Testosterone Therapy: No Link with Blood Clot Disorders

Source: EurekaAlert! A new study from The University of Texas Medical Branch at Galveston of more than 30,000 commercially insured men is the first large comparative analysis to show that there is no link between testosterone therapy and blood clots in veins. The study found that middle-aged and older men who receive testosterone therapy are not at increased risk of this illness. The findings are detailed in Mayo Clinic Proceedings.

Venous thromboembolism is a disease where blood clots form in the veins and cause blockages. The most common forms of VTE are deep vein thrombosis, which occurs often in the legs and pulmonary embolism, which is a clot in the lungs. VTE is the third most common cardiovascular illness, after heart attack and stoke.

"In 2014, the Federal Drug Administration required manufacturers to add a warning about potential risks of VTE to the label of all approved testosterone products," said Jacques Baillargeon, professor of epidemiology in the department of preventive medicine and community health and lead author of the study. "The warning, however, is based primarily on post-marketing drug surveillance and case reports. To date, there have been no published comparative, large-scale studies examining the association of testosterone therapy and the risk of VTE."

As a result of this conflicting evidence and the broad media attention it has received, there are many men with medically confirmed low testosterone who are afraid to receive testosterone therapy and there may be physicians who are reluctant to prescribe testosterone therapy based on this conflicting information.

The case-control study included 30,572 men 40 years and older who were enrolled in one of the nation's largest commercial insurance programs between Jan. 1, 2007 and Dec. 31, 2012. Cases were defined as men who had a primary diagnosis of VTE and received an anticoagulant drug or an intravascular vena cava filter in the 60 days following their diagnoses. Cases were matched with three control subjects on age, geographic region, diagnosis of low testosterone and diagnosis of any underlying pro-clotting condition.

The researchers found that having a prescription for testosterone therapy was not associated with an increased risk of VTE. In addition, none of the specific routes of administration examined -- topical creams, transdermal patches or intramuscular injections -- were associated with an increased risk. There were no differences between men who received the therapy 15, 30 or 60 days before being diagnosed with VTE.

"It is important to acknowledge, for a man who has medically-diagnosed low testosterone, that there are clear risks to not receiving testosterone therapy, including osteoporosis, sexual dysfunction, increased amounts of fat tissue, decreased lean muscle mass, possible metabolic syndrome and cardiovascular disease," said Baillargeon. "It's also important to note that further research needs to be conducted to rigorously assess the long-term risks of testosterone therapy.

These findings may help to inform the benefit-risk assessment for men with testosterone deficiency considering treatment.

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Other authors include UTMB's Randall J. Urban, Gwen Baillargeon, Gulshan Sharma and Yong-Fang Kuo; Abraham Morgentaler from Men's Health Boston at Harvard Medical School and Charles J. Glueck from Jewish Hospital at Mercy Medical Physicians in Cincinnati, OH.

This research was supported by the National Institutes of Health.

Normalized Testosterone Levels Linked to Fewer Heart Attacks, Strokes

Men with low testosterone whose levels normalize with testosterone replacement therapy (TRT) may enjoy lower risks of heart attack, stroke, and early death, a new study suggests. The research provides valuable information amid recent studies that found increased cardiovascular risks for particular TRT users. Following the concerning findings, the FDA issued a safety alert.

For the study, investigators led by Rajat Barua, MD, from the VA Medical Center in Kansas City, Mo., examined the medical records of 83,010 male veterans with low total testosterone levels confirmed by repeat testing. They defined low testosterone as the lower limit of normal reported on laboratory tests to avoid an arbitrary cutoff and to reduce disparities in ranges used by various reporting units. Importantly, the men had no history of myocardial infarction or ischemic stroke.

The researchers categorized the men into 3 groups according to whether they received a TRT prescription (injection, gel, or patch). Group 1 received TRT and subsequently saw normalization of their testosterone levels (confirmed by repeat testing). Group 2 took TRT but experienced no such normalization. And group 3 did not receive TRT. The investigators used propensity score matching to account for covariates, such as age, body mass index, diabetes, hypertension, coronary artery disease, and use of aspirin or statins.

Men who took TRT and also saw their levels normalize (group 1) had lower risks of all-cause mortality (56%), myocardial infarction (24%), and ischemic stroke (36%) compared with men who did not take TRT (group 3) after an average 6.2 years of follow up, the investigators reported in the European Heart Journal.

Similarly, men with normalized testosterone levels (group 1) fared better than those who took TRT but failed to see normalization of testosterone (group 2). They had lower risks of early death, myocardial infarction, and ischemic stroke by 57%, 18%, and 30%, respectively. The researchers observed no difference in heart attack or stroke risk between groups 2 and 3, neither of which achieved testosterone normalization.

