Lowering the Bar is a 麻豆传媒/Milwaukee Journal Sentinel series that investigates the growth of new diseases in the 21st century -- diseases that often provide new targets for pharmaceutical industry products. This installment focuses on "Low-T" and "hypoactive sexual desire disorder."
As the Baby Boomers grew to adulthood, drug companies had a major hand in keeping them healthy -- from polio vaccines when they were children, to life-saving cholesterol drugs when they reached their 40s.
And when they reached their 50s and 60s, and encountered one of the curses of aging -- diminished libido -- it's not surprising that they would turn again to that industry for help.
Industry was eager to offer that help, even though it would mean pivoting from seeking treatments for well-recognized illnesses to developing a "cure" for a condition not usually considered a disease.
We Have a Name for That
For men, it is "Low T" -- declining testosterone levels often accompanied by low libido, a natural element of aging. Thanks to a , suddenly 38% of men over 45 -- some 14 million Americans -- were deemed to have it.
For women, it is hypoactive sexual desire disorder -- recently renamed female sexual interest/arousal disorder -- which critics say is a questionable medical diagnosis.
In 1999, a paper written by authors with drug industry financial ties found that 43% of women had some form of sexual dysfunction, including a lack of interest in sex.
Other drug industry-funded studies in the mid-2000s claimed some 9 million women had sexual dysfunction and were troubled by it.
Consider hypoactive sexual desire disorder and the drug flibanserin (Addyi).
After twice rejecting the drug, the FDA approved it last year over serious concerns about its safety raised by the agency's own doctors. The FDA researchers said the drug could cause a dramatic drop in blood pressure when taken with alcohol. That, in turn, could lead to women passing out.
When the agency told Sprout Pharmaceuticals -- the company that took over development of the drug after Boehringer Ingelheim backed off -- to investigate the blood pressure-alcohol link, the company responded with a study of 25 people -- 23 of the whom were men.
The FDA accepted Sprout's contention that it could not find moderate female drinkers to enroll in the study, a Journal Sentinel/麻豆传媒 review of agency records found.
In the end, the records show, several participants in the test needed medical attention because they passed out, or had blood pressure drops of 22 to 48 mm Hg. The FDA's internal reviewer said this raised the possibility that non-drinkers may have an even more severe reaction if they were to have something to drink.
The reviewer said the drug should not be approved until a study on women -- "the only gender for whom this drug is indicated" -- was done.
"Drink to Me Only With Thine Eyes ..." Really
Nonetheless, the FDA approved the drug and women who use it were warned not to drink.
"I disagree with that on so many different levels," said , president of the National Center for Health Research, a nonprofit think-tank that analyzes health research.
"You call something a medical condition; you find a solution for it; the solution actually doesn't work and it has substantial risk. The scientists say don't approve it and the FDA approves it anyway," Zuckerman said.
In an email, FDA spokesperson Sarah Peddicord said the agency recognized the drug's serious side effects. She noted the agency is requiring the company that markets Addyi to conduct three studies in women to better understand the blood-pressure drops that can occur -- and the drug carries a REMS (risk evaluation and mitigation strategy). The drug also carries the FDA's most stringent black box warning.
"As with all medications, some patients will obtain more benefit than others," Peddicord said. "Because (the condition) is symptomatic, patients can gauge whether they have meaningful benefit from Addyi."
A for the drug.
It found it barely performs better than a placebo.
What Price Desire?
The Addyi story has a familiar ring -- and it's not cha-ching. The financial success of Addyi is limited -- $100 million a year in sales at the most -- said Ram Selvaraju, a healthcare stock analyst and managing director with Rodman & Renshaw Research in New York.
He cited its poor effectiveness, $800 a month cost, and the fact alcohol should not be used with it.
"You want to have a glass of wine with your husband?" he said. "You can't do that."
Valeant, the company that markets Addyi, said that while women may have a drop in blood pressure or pass out if they use alcohol, the incidence of that is low -- though the company's statement did not cite any numbers. The studies it now is doing will evaluate the "real-world" effects of alcohol in women who use the drug, the company said.
"Our goal is to make Addyi affordable and accessible to the millions of women," the statement said. "We believe this product has strong potential and are committed to realizing that potential."
Independent experts say lack of sexual desire, both in men and women, is another example of a condition of everyday life that has been turned into a medical or psychiatric disorder that then can be treated with expensive -- and often dangerous -- drugs, a process known as medicalization.
