Hemangiosarcoma Awareness

The Luteinizing Hormone

If you have followed canine cancer research over the last several years, you may have come across mentions of "the LH theory" or "luteinizing hormone receptor activation" in connection with diseases that show up more often in spayed and neutered dogs. The theory is relatively new, still actively being studied, and not yet fully proven. But the evidence behind it has accumulated quietly and steadily, and it is now coherent enough that veterinarians, researchers, and informed dog owners are starting to think differently about the trade-offs of spay and neuter decisions. This article is our best effort to lay out, in plain language, what the LH theory actually proposes, what science currently supports it, and what is still unknown.

This page is educational and does not replace veterinary care. If your dog is showing sudden collapse, pale gums, or acute weakness, please treat it as an emergency and contact a veterinarian right away.

Table of Contents

  1. A Note Before You Begin
  2. What Luteinizing Hormone Is
  3. What Happens After Spay or Neuter
  4. The History of the LH Theory
  5. Where LH Receptors Are in the Body
  6. The Conditions Currently Linked to Elevated LH
  7. The Intervention: Suprelorin and Deslorelin
  8. What Is Known Versus What Is Still to Be Learned
  9. What This Means for Dog Owners
  10. A Few Closing Words
  11. Sources and Further Reading

A Note Before You Begin

This article goes into some depth on the biology, and we have written it carefully because the implications matter. Most of the structure and many of the specific data points come from a review paper published by Dr. Michelle Kutzler of Oregon State University in the journal Theriogenology in 2022. That paper, and the long line of research it summarizes, is the foundation of everything that follows. The companion source we draw from is the published interview between Dr. Christensen of Cocopelli Veterinary Center and Nicholberry Goldens, where the LH theory is explained in clinical practice terms.

We are not veterinarians, and nothing here is medical advice. We are dog people who lost our golden retriever Lyla to hemangiosarcoma, and we are sharing what we wish we had known sooner. If you have an already-spayed or neutered dog and you find the material here unsettling, please breathe. Read on to the section near the end called "What This Means for Dog Owners." The honest answer is that this is information to bring to your next vet visit, not a verdict on anything that has already happened.

What Luteinizing Hormone Is

To understand the theory, you have to start with what luteinizing hormone (LH) is in a healthy, intact dog.

LH is one of two hormones, the other being follicle-stimulating hormone or FSH, produced by the anterior pituitary gland, a small gland at the base of the brain. The pituitary itself responds to signals from another part of the brain, the hypothalamus, which sends out gonadotropin-releasing hormone (GnRH) at certain rhythms.

In an intact dog, the cascade looks like this. The hypothalamus releases GnRH. GnRH tells the pituitary to release LH and FSH. LH and FSH travel through the bloodstream to the gonads, which are the testicles in males and the ovaries in females. In response, the gonads produce reproductive steroid hormones: testosterone in males, estrogen and progesterone in females. Those steroid hormones then travel back through the bloodstream and tell the brain to ease off on the GnRH and LH signals. This is called negative feedback, and it keeps the system in balance.

In a healthy intact dog, LH stays at low baseline levels almost all the time, less than 1 nanogram per milliliter of blood. There are brief surges when they matter, such as the LH surge that triggers ovulation in a female during her heat cycle. Then it returns to baseline. Most of the time, the gonads are doing their job quietly, and the brain is satisfied. Now imagine you remove the gonads.

What Happens After Spay or Neuter

When a dog is spayed (ovaries removed) or neutered (testicles removed), the negative feedback loop is broken. There are no longer any gonads to produce the steroid hormones that used to tell the brain to ease off. So the brain keeps signaling. The pituitary keeps releasing LH and FSH. And because nothing is telling them to stop, LH levels rise and stay elevated, permanently.

How much do they rise? The published research is striking. In intact dogs, baseline LH stays under 1 ng/mL. In gonadectomized dogs, LH concentrations have been measured up to 100 ng/mL. That is roughly a hundredfold increase, sustained for the rest of the dog's life.

For decades, this was understood mostly as an interesting endocrinological consequence of gonadectomy, with no particular pathological significance. The body did not seem obviously different. The dog seemed fine. The hormones that needed to do their reproductive job were gone, and the LH increase was just a downstream artifact. That picture has changed.

