The developer of a compounded sex-hormone cream named in a scientific paper about fur loss in accidentally exposed dogs says she’s known for years that pets may get swollen nipples and genitals, as well as lose fur, from coming in contact with their owners’ drugs. She believes the consequences are harmless.

T.S. Wiley, inventor of a hormone-therapy approach known as the Wiley Protocol, told the VIN News Service in a recent telephone interview that she’s been aware of unintentional exposures in dogs since she began exploring the effects of hormone supplementation in women more than a decade ago.

“The dogs do not seem, over the decade I’ve watched, to be permanently harmed in any way. It’s more cosmetic than deleterious to their health,” said Wiley, who has a bachelor's degree in anthropology. She is not a physician or scientist.

The VIN News Service contacted Wiley and the company Perrico PLC, which markets the commercial estrogen-based spray Evamist, because their products are implicated in alopecia (fur loss) in dogs described in a paper published in the current issue of the Journal of the American Animal Hospital Association (JAAHA).

Veterinarians generally do not consider exposure of pets to exogenous, or outside, sources of estrogen or other sex hormones to be benign. “We have no idea what the long-term effects may be,” said Dr. Sherri Wilson, an internal-medicine consultant at the Veterinary Information Network, an online community for the profession. VIN is the parent of the VIN News Service.

A spokeswoman for Perrigo expressed concern about unintended exposures. “We take the health of our patients and their pets very seriously,” said Dr. Grainne Quinn, vice president of global patient safety for the company, which is headquartered in Ireland.

The VIN News Service has reported since 2010 on accidental exposures in pets to topical hormones and has tallied more than 100 anecdotal reports dating to 2003. Signs of exposure in some dogs lasted for years, and some owners invested substantial time and money in veterinary visits seeking an accurate diagnosis. In some instances, the quest for an answer involved exploratory surgery.

Transdermal drugs containing sex hormones — usually estradiol (a form of estrogen), progesterone and/or testosterone — are available for women and men alike. The products may be commercial drugs regulated by the U.S. Food and Drug Administration or compounded preparations, which fall into a regulatory gray zone. Compounded sex hormones, typically referred to as bioidentical hormones, have been touted by celebrities such as Oprah and Suzanne Somers.

The scope of sex-hormone therapy use is unknown, but according to a recently published estimate in the journal Menopause, between 1 million and 2.5 million women in the United States aged 40 years and older use compounded hormone therapies each year, accounting for somewhere between 28 percent and 68 percent of hormone therapy prescriptions.

Wiley, a book author and co-author of several scientific articles, estimates that 1 percent of users of topical compounded hormones follow her protocol. Based on the estimate of total compounded hormone use, that would make for 10,000 to 25,000 Wiley adherents.

Wiley said she does not believe that dogs exposed to Wiley Protocol products are harmed but acknowledged that users should be made aware of the signs of exposure in pets. She promised to revise the two-page instruction sheet for her products to provide more detailed information.

On the existing instruction sheet, a single allusion to accidental exposures reads: “Cover arms/thighs with clothing after application if you are in direct skin-to-skin contact with children, animals or others until it is absorbed (4 hours).” The four-hour time period is derived from existing studies on skin absorption of lipid-based products, Wiley said.

A Wiley Protocol product was identified as causing fur loss in a 19-month-old castrated Boston terrier whose case was described in the JAAHA paper. The terrier was one of six dogs found by a team of veterinary dermatologists to have alopecia driven by unintended exposure to human topical hormone therapies.

Besides balding, some of the dogs had enlarged nipples and genitals. In all cases, when the owners stopped applying hormones to their skin, the dogs went back to normal.

Wiley said she was more troubled that the owners discontinued the hormones than that their dogs absorbed the drugs. “I think the hormones are very important, and to go off of it because your dog has swelling, I think it’s kind of a rash decision,” she said.

As for the dogs’ health, Wiley said altering their natural hormone levels through spaying and castration is a more serious matter. “My thought about these animals getting extra hormones is ‘bonus.’ It might make them healthier,” she said.

Bone-marrow damage a risk

Wiley, who has no formal medical training, was unaware that exposure to exogenous estrogen can have toxic effects on dogs' bone marrow, causing life-threatening anemia and other health problems. A review published in October 2009 by the Canadian Veterinary Journal states: “Due to the risk of stimulating the development of uterine diseases and the potential for inducing aplastic anemia, estrogen use in dogs is best avoided where possible.”

The type of exposure addressed by the authors comes from using estrogens to manage diseases in canine patients and in experiments. But unintentionally exposing a dog to a person’s topical estrogen therapy apparently can carry the same risk.

It happened in a 12-year-old neutered, overweight beagle seen in 2013 by Dr. Lisa Ethridge at Canyon Pet Hospital in Flagstaff, Arizona. “He almost died,” Ethridge reported recently on a VIN message board.

Ethridge said the beagle had been generally unwell for about two months, then took a sharp turn for the worse, losing his appetite and developing diarrhea. He was admitted to the hospital, and Ethridge took the case a week later.

Talking with the beagle’s owner about what the problem could be, Ethridge said she suspected cancer but would need to biopsy the bone marrow to be sure. The owner pressed: Wasn’t there anything else the veterinarian could think of? Ethridge offered what she thought was a remote possibility — estrogen toxicity. At that, the owner “blurted out that she had started topical estrogen therapy about one month before” the dog became unwell, Ethridge recounted. “She then burst into tears … saying that she had ‘killed her dog.’ ”

It came out that the owner applied a hormone gel inside her forearms before she left for work every morning, Ethridge reported. “Then this dog (she has three others) always wanted a great big hug right as she was walking out the door. The other dogs did not get this hug. This dog is also an obsessive skin-licker.”

