude of effects on the underlying physiology of an organism, but we know so little about how it interacts with other hormone systems.”

In 2012, another study published in Science Daily indicated that the release of insulin, which regulates blood sugar levels, is known to be regulated by melatonin. Yet, in 2013 when we received Billy’s hormone panel results and treatment recommendations, the following is what was recommended by the University of Tennessee “experts” regarding Billy’s hyperestrinism: “Melatonin. Often used as a first treatment, especially if alopecia (fur loss) 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 6 mg. is given q12 hrs. (BID) for dogs over 30 lbs.”

There is no mention that melatonin could raise blood glucose levels. Billy was an uncontrolled Type 2 diabetic with routine blood glucose readings at or near 400. The “experts” were recommending a treatment that could not be considered prudent. There is still no mention of anastrozole, which was then available to pet guardians under pharmacy pet plans for as little as $30.00/month (and does not raise blood glucose levels or have other significant side effects reported in the literature).

Aside from the failure to associate melatonin with insulin and blood glucose regulation, or any other significant side effects, there is also the matter of the dose. How did the “experts” come up with a 6 mg. dose twice a day?  Just this year (2016), in a newly published study researchers showed that insulin-producing cells respond to increased levels of melatonin by reducing the amount of insulin they release. The study was designed to assess the effect of melatonin upon a population with a genetic variant, however the controls in the study did not possess the genetic variant. For 3 months, participants with and without the gene variant took 4 milligrams of melatonin before they went to bed at night. The researchers compared blood sugar and insulin levels taken at the start and end of the treatment period. After 3 months of melatonin treatment, all participants had higher levels of blood sugar, (even those without the genetic variant). If a person weighing 150 pounds has a significant increase in blood sugar while taking only 4 milligrams of melatonin a day, what would you expect for a 40 pound dog taking 12 milligrams of melatonin a day?

Even today, if you go to their web site (https://vetmed.tennessee.edu/vmc/dls/Endocrinology/Pages/default.aspx) the veterinarians at Tennessee are still recommending melatonin and lignans (flax seed hulls – believed to be weak aromatase inhibitors) to combat excess estradiol. The most recent study reported on their web site was: Melatonin-Lignan “Effect of combined lignan phytoestrogen and melatonin treatment on secretion of steroid hormones by adrenal carcinoma cells”. How can a study on human adrenal cells alone possibly take into consideration the “master hormone” effects of melatonin, including its effect upon insulin secretion and blood sugar?

At this point in time, we found ourselves at an impasse with the veterinary community.  It appears to us that the hormonal imbalance created by spay/neuter can lead to the development of hypothyroidism, Cushings, “Atypical Cushings”, and Type 2 diabetes.

Our dog Billy did not fit any of the accepted veterinary diagnoses or treatment plans. Billy did not have traditional Cushings because his cortisol was not elevated. However Billy had been diagnosed with elevated blood glucose that was consistent with Type 2 diabetes. Type 2 diabetes does not exist in the veterinary literature. but is associated with traditional Cushings in humans.  Billy suffered with severe hyperestrinism as he had 6 times the normal amount of estradiol for a male.  Billy also had NO testosterone. Most veterinarians classified Billy’s condition as “Atypical Cushings”.  The experts’ recommendation for treatment of Billy’s hyperestrinism (melatonin supplementation) was contraindicated due to his uncontrolled Type 2 diabetes.  Billy’s blood glucose was barely responding to insulin injections; his average daily blood glucose readings were at or near 400, when normal is 80-120. We tried different insulins with no success.

It is only through research of studies with humans as the subjects that we were able to make sense of Billy’s situation. Initially, the most helpful study we found was conducted on humans and states:

“We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.”

We determined if this research was applicable, reducing Billy’s estradiol should diminish his insulin resistance, thereby improving his blood glucose. We researched the connection between Cushings and Type 2 diabetes and found further helpful references.  One was excerpted from a presentation at the  International Congress of Endocrinology and the Endocrine Society in 2014:

“Undiagnosed Cushing’s syndrome is common in type 2 diabetics. There are a substantial number of patients with type 2 diabetes who have Cushing’s 97 syndrome as a contributing factor to their diagnosis. You can substantially improve their diabetes and possibly eliminate it, if they are treated for their Cushing’s syndrome…”

Based upon these two references, even though Billy did not have traditional Cushings, our only option seemed to be normalization of Billy’s hormones. We felt if we did so, we might be able to improve his insulin resistance, and his diabetes. We researched to find effective medications that would reduce Billy’s estradiol (other than melatonin) and we discovered anastrozole 96,98 – an aromatase inhibitor utilized for women with estrogen sensitive breast cancer. We were able to convince the veterinary Internal Medicine specialist to prescribe anastrozole for Billy. It reduced his estradiol levels and we were able to bring his average daily blood glucose readings to just under 300.

There were many studies which associated low testosterone with insulin resistance in men, although none were able to clearly prove that low testosterone caused the insulin resistance. However, in 2010, the high prevalence of a low serum testosterone level in patients with type 2 diabetes was addressed in the Endocrine Society’s Clinical Practice Guideline within the context of testosterone replacement therapy in adult men with androgen deficiency syndrome. Since Billy was a male and had NO testosterone at all, we felt testosterone replacement could be helpful. The Internal Medicine specialist refused to prescribe testosterone for Billy.  Thankfully, our primary care veterinarian was willing to help us, and gave Billy testosterone injections to bring him to a normal level of testosterone.  Almost immediately, his blood glucose levels came down to the low 200s and over the last year of Billy’s life, his average daily blood glucose readings continued to drop until they were in the mid 100s. There is now accumulating evidence that low serum testosterone level is associated with type 2 diabetes. (2 cites)

Based upon our experience, we would suspect that spay/neuter caused Billy’s Type 2 diabetes and his hyperestrinism and testosterone deficit were contributory. We suspect spay/neuter could cause Type 2 diabetes in female dogs as well. For the female dogs we have no personal experience, however we did note in our research that there is a common endocrine system disorder in women of reproductive age termed polycystic ovary syndrome (PCOS).  The web site at the Mayo Clinic indicates a feature of this condition is elevated levels of male hormones (androgens) which can cause androgenic alopecia and a complication of this disorder is type 2 diabetes.

Much more research needs to be undertaken to clarify the underlying cause/s for the emergence of Cushings, “Atypical Cushings” and Type 2 diabetes in dogs. However, it may be more pragmatic to move as soon as possible to tubal ligation and vasectomy instead of spay/neuter. There is great value in that approach as it would improve behavioral issues, and reduce the incidence of orthopedic problems and cancer in dogs. It would be helpful at that point to evaluate the incidence of Cushings, “Atypical Cushings” and Type 1 and 2 diabetes. A significant change in incidence (or not) could direct additional research.

 

 

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