The History of the LH Theory

The idea that elevated LH might be doing something harmful began to take serious shape through several converging lines of research.

One line came from human medicine. In humans, women who go through menopause, or who have their ovaries surgically removed, also experience large rises in LH that persist, because the same feedback mechanism is broken. Researchers studying postmenopausal women found that elevated LH was associated with higher rates of certain conditions, including hypothyroidism and certain cancers. This raised the question of whether something similar might be happening in dogs.

A second line came through Dr. Michelle Kutzler at Oregon State University. As Dr. Kutzler has discussed in interviews, her husband's family had bred Rottweilers for years, and over time those dogs kept developing cancers and other serious conditions. Her interest in why led her to look more closely at what happens to LH in gonadectomized dogs, and at what tissues throughout the body might be affected.

The breakthrough conceptually was the recognition that LH receptors are not only in the gonads. They are present in tissues throughout the body.

Where LH Receptors Are in the Body

In the Kutzler 2022 review, LH receptors are described in a broad and somewhat startling list of tissues. They are present in:

  • The thyroid gland
  • The bladder and urethra, which form the lower urinary tract
  • Vascular endothelial cells, the cells that line the inside of blood vessels
  • Vascular smooth muscle
  • The skin
  • The adrenal cortex
  • Ligaments and bone
  • Lymphocytes, which are white blood cells
  • And other tissues

For most of these locations, LH receptors had been documented in the literature for years. What was not as clear was what those receptors actually did. They were, until recently, assumed to be either vestigial (left over from development) or only weakly active. The newer research, much of it from Dr. Kutzler's lab and collaborating labs, has begun to show that these receptors are functional. When LH binds to them, real things happen at the cellular level. Cells that should be quiescent start proliferating. Cells that should stay where they are start migrating. Tissues that should respond to one signal end up responding to two, and the responses interfere with each other.

In short: chronic supraphysiologic LH exposure, the kind that happens permanently after gonadectomy, may be activating receptors throughout the body in ways that contribute to several long-term health problems.

The Conditions Currently Linked to Elevated LH

The Kutzler 2022 paper organizes its review around five specific conditions, each with a "what we know" section and a "what we still need to learn" section. This honest framing is one of the things that makes the paper credible. The author is not claiming certainty where it does not exist.

Urinary Incontinence

This is the longest-known and best-documented connection. Urinary incontinence, specifically urethral sphincter mechanism incompetence, affects up to 30 percent of female dogs after spaying. The association was first described in 1965 by a researcher named Joshua, and the literature has grown steadily since.

What the research shows is that LH receptors are abundant in the lower urinary tract of dogs, both in the epithelial cells lining the urethra and bladder, and in the smooth muscle that controls them. After spay, the gene expression for these receptors actually increases. And several treatments that effectively lower circulating LH, including estrogens, GnRH agonists like Suprelorin, and GnRH immunization, have been shown to restore urinary continence in spayed incontinent dogs.

The picture is therefore quite clear here. Continuous LH receptor activation in the urinary tract appears to contribute to the loss of bladder control that some spayed dogs develop. What is still unclear is why the timing of the surgery affects risk in inconsistent ways across studies, why some breeds are much more affected than others (Boxers, Dobermans, Giant Schnauzers, and Rottweilers are over-represented; German Shepherds and Labradors are not), and whether the structural changes in the bladder are reversible.

Hypothyroidism

Hypothyroidism is one of the most common endocrine disorders in dogs. The Kutzler paper states, citing prior research, that gonad removal is the single most significant cause of hypothyroidism in dogs. Approximately 30 percent more gonadectomized dogs develop hypothyroidism compared to intact dogs.

The proposed mechanism is mechanistically detailed. LH receptors are present on canine thyroid cells, called thyrocytes, and they are co-located with thyroid-stimulating hormone (TSH) receptors on the cell surface. Both receptors use the same intracellular signaling pathway, involving cyclic AMP and adenylate cyclase. When LH is chronically activating its receptor, it may be consuming the cellular machinery that TSH needs to do its job. The TSH signal does not get through properly, the thyroid produces less thyroxine, and the dog becomes hypothyroid.