Ethridge did not know what the hormone product was, only that it came in gel form.

Once the mystery was solved, the owner began applying the gel to her thighs rather than her arms, and the beagle recovered, Ethridge said.

(Putting the product on thighs may lessen the chance of exposure to others but doesn’t completely eliminate it. Wiley said she knew a patient who applied hormone cream to her inner thighs and accidentally exposed her dog by allowing it under the covers in bed with her and sleeping bare-legged.)

After hearing about the beagle's life-threatening illness, Wiley surmised that the dog must have been exposed to “an awful lot of hormone,” and reiterated that products compounded in accord with the Wiley Protocol do not pose an unsafe level of exposure.

Wiley said her assurance stems in part from conversations with a veterinarian in Santa Fe, New Mexico, with whom she “followed some cases” a few years ago. She concluded that unintended exposures aren’t a problem.

The veterinarian, Dr. Mark Terry, remembers their conversations differently. In an interview with the VIN News Service, Terry said he contacted Wiley four or five years ago after seeing two dogs with alopecia whose owners followed the Wiley Protocol. Terry said the women had been advised not to use gloves when applying the hormone cream. Terry discovered that Wiley lived in Santa Fe, so he called her and they discussed the matter over lunch.

Terry recalled Wiley explaining that the dosing was predicated on using bare hands to apply the cream. He remembered responding that pets would be safer if their owners used gloves and applied the product somewhere that pets didn’t lick or otherwise touch. “I encouraged her to consider those issues from a spousal and child perspective, as well,” he added.

Whether exposure brings potential long-term ramifications in dogs is hard to say because most patients don’t have blood-chemistry analyses to determine the level of hormone in their bodies, Terry said. “As far as it being a purely cosmetic issue … since we don’t know what blood levels are really being attained, we don’t know,” he said. “That was certainly the message I intended to leave with (Wiley). It doesn’t sound like that is what she took away, or the years have blurred her memory, as well. Our conversation was a while ago.”

Wilson, the veterinary internal-medicine specialist, said that in some cases, exposure to their owners’ hormone products may result in only superficial issues for dogs, as Wiley submits. But the problem with that assumption, Wilson said, echoing Terry, is that the long-term consequences of such exposure largely are unknown. “Exposed dogs could develop mammary cancer, stump pyometra (uterine infection), not to mention decreased bone-marrow function,” she said.

As for questioning the effects of spaying and castration on dogs’ natural hormone levels, Wiley’s concern is well-placed, Wilson said. She noted that emerging research suggests that neutering a dog before it’s fully grown can, in at least some breeds, have a variety of detrimental health effects.

However, random exposure to people’s transdermal hormone therapies would not be the way to counter those effects, Wilson said. “The exposure to exogenous estrogen does not mimic their natural cycles,” she said.

Evamist label gives cautions on children, pets

Promoters of Evamist, a commercial estradiol spray designed to alleviate hot flashes in menopausal women, also have known for years that the drug poses a secondary-exposure risk. In 2009, Ther-Rx Corp., the company that marketed Evamist at the time, took steps to modify the product label to caution against accidental exposures in children and pets.

The updated label was put into use in October 2011, according to Quinn, vice president of global patient safety for Perrigo, which acquired the marketing rights to Evamist last fall. (Perrigo also has an animal-health arm that markets the brands Sergeant's, Sentry and Pet Armor.)

The current label for Evamist contains a black-box warning that includes this language: “Unintentional Secondary Exposure: Breast budding, breast masses and gynecomastia have been reported in children following unintentional secondary exposure to Evamist.”

Other sections about unintentional secondary exposure to estrogen elsewhere on the six-page drug insert elaborate on the nature of secondary exposure in children. On the fourth page is the line “Pets may also be unintentionally exposed to Evamist if above precautions are not followed.”

The patient information sheet contains this reference to pet exposure: “Do not let pets lick or touch your arm where you have sprayed Evamist, especially small pets. Evamist may harm them. Cover your skin with clothing where you have sprayed Evamist if you think a pet could come in contact with that area of your skin. If a pet accidentally comes in contact with the area of your skin where you have sprayed Evamist, the area of the pet’s skin should be washed with soap and water right away.”

Instructions for use include the directive “Always replace the cover over the cone of your Evamist applicator before you throw it away to prevent accidental exposure to other people or pets.”

In a telephone interview, Quinn said she believes the issue is “covered really well in the drug label.”

Asked whether it would be feasible and desirable to detail the clinical signs of exposure in dogs as is done for children, Quinn said doing so could introduce another problem. “If you put specifics about dogs (only), if I’m a cat owner, then I might think, ‘Oh, that’s about dogs so I don’t need to worry.’ I don’t want to falsely reassure cat owners.”

Quinn also said she does not think it necessary for the black-box warning about unintentional exposures to include a reference to pets in addition to children because references to pets appear elsewhere in the label. Asked whether patients are likely to read the label thoroughly, Quinn said, “They should read the label. We have a responsibility to read the label if we take a drug.”

She added, “The point is, we all shoulder this responsibility for the pets — the vets, the owners and the pharmaceutical companies. It’s a community approach.”