Last month, a Journal Sentinel/麻豆传媒 investigation found that eight common conditions, including Low T in men and lack of sexual desire in women, that were not part of mainstream medicine 20 years ago now are said to affect more than 180 million people.
The conditions came into prominence thanks to new definitions or lowered thresholds issued by medical organizations and doctors with financial ties to drug companies.
"The formula is you have to convince people there is an incredibly prevalent problem that has been totally ignored and now, all of a sudden, we are on the verge of developing miracle treatments to fix it," said , of the Dartmouth Institute for Health Policy and Clinical Practice.
"Low T" & Adverse Events
After more than a decade of trying by drug companies, the potential remedies for low sexual desire have been anything but miraculous.
For men, libido drugs mainly have been testosterone products.
However, testosterone never was approved specifically to increase sexual desire in men and it has not been shown to substantially improve it. Research has shown it carries an increased risk of prostate cancer -- although other studies have challenged that link -- as well as blood clots and cardiovascular problems.
The FDA originally approved testosterone products to treat hypogonadism, a relatively rare condition marked by abnormally low testosterone due to a medical condition, such as genetic problems or damage to the testicles.
The market grew quickly after a funded by testosterone drugmaker Solvay Pharmaceuticals claimed that 14 million men age 45 and older had "Low T." The study's five authors all had financial ties to Solvay -- a consultant, an employee, and three who worked for a company hired by Solvay to do the study.
A series of TV commercials that began airing in the late 2000s spurred a massive growth in testosterone, largely because it was being prescribed in unapproved ways -- to counter the effects of age-related testosterone loss, such as low-libido.
In 2000, just under 1 million prescriptions were written for testosterone products.
Alarm Sounded
As early as said the rapidly growing use of testosterone by men seeking to fend off the effects of aging had outpaced the scientific evidence on the hormone's benefits and risks.
In also noted the lack of clear evidence of the benefits of testosterone for age-related testosterone loss.
Between 2010 and 2014, more than 30 million prescriptions for testosterone products costing nearly $10 billion were written, according to data from IMS Health, a drug market research firm.
Last year, compared testosterone with a placebo in more than 300 men in their 60s with low to low-normal testosterone levels. It found no improvement in sexual function or health-related quality of life.
In February, the results of a 12-month study of testosterone therapy involving 790 men age 65 and older were The study used a questionnaire to assess changes in sexual function over the course of 1 year. Sexual desire and erectile function showed modest improvement, but the benefit appeared to diminish somewhat by the 12th month. And the study noted drugs such as Viagra are much better at improving erectile function.
Despite the mounting evidence of problems, it wasn't until last year that the FDA said the products are not approved for testosterone loss due to aging. The agency also warned that the products increased the risk of heart attacks and strokes.
Peddicord, the FDA spokesperson, said the agency acted quickly in the wake of the new studies.
In addition to the warnings, she said, the FDA also named an advisory committee to review cardiovascular safety "in light of the real-world use of testosterone." And the agency is requiring testosterone makers to conduct a clinical trial to examine the possible increased risk of heart attacks and strokes.
But between 2003 and the FDA's 2015 warning about testosterone, the agency approved several more testosterone products, bringing the total to at least 10 that are now on the market.
Since 2013, testosterone drugs were listed as the primary cause behind more than 14,000 reports to the FDA of serious medical complications, including more than 1,900 hospitalizations and 444 deaths, according to a 麻豆传媒/Journal Sentinel analysis of the FDA's database of adverse event reports.
The analysis included only reports from manufacturers and health professionals, not reports from patients.
The reports spiked in 2015, with some 9,000 reports of reactions caused by testosterone filed. Almost all products saw significantly more reports. Depo-testosterone jumped from 62 reports in 2014 to 719 in 2015; Testim went from 112 reports to 670. Axiron saw its reports go from 152 in 2014 to 4,432 the next year.
Reports of problems caused by market leader Androgel held steady at about 2,400. Since 2013, the drug has been listed as the primary suspect in nearly half of all testosterone-related reports.
A spokesperson for Abbvie, the company that makes Androgel, declined to comment, citing pending litigation.
Scott MacGregor, a spokesperson for Axiron manufacturer Eli Lilly, maintained that the product is useful for FDA-approved conditions.