What is still to be proven is the direct demonstration of this interference in living animals. The receptor co-localization has been shown. The pathway sharing has been shown. The epidemiology fits. But a clinical trial showing that lowering LH, with a GnRH agonist like Suprelorin, restores thyroid function in hypothyroid spayed dogs has not yet been completed.

Anterior Cruciate Ligament Rupture

The connection between gonadectomy and cruciate ligament rupture is one of the most striking in the entire literature. The risk is doubled in gonadectomized dogs compared to intact dogs, and this holds independently of breed, sex, body weight, or body condition. A summary of nine separate epidemiological studies found gonadal status to be the single most important factor, more important than obesity or any specific breed.

This matters because cruciate ligament rupture is not a small problem. Half of dogs that rupture one cruciate ligament will rupture the contralateral one, the other knee, within a year. Without surgical repair, the joint becomes painful with osteoarthritis, often for the rest of the dog's life.

The mechanism, as proposed in the Kutzler 2022 paper, involves LH receptors expressed in the cruciate ligament itself. LH receptor activation in the reproductive tract is known to increase local nitric oxide release, which has effects on tissue laxity and on collagen expression. In the cruciate ligament, increased nitric oxide and altered collagen could mean the ligament becomes more lax, less able to handle stress, and more prone to rupture under loads that an intact dog's ligament would withstand.

There is also a structural consideration in dogs spayed or neutered very early. Pre-pubertal gonadectomy delays the closure of the tibial growth plate, which extends the length of the tibia and steepens the tibial plateau angle. A steeper tibial plateau increases the forward forces on the cruciate ligament during normal movement. So an early-spayed dog may be at risk both because of the structural geometry of her stifle (knee) and because of the ongoing LH receptor activation in the ligament tissue itself.

What needs to be proven is a direct mechanistic study of whether activating LH receptors in actual canine cruciate tissue produces measurable laxity, and a clinical study testing whether lowering LH after a unilateral cruciate rupture improves the chance of preserving the second ligament.

Hemangiosarcoma

This is the section most directly relevant to the mission of this site, and the one where, for us, the implications are most personal.

Hemangiosarcoma is a rapidly growing, highly invasive cancer that arises from the lining of blood vessels. It occurs almost exclusively in dogs, and it is associated with a notably poor prognosis. The median survival after surgical removal of the primary tumor alone is two months or less. Adding chemotherapy can extend median survival to 6 to 12 months. Affected dogs are typically older than 5 years, though it can occur younger.

Three breeds are dramatically over-represented in canine hemangiosarcoma diagnoses: German Shepherds, Golden Retrievers, and Labrador Retrievers. Together, they account for about 34 percent of all purebred dogs diagnosed with splenic hemangiosarcoma. In addition to age and breed, gonadectomy itself raises the risk. Compared to intact females, spayed female dogs have between 2 and 10 times the risk of developing hemangiosarcoma. That is a substantial and well-documented increase. The risk pattern in goldens specifically was documented in the University of California, Davis study of 759 Golden Retrievers, which found that 7 percent of females spayed at or after one year of age developed hemangiosarcoma, more than four times the rate seen in intact and early-spayed females.

What is the evidence for an LH role in this cancer specifically?

The evidence is more direct than for some of the other conditions. LH receptors have been documented in vascular endothelial cells and vascular smooth muscle, the same cells that hemangiosarcomas originate from. Dr. Kutzler's lab has demonstrated LH receptor expression in actual canine hemangiosarcoma tumors of multiple anatomic locations: splenic, cardiac, cutaneous, and dermal. These receptors are not vestigial or incidental. In isolated canine hemangiosarcoma cells in culture, activating LH receptors with recombinant canine LH causes the cancer cells to proliferate.

So the picture as currently understood is this: hemangiosarcoma cells have LH receptors, those receptors are functional, and in a spayed or neutered dog whose LH is chronically elevated about a hundredfold, those receptors are being continuously stimulated. The result is a growth signal feeding into cells that already have the cancer's other defects, in a dog whose breed already may carry genetic predispositions to that cancer.

There is also an interesting anatomical observation in the Kutzler review. In both dogs and humans, nearly all cardiac hemangiosarcomas originate from the right atrium of the heart, more specifically from a small pocket called the right auricle. The reasons for this anatomic predilection are not fully understood, but it raises questions about whether LH receptor density varies by location within the heart, and whether some regions of vascular tissue are more susceptible than others. This is one of several specific questions that Dr. Kutzler's lab and others are working on.