“It is the first study to demonstrate that significant benefit is observed only if the dose is adequate to normalize the [total testosterone] levels,” the investigators stated. “Patients who failed to achieve the therapeutic range after TRT did not see a reduction in [myocardial infarction] or stroke and had significantly less benefit on mortality.” In this study, normalization of testosterone was used as a marker of adequate therapy using TRT.

The mechanisms underlying these effects “remain speculative,” the investigators noted. Normalized testosterone levels may have beneficial effects on adipose tissue, insulin sensitivity, and lipid profiles or exert anti-inflammatory and anticoagulant effects. Conversely, adverse mechanisms that increase cardiovascular risks—such as sodium retention, congestive heart failure, increased platelet aggregation, or changes in high density lipoprotein—may account for the observed effects.

The investigators noted that off-label use of TRT remains a concern. They urge randomized controlled trials with long-term follow-up to obtain definitive conclusions. In the meantime, they point to a need for guidelines on TRT use and active surveillance of patients.

Source Sharma, R; Oni, OA; Gupta, K; et al. European Heart Journal; doi: 10.1093/eurheartj/ehv346.

Originally posted at: http://www.renalandurologynews.com/

F.D.A. Approves Addyi, a Libido Pill for Women

By ANDREW POLLACK, AUG. 18, 2015 - NY Times The first prescription drug to enhance women’s sexual drive won regulatory approval on Tuesday, clinching a victory for a lobbying campaign that had accused the Food and Drug Administration of gender bias for ignoring the sexual needs of women.

The drug — Addyi from Sprout Pharmaceuticals — is actually the first drug approved to treat a flagging or absent libido for either sex. Viagra and other drugs available for men are approved to help achieve erections, or to treat certain deficiencies of the hormone testosterone, not to increase desire.

Advocates who pressed for approval of Addyi, many of them part of a coalition called Even the Score, said that a drug to improve women’s sex lives was long overdue, given the many options available to men.

“This is the biggest breakthrough for women’s sexual health since the pill,” said Sally Greenberg, executive director of the National Consumers League.

Continue reading the main story RELATED COVERAGE

A luncheon at Ris in Washington in July honored Cindy Whitehead, center, chief operating officer of Sprout Pharmaceuticals.Aid to Women, or Bottom Line? Advocates Split on Libido Pill JUNE 13, 2015 A tablet of flibanserin, a drug to increase sexual desire in women. The medicine had been rejected twice by the F.D.A. before being recommended for approval by an advisory committee.‘Viagra for Women’ Is Backed by an F.D.A. PanelJUNE 4, 2015 Barbara Gattuso, 66, with her husband, Gregg, 67, in Boston last week, on vacation from their home in San Diego. “I was the one initiating sex, much to the surprise of my husband,” Ms. Gattuso said at the F.D.A. workshop in October.‘Viagra for Women’ Gets Push for F.D.A. ApprovalMAY 31, 2015 But critics said the campaign behind Addyi had made a mockery of the system that regulates pharmaceuticals and had co-opted the women’s movement to pressure the F.D.A. into approving a drug that was at best minimally effective and could cause side effects like low blood pressure, fainting, nausea, dizziness and sleepiness.

In announcing the approval, Dr. Janet Woodcock, a senior F.D.A. official, said the agency was “committed to supporting the development of safe and effective treatments for female sexual dysfunction.”

The F.D.A. decision on Tuesday was not a surprise since an advisory committee of outside experts had recommended by a vote of 18 to 6 in June that the drug be approved, albeit with precautions required to try to limit the risks and ensure that it was not overused.

Addyi’s label has a boxed warning — the strongest kind — saying the drug should not be used by those who drink alcohol, since that can increase the risk of severely low blood pressure and fainting. It is also not to be used with certain other drugs and by people with liver impairment.

The pill can be prescribed or dispensed only by doctors and pharmacists who watch an online slide presentation and pass a test of their comprehension. Women are advised to stop using the drug if they see no effect after eight weeks.

The big question now is how many people will use Addyi (pronounced ADD-ee), which is also known as flibanserin and has been called the “pink Viagra.”

According to one survey, about 10 percent of women suffer from hypoactive sexual desire disorder. The F.D.A. said the drug was approved for women whose loss of sexual desire causes marked distress or interpersonal difficulty and is not the result of illness, relationship problems or side effects of other medicines.

Dr. Lauren Streicher, associate professor of clinical obstetrics and gynecology at Northwestern University, said she sensed great interest for a drug like Addyi among her patients. She said the drug’s availability would encourage many women to talk to doctors about their sexual problems for the first time.

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“I think this is going to change the conversation that’s taking place in medical offices across the country,” she said, much as the 1998 approval of Viagra made it acceptable for men to talk about erectile dysfunction.