"The overall benefit-risk profile for Axiron remains favorable when used for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone," MacGregor wrote in a statement.
'The Only Thing it Did Was About Kill Me'
The FDA warnings came too late for William Grizzell, 48, of Crittenden, Ky.
In early 2012, he went to his doctor seeking a Viagra prescription for erectile dysfunction and low libido. His wife was being treated for breast cancer and, he said, with all the intense therapies she was going through, intimacy had become a challenge.
Instead, Grizzell's doctor tested him for low testosterone. Rather than leave with a prescription for an erectile dysfunction drug, several of which have been proven to work, he was told he needed to visit the clinic for weekly testosterone injections.
Since the weekly appointments were time-consuming, Grizzell asked his doctor for another solution, and was handed a prescription for Testim, a testosterone gel.
"I was taking it for 3 or 4 months and didn't see any results," Grizzell said. "But then one night I thought I was having a heart attack."
After he was taken to a hospital in September 2012, Grizzell was told he had a pulmonary embolism, a serious blood clot in the lungs. There were other clots in his legs.
He was hospitalized in for several days and needed to take blood thinners for the next 6 months. During that time, he continued to take Testim.
Grizzell's wife, Dana, died in early 2013, and he had a second pulmonary embolism the following June, after he had come off the blood thinners.
After his second brush with death, he stopped taking Testim. The doctor who had prescribed it had left the practice. A new doctor told him to drop it, since it could be the cause of his troubles.
Grizzell, who is a home goods manufacturer, hasn't had any blood clots since stopping Testim -- although he said he will now be on blood thinners the rest of his life.
Grizzell is now involved in a national lawsuit involving more than 5,000 men that is seeking damages from testosterone drug makers for side effects such as heart attacks, strokes, and clots such as pulmonary embolisms.
A spokesperson for Endo Pharmaceuticals, which bought the company that makes Testim, said the company cannot comment on ongoing litigation, but that it "continue[s] to believe the decision to use any form of testosterone replacement therapy should be made through an informed discussion between the healthcare professional and patient diagnosed with hypogonadism."
Grizzell said if he had been aware of the risks, he would have never taken testosterone.
"I've got two young girls," he said. "If I knew it was going to affect my life the way it did, I would never have done it, because sex just wasn't as important as being a dad."
"The only thing it did for me was about kill me," he said.
Is Sexuality a Medical Matter?
, president of the International Society for the Study of Women's Sexual Health, says the data on Addyi are better than the alternative: Drugs being used in unapproved ways, for which there's no strong evidence that they work.
That includes a host of experimental agents, from dopamine agonists used in Parkinson's disease to stimulant medications for attention deficit hyperactivity disorder (ADHD).
Goldstein runs a 6,000-square-foot sexual medicine clinic in San Diego, and is also the director of sexual medicine at Alvarado Hospital in that city.
He was a paid consultant for Pfizer on Viagra, Eli Lilly on Cialis, and Bayer on Levitra, another erectile dysfunction drug.
In addition, he has worked for testosterone companies and has been a consultant and an advisor to Sprout and Valeant.
From 2013 through 2015, Goldstein received more than $120,000 in general payments and more than $250,000 in research-related payments from drug companies, according to the federal Open Payments database.
"Working with companies so I can use my expertise and help my patients get treatments, I'm very for that," he said.
Addyi may be the first drug approved to treat lack of interest in sex for females, but over the last 15 years more than 20 others have been tried or are in the process of clinical testing.
revealed dozens of studies aimed at finding treatments for low sexual desire in women, and to a lesser extent in men.
These include a pill called Lybrido that combines testosterone and Viagra; the antidepressant Wellbutrin for orgasm problems; the experimental injectable drug bremelanotide, which works on the brain; and the topical solution Alista (alprostadil) that expands blood vessels and was nicknamed "orgasm cream."
Even alternative therapies such as acupuncture, homeopathic agents, and a study of mindfulness training that used a device called an "arousometer" have been tested.
Critics questions whether medications are needed at all.
"Diagnoses in the field of sexuality are very vague," said , a psychologist who studies human sexuality at New York University. "They make the heroic but ultimately impossible effort to pin down something that is historically, subjectively, culturally, and psychologically variable."
"Sexuality is not a medical matter," she said, "and trying to stuff it into medical definitions is doomed in my opinion."