What is still needed is a clinical trial in dogs to test whether lowering LH, again with a GnRH agonist implant like Suprelorin, at the time of hemangiosarcoma diagnosis can extend survival by slowing the growth of residual tumor cells. That trial has not yet been done. Until it is, the theory remains a theory, well-supported but unproven at the level of treatment outcomes.

Lymphoma

Lymphoma is the most common cancer overall in dogs, accounting for up to 24 percent of all canine cancers. Several breeds are over-represented, including the same goldens, German Shepherds, and Labrador Retrievers that appear in the hemangiosarcoma list. Gonadectomy increases lymphoma risk by a factor of 3 to 4. That is a major effect.

LH receptors are present in lymphocytes and in lymphoid tissue. In Dr. Kutzler's research, the percentage of circulating LH-receptor-positive T-lymphocytes is significantly higher in gonadectomized dogs than in intact dogs. And up to 45 percent of isolated neoplastic T-lymphocytes, in lymphoma, express LH receptors.

What is most concerning, mechanistically, is what happens when those receptors are activated. In cell culture experiments, activating LH receptors on cancerous T-lymphocytes causes them to proliferate, to adhere to other cells, and to migrate through endothelial cell monolayers. Adhesion and migration through endothelial cells is essentially the mechanism of cancer metastasis. So LH receptor activation may not just be making lymphoma cells grow. It may be making them more able to spread. The same caveat applies. The receptor work, the in vitro work, and the epidemiology all converge on the LH theory. A clinical trial testing whether lowering LH in dogs with lymphoma improves outcomes is still needed.

Other Possible Connections

The Kutzler 2022 paper focuses on the five conditions above. But veterinarians working in this space, including Dr. Christensen, Dr. Kutzler, and others, have mentioned other possible links that are not yet documented in the formal literature.

Dr. Kutzler, in interviews, has described a colleague who used a deslorelin implant in her own dog who had been on Cytopoint injections every 2 to 3 months to control atopic skin allergies. After the implant, the dog did not need Cytopoint for over 6 months. This is a single case, but it raises the question of whether LH receptor activation in the skin might contribute to allergic conditions in some dogs.

Other speculative connections include seizures, certain behavioral changes, and mast cell tumors. None of these are formally established. They are mentioned here only to indicate that the LH theory may have implications beyond the five conditions currently best documented, and that the field continues to develop.

The Intervention: Suprelorin and Deslorelin

If the LH theory is correct, then the most important practical question is whether lowering LH in already-spayed or neutered dogs can prevent or treat these conditions. The candidate intervention is a class of drugs called GnRH agonists, the best known of which in veterinary use is deslorelin, marketed as Suprelorin (sometimes called Superlorin).

A GnRH agonist works through a counterintuitive but well-understood mechanism. GnRH normally pulses from the hypothalamus in rhythmic bursts. The pituitary responds to those bursts. When a GnRH agonist is given continuously through a long-acting implant, the pituitary is exposed not to pulses but to a constant signal. After an initial brief surge in LH and FSH, lasting a few days, the system shuts down. The pituitary essentially gets desensitized and stops responding. Both LH and FSH production drop to near zero.

In a spayed female dog, this means the chronically elevated LH that has been signaling throughout the body for years is suddenly turned off. There is no risk of ovarian cysts, the main side effect concern in intact females given GnRH agonists, because there are no ovaries to become cystic. The implant simply silences the LH signal.

This intervention is being studied in several contexts, and there is at least one published case report (Brent, Lissner, and Kutzler, 2021) describing improvement in hormonal parameters and overall health in a male neutered dog given supportive hormonal therapy. Other clinical studies are in development.

In terms of access, the regulatory situation differs by country. In Canada, deslorelin implants are approved for use in dogs, available without a special permit. In the United States, the only deslorelin implants formally approved are labeled for ferrets, and veterinarians need a special import permit through USDA to use them in dogs legally. The drug itself is identical. The labeling is not. This is one of the practical challenges in turning the LH theory into widely available clinical practice in the United States. Many veterinarians either do not know about the option or face regulatory friction in using it. For owners interested in exploring it, the path is usually through a reproductive specialist, called a theriogenologist, rather than a general practice vet.