Leonore Tiefer, a sex therapist at the New York University School of Medicine and critic of the drug, predicted the restrictions on use would keep Addyi from becoming popular. “It’s going to be more trouble than it’s worth,” she said.

Cindy Whitehead, the chief executive of Sprout, declined to predict sales of Addyi, which she said would be available starting Oct. 17.

To allay concerns that the drug would be overused, Sprout has said it would not advertise on radio or television for 18 months after the drug’s approval. Ms. Whitehead said the company would focus its marketing on doctors, not consumers. She said Sprout planned to hire 200 sales representatives, enough to call on about 30,000 doctors, mainly obstetricians and gynecologists but also some psychiatrists and primary care physicians.

She said the exact price of Addyi had not been decided, but suggested it would be roughly equivalent on a monthly basis to erectile dysfunction pills. Those pills are generally taken when needed, while Addyi is supposed to be taken every night before bedtime. That makes a direct comparison difficult. But 10 Viagra tablets, a possible monthly allotment, cost about $400.

It is not clear if insurance companies will pay for Addyi.

Ms. Whitehead said that she expected many would, with a co-payment of about $30 to $75 a month. Sprout will assist patients with co-payments, she said.

Some doctors might use the drug beyond the uses in the label, which doctors are allowed to do.

Dr. Streicher said that although the drug was approved for premenopausal women only, she “absolutely” would prescribe it for postmenopausal women as well.

Dr. Irwin Goldstein, a sex-medicine doctor in San Diego who has been a consultant to Sprout, said he would not necessarily withhold the drug from casual drinkers. Some women might find the risk of side effects acceptable if their relationships are in jeopardy because of a lack of desire, he said. “That’s a risk, too.”

Dr. Goldstein said he would also not rule out prescribing the drug off-label to men.

Ms. Whitehead said there was interest in learning whether the drug would work for men, but Sprout’s priorities would be to get it approved next for postmenopausal women and in foreign markets.

Continue reading the main story RECENT COMMENTS

Juliet 5 hours ago I understand objection to this pill in terms of thinking we are in an already over-medicated society.But I don't understand the smug,... Katherine 5 hours ago This drug doesn't work (look at the data). If somebody wants something that actually really works I suggest taking a trip to Washington or... rick baldwin 5 hours ago AH,Spanish Fly meets the drugstore-this stuff will be resold to men starting tomorrow. Big Pharma strikes again. SEE ALL COMMENTS WRITE A COMMENT Addyi is thought to work by changing the balance of certain brain neurotransmitters like dopamine and serotonin.

There are disagreements among researchers as to what constitutes normal sexual desire in women. And there have been difficulties bringing to market a drug that would treat low desire.

Procter & Gamble failed to win approval for a testosterone skin patch for women about a decade ago. The F.D.A. rejected Addyi twice, in 2010 and 2013, citing marginal effectiveness and the side effects.

In one trial, for instance, women who took the drug had an average of 4.4 “satisfying sexual experiences” a month, compared with 3.7 for women getting a placebo and 2.7 before the study began. The drug did not increase desire more than a placebo when measured by a daily diary, but did do so modestly when measured by a monthly questionnaire.

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After the first rejection, Boehringer Ingelheim abandoned the drug. Ms. Whitehead and her husband, Robert, were at the time running a company that sold a testosterone product for men. The Whiteheads sold that business and formed Sprout to acquire flibanserin. Based in Raleigh, N.C., Sprout, a privately held company, had raised about $100 million, Ms. Whitehead said.

After the second rejection, various women’s and health groups formed Even the Score.

Sprout is paying at least part of the expenses for the coalition, whose members include the National Council of Women’s Organizations, the Black Women’s Health Imperative and the Association of Reproductive Health Professionals.

Even after the favorable advisory committee vote, critics of the drug sent letters to the F.D.A. urging it to reject Addyi. The agency usually follows the advice of its committees, but does not have to.

One letter, written by Dr. Tiefer of N.Y.U. and signed by about 100 others, said it was “absurd” to expect that young women taking Addyi would refrain from drinking alcohol. Another, by the PharmedOut project at Georgetown University Medical Center, which also had more than 100 signatures, said that the “unprecedented and unwarranted manufacturer-funded public relations campaign” may have confused the advisory committee members. A third letter, from sex researchers in the Netherlands and Belgium, said the drug was based on the mistaken notion that lack of spontaneous sexual desire, absent stimuli, was abnormal.

CONTINUE READING THE MAIN STORY 149 COMMENTS Even the Score is planning to stay in business, hoping that the approval of Addyi will spur other companies to develop drugs for women’s sexual health.

“It’s never been about one treatment,” said Ms. Greenberg of the National Consumers League, which received a contribution from Sprout and which formally joined Even the Score this month.

“For us to fold up our tent would be premature.”