Treating unexplained infertility: Answers still needed

Men who have slow growing, low-risk prostate cancer may not live long enough to die of their illness. And since there’s no conclusive evidence that treating low risk prostate cancer extends survival, doctors might recommend monitoring the cancer and treating it only when it begins to spread.

That’s called active surveillance. It’s generally reserved for men with small, slow-growing tumors and a normal life expectancy of less than 10 to 15 years after diagnosis. Older men in particular are far more likely to die of heart disease and other causes than low-risk prostate cancer. That’s fueled mounting concerns that low-risk cases are being overtreated, with too many men experiencing side effects without benefits.

Doctors monitor men on active surveillance in three ways:

    periodically measuring the amounts of prostate-specific antigen in blood
    checking for tumor growth with digital rectal exams
    giving repeat biopsies at varying intervals.

Active surveillance takes off

Though it has a long history, active surveillance has only recently broadened its reach from academic cancer centers into the wider community. Now a new study shows its adoption is accelerating. “The trend is real and it’s a step in the right direction,” said Matthew Cooperberg, an associate professor of urology, biostatistics, and epidemiology at the University of California, San Francisco Medical Center, and the study’s lead author.

Cooperberg and his co-author Peter Carroll, chair of the UCSF urology department, reviewed data from more than 10,000 men with low-risk prostate cancer treated at 45 urology practices throughout the United States. From 1990 to 2009, the rate of using active surveillance among men who were an average of 66 years old when diagnosed hovered at just under 15%. But between 2010 and 2013, the rates spiked suddenly, to more than 40%. A similar trend was observed for men 75 years or older at diagnosis — active surveillance rates increased from 54% to 76% over the same time period.

“Over-treatment of low-risk prostate cancer is a significant problem, and these results suggest that it’s abating,” Cooperberg said.

With studies from Sweden, Australia, Michigan, and elsewhere showing similar increases, active surveillance “appears to be gaining traction as a standard management practice,” said Stacy Loeb, a urologist and researcher at New York University School of Medicine in New York City.
 The future of prostate cancer monitoring

Long-term data attest to the safety of active surveillance for low-risk disease. For instance, a Canadian study published this year showed that only 1.5% of 993 men enrolled in an active surveillance protocol in 1995 had died of prostate cancer two decades later. The men were 69 years old on average when diagnosed. “But active surveillance is not just for older men,” Cooperberg emphasized. “Our data show that it can be effective in younger men too.”

Scientists are also looking for less invasive ways to monitor tumor progression — for instance, with imaging tests or more accurate markers in blood and urine. These alternative approaches could make active surveillance far less burdensome in time.

“Active surveillance serves as a middle-ground option,” said Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and Editor in Chief of HarvardProstateKnowledge.org. “For example, men who are uncertain about considering PSA testing in the first place and who are concerned about overtreatment if they are diagnosed with prostate cancer may find the option of active surveillance attractive. That’s especially true given the lack of evidence that treating early-stage prostate cancer extends lives. Hopefully research will one day provide ways to predict if a given treatment will work based on the genetic makeup of a man’s tumor.” This week, a patient came in reporting two awful urinary tract infections that she had this summer while traveling on vacation. She is in her 50s, postmenopausal, and fit and healthy. After having sex with her partner, she woke up with burning and pain with urination. She was treated for a urinary tract infection with antibiotics and felt better in a few days. She did fine for two weeks until they had sex again, when the same symptoms returned. Although antibiotics worked again, and quickly, at this point she felt consumed by the whole thing. She was unable to enjoy her vacation, and she was afraid to have sex. It took several weeks before she felt normal “down there.”

If this sounds familiar, then you may be suffering from recurrent urinary tract infection (UTI). Recurrent UTIs are defined as either three episodes of infection in the previous 12 months or two episodes in the previous 6 months.

Recurrent UTIs are common among both young healthy women and healthy women at midlife. Here’s why. There are many types of bacteria that normally live in the vagina and happily coexist. And they keep each other in check, like a mini-ecosystem. The hormone estrogen allows the “good” bacteria called Lactobacillus to thrive. These bacteria produce acid, which lowers the pH in the vagina, which helps keep the “bad” bacteria in check.

For younger women, frequent sex is one of the biggest risk factors for a UTI. Sexual intercourse can cause the bacteria in the vagina and rectum to get into the urinary tract, since they are close neighbors. But at midlife, the main culprits behind recurrent UTIs are physical changes, including thinning of vaginal tissue, pelvic organ prolapse, incontinence, and trouble completely emptying the bladder. The lower levels of estrogen after menopause are also a factor.