What Is Known Versus What Is Still to Be Learned

This is the most important section, because it determines how to think about the LH theory honestly.

What is well established:

  1. LH levels rise sharply and persistently after gonadectomy in dogs.
  2. LH receptors are present in many tissues throughout the body, not just the gonads.
  3. Several conditions are significantly more common in gonadectomized dogs: urinary incontinence, hypothyroidism, cruciate ligament rupture, hemangiosarcoma, and lymphoma.
  4. LH receptors are present and functional in the specific tissues where these conditions arise, including in tumor tissue itself.
  5. Activating those receptors in cell culture produces effects (proliferation, adhesion, migration) that are biologically consistent with the diseases observed.
  6. Lowering LH improves at least one of these conditions, urinary incontinence, in clinical practice.

What is not yet established:

  1. The direct causal chain between elevated LH and the development of each of the cancers in living dogs. Correlation and mechanism are strong; full causation is not yet proven.
  2. Whether lowering LH after diagnosis improves survival in dogs with hemangiosarcoma or lymphoma. The clinical trials have not been completed.
  3. Whether lowering LH preventatively in already-spayed or neutered dogs reduces their cancer risk. This is a longer and more expensive study to do.

A balanced scientific view, including from Dr. Robert Rebhun in the oncology department at UC Davis, has appropriately cautioned against running too far with this theory before the clinical trials are done. Age is also a major risk factor for any cancer, in any dog of any sex or surgical status. The LH theory does not replace other risk factors. It adds a new lens for understanding them.

The honest current state of the science is this: the LH theory is the leading explanation for a real set of correlations. It has mechanistic support. It has plausibility. It has cellular evidence. It does not yet have clinical proof. That proof is the next step, and several research groups are working on it.

What This Means for Dog Owners

For dog owners trying to make practical decisions today, the implications of the LH theory are not a verdict. They are an additional consideration in an already complex conversation.

For dogs not yet spayed or neutered, the theory adds weight to the case for hormone-sparing options (vasectomy in males, ovary-sparing spay in females) when they are appropriate to your situation. It does not mean every dog should be left intact. Pyometra is real. Unwanted breeding is real. The right answer is the one that fits your specific dog, your specific household, and your specific veterinarian's expertise. For a fuller account of the options, see our companion article on spay and neuter.

For dogs already spayed or neutered, which is most dogs in the United States, the theory does not change the past, and it does not mean that anything is wrong now. Most spayed and neutered dogs live long, healthy lives. The theory simply describes elevated baseline risks, not destinies.

For owners of breeds at elevated cancer risk, including goldens, German Shepherds, Labrador Retrievers, and others, the practical implications include regular senior wellness checks with bloodwork, learning the warning signs of the cancers your breed is prone to, and being attentive to changes that warrant a vet visit. Some owners and vets are also considering deslorelin implants in already-spayed dogs as a precautionary intervention. This is not yet standard care, and the decision involves careful conversation with a veterinarian who is knowledgeable about the LH theory specifically.

A Few Closing Words

Lyla was a golden retriever. She was spayed traditionally when she was young, as the standard advice of the time recommended. Years later, she died of hemangiosarcoma. We do not know how much, if anything, would have changed if we had known then what we are learning now. Maybe a great deal. Maybe nothing. Cancer is multifactorial, and no one decision determines its course.

What we do know is that the conversation is bigger than it used to be. The science is moving. The questions worth asking your vet have expanded. And the small, careful effort of reading something like this article, and bringing the questions it raises to your next vet visit, may be the most useful thing you can do for the dog who is by your side right now.

That is the whole point of this site, and of writing about something as technical as the LH theory in language as plain as we can make it. The dogs who come after Lyla deserve every advantage we can give them. So do you, as the people who love them.

Sources and Further Reading

This article draws primarily on:

Other key references cited within the Kutzler 2022 paper include:

The full reference list in the Kutzler 2022 paper includes nearly 100 sources spanning the underlying biology, the epidemiology, the cellular research, and the clinical experience that together support the LH theory. For readers who want to go deeper into the primary literature, that reference list is the best place to start.

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