There are effective prevention strategies for healthy women at midlife who are struggling with recurrent UTIs. A good place to start is with urination habits. When sitting on the toilet, make yourself as comfortable as possible in a relaxed seated position (not squatting). Start the stream of urine by relaxing the pelvic floor muscles, rather than straining to urinate. Allow enough time for your bladder to completely empty. Also empty your bladder after intercourse. This can help wash away any bacteria that might have been introduced into the urinary tract during sex. Some studies suggest that cranberry extracts can help prevent UTIs by decreasing the “stickiness” of the bacteria. I prefer cranberry supplements to cranberry juice, which tends to be very high in sugar and calories.

Vaginal estrogen creams or rings can help restore the normal bacterial balance of the vagina. Ask your doctor about taking antibiotics preventively, either after sex, or regularly at a low dose. Your doctor can also check to see if you have pelvic organ prolapse, which can be associated with an inability to fully empty your bladder.

Take charge of your bladder health, and don’t let recurrent UTIs get in the way of your active lifestyle. If you are struggling with recurrent UTIs, see your doctor for a thorough check-up — and know that this condition is both entirely preventable and easily treatable. Unexplained infertility is frustrating for couples and their doctors. Without a clear reason why a woman is having trouble becoming pregnant, it is difficult to choose a treatment that has a high rate of success but doesn’t increase the chances of a high-risk multiple pregnancy. A study published today in The New England Journal of Medicine compared three drugs commonly used to treat unexplained infertility. Unfortunately, there was no clear winner.

Infertility is defined as the inability to become pregnant after about a year of appropriate and well-timed efforts. Infertility affects about 10% of women ages 15 to 44. For those desiring a child, the inability to become pregnant can be devastating, and the drive to seek treatment is understandable. The usual first step along that path is a detailed evaluation of the couple. Almost half the time, when an issue is identified, it is with the male partner, usually a problem with his sperm. Sometimes we discover a woman has blocked fallopian tubes (so eggs can’t be fertilized and travel to the uterus) or abnormalities of the uterine cavity, such as fibroids (which may prevent a fertilized egg from implanting).

But in 15-20% of cases, no reason is identified — so-called “unexplained infertility.”

Many with unexplained infertility will become pregnant on their own simply with more time. But for those reluctant to just wait, a first step is to try using medicines to push the ovaries to mature more than just one egg (this is called ovulation induction). With more eggs available for fertilization per cycle, the hope is that at least one will result in a pregnancy. This therapy is simpler and much less expensive than in vitro fertilization (IVF). Cost is an important issue because finances can be a huge barrier to infertility treatment. Very few states mandate that insurance plans provide coverage for IVF, which can easily run more than $10,000 for each cycle, or “try.”

But every time you drive the ovaries to produce more eggs, you run the risk of “super-ovulation,” or making many eggs available for fertilization. This in turn means you run the risk of a “multiple pregnancy” — twins, triplets, and beyond. For couples desperate to build a family, more babies may sound like hitting the jackpot. But multiple pregnancies are the biggest risk of infertility treatments, and arguably should be counted as failures rather than successes. These pregnancies — even with “just” twins — mean the babies are more likely to be born prematurely and the mothers are more likely to experience complications. Both these situations can be serious and have long-term consequences.

So which drugs are best at meeting the goals of infertility treatment — that is, achieving a pregnancy with one baby? In this study, a national network of investigators looked at how the drug letrozole compared with two standard drugs to stimulate ovulation. Letrozole works to stimulate ovulation through a different path than traditional fertility medications.

Investigators assigned cver a thousand couples with unexplained infertility to as many as four rounds of treatment with either letrozole or one of two “standard treatments”: gonadotropin (Menopur is one brand name) or clomiphene (Clomid is a common brand name). The results: live birth rates were lower in the women who took letrozole (19%) as compared with gonadotropin (32%), but were statistically similar to clomiphene (23%). On the other hand, rates of multiple pregnancies (all twins and triplets in this study) were higher in the gonadotropin group (all the triplets in were in this treatment group) than in the letrozole and clomiphene groups (which had about the same rate).

Hardly a home run for those who were hoping letrozole would be the answer. Over all, the numbers indicate that for couples with unexplained infertility, these alternatives to IVF may help them achieve a pregnancy — but success is hardly a sure thing. The drugs that bring a higher chance of pregnancy, also bring a greater chance that pregnancy will be a high-risk one.

While disappointing, the results argue for more work to optimize fertility therapies. A very important part of this work — whether we’re talking about ovulation induction or IVF — are continued efforts to reduce the unsatisfactorily high rate of multiple pregnancies that current treatment options carry. Until we have answers, judicious therapy means appropriately limiting the doses of ovulation induction drugs, and in the case of IVF, limiting the number of embryos transferred. That means doctors need to help patients make wise decisions, especially when there is more than one embryo available for transfer.

The true and heartfelt goal of couples and their doctors isn’t just a pregnancy, but a pregnancy with a good outcome—a healthy mom and a healthy baby. Here, more does not translate into better.

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