New Options Are Emerging in the Search for Better Birth Control
A decade ago, Elizabeth Summers' options for birth control suddenly narrowed. Doctors diagnosed her with Factor V Leiden, a rare genetic disorder, after discovering blood clots in her lungs. The condition increases the risk of clotting, so physicians told Summers to stay away from the pill and other hormone-laden contraceptives. "Modern medicine has generally failed to provide me with an effective and convenient option," she says.
But new birth control options are emerging for women like Summers. These alternatives promise to provide more choices to women who can't ingest hormones or don't want to suffer their unpleasant side effects.
These new products have their own pros and cons. Still, doctors are welcoming new contraceptives following a long drought in innovation. "It's been a long time since we've had something new in the world of contraception," says Heather Irobunda, an obstetrician and gynecologist at NYC Health and Hospitals.
On social media, Irobunda often fields questions about one of these new options, a lubricating gel called Phexxi. San Diego-based Evofem, the company behind Phexxi, has been advertising the product on Hulu and Instagram after the gel was approved by the Food and Drug Administration in May 2020. The company's trendy ads target women who feel like condoms diminish the mood, but who also don't want to mess with an IUD or hormones.
Here's how it works: Phexxi is inserted via a tampon-like device up to an hour before sex. The gel regulates vaginal pH — essentially, the acidity levels — in a range that's inhospitable to sperm. It sounds a lot like spermicide, which is also placed in the vagina prior to sex to prevent pregnancy. But spermicide can damage the vagina's cell walls, which can increase the risk of contracting sexually transmitted diseases.
"Not only is innovation needed, but women want a non-hormonal option."
Phexxi isn't without side effects either. The most common one is vaginal burning, according to a late-stage trial. It's also possible to develop a urinary tract infection while using the product. That same study found that during typical use, Phexxi is about 86 percent effective at preventing pregnancy. The efficacy rate is comparable to condoms but lower than birth control pills (91 percent) and significantly lower than an IUD (99 percent).
Phexxi – which comes in a pack of 12 – represents a tiny but growing part of the birth control market. Pharmacies dispensed more than 14,800 packs from April through June this year, a 65 percent increase over the previous quarter, according to data from Evofem.
"We've been able to demonstrate that not only is innovation needed, but women want a non-hormonal option," says Saundra Pelletier, Evofem's CEO.
Beyond contraception, the company is carrying out late-stage tests to gauge Phexxi's effectiveness at preventing the sexually transmitted infections chlamydia and gonorrhea.
Phexxi is inserted via a tampon-like device up to an hour before sex.
Phexxi
A New Pill
The first birth control pill arrived in 1960, combining the hormones estrogen and progestin to stop sperm from joining with an egg, giving women control over their fertility. Subsequent formulations sought to ease side effects, by way of lower amounts of estrogen. But some women still experience headaches and nausea – or more serious complications like blood clots. On social media, women recently noted that birth control pills are much more likely to cause blood clots than Johnson & Johnson's COVID-19 vaccine that was briefly paused to evaluate the risk of clots in women under age 50. What will it take, they wondered, for safer birth control?
Mithra Pharmaceuticals of Belgium sought to create a gentler pill. In April, the FDA approved Mithra's Nextstellis, which includes a naturally occurring estrogen, the first new estrogen in the U.S. in 50 years. Nextstellis selectively acts on tissues lining the uterus, while other birth control pills have a broader target.
A Phase 3 trial showed a 98 percent efficacy rate. Andrew London, an obstetrician and gynecologist, who practices at several Maryland hospitals, says the results are in line with some other birth control pills. But, he added, early studies indicate that Nextstellis has a lower risk of blood clotting, along with other potential benefits, which additional clinical testing must confirm.
"It's not going to be worse than any other pill. We're hoping it's going to be significantly better," says London.
The estrogen in Nexstellis, called estetrol, was skipped over by the pharmaceutical industry after its discovery in the 1960s. Estetrol circulates between the mother and fetus during pregnancy. Decades later, researchers took a new look, after figuring out how to synthesize estetrol in a lab, as well as produce estetrol from plants.
"That allowed us to really start to investigate the properties and do all this stuff you have to do for any new drug," says Michele Gordon, vice president of marketing in women's health at Mayne Pharma, which licensed Nextstellis.
Bonnie Douglas, who followed the development of Nextstellis as part of a search for better birth control, recently switched to the product. "So far, it's much more tolerable," says Douglas. Previously, the Midwesterner was so desperate to find a contraceptive with fewer side effects that she turned to an online pharmacy to obtain a different birth control pill that had been approved in Canada but not in the U.S.
Contraceptive Access
Even if a contraceptive lands FDA approval, access poses a barrier. Getting insurers to cover new contraceptives can be difficult. For the uninsured, state and federal programs can help, and companies should keep prices in a reasonable range, while offering assistance programs. So says Kelly Blanchard, president of the nonprofit Ibis Reproductive Health. "For innovation to have impact, you want to reach as many folks as possible," she says.
In addition, companies developing new contraceptives have struggled to attract venture capital. That's changing, though.
In 2015, Sabrina Johnson founded DARÉ Bioscience around the idea of women's health. She estimated the company would be fully funded in six months, based on her track record in biotech and the demand for novel products.
But it's been difficult to get male investors interested in backing new contraceptives. It took Johnson two and a half years to raise the needed funds, via a reverse merger that took the company public. "There was so much education that was necessary," Johnson says, adding: "The landscape has changed considerably."
Johnson says she would like to think DARÉ had something to do with the shift, along with companies like Organon, a spinout of pharma company Merck that's focused on reproductive health. In surveying the fertility landscape, DARÉ saw limited non-hormonal options. On-demand options – like condoms – can detract from the moment. Copper IUDs must be inserted by a doctor and removed if a woman wants to return to fertility, and this method can have onerous side effects.
So, DARÉ created Ovaprene, a hormone-free device that's designed to be inserted into the vagina monthly by the user. The mesh product acts as a barrier, while releasing a chemical that immobilizes sperm. In an early study, the company reported that Ovaprene prevented almost all sperm from entering the cervical canal. The results, DARÉ believes, indicate high efficacy.
A late-stage study, slated to kick off next year, will be the true judge. Should Ovaprene eventually win regulatory approval, drug giant Bayer will handle commercializing the device.
Other new forms of birth control in development are further out, and that's assuming they perform well in clinical trials. Among them: a once-a-month birth control pill, along with a male version of the birth control pill. The latter is often brought up among women who say it's high time that men take a more proactive role in birth control.
For Summers, her search for a safe and convenient birth control continues. She tried Phexxi, which caused irritation. Still, she's excited that a non-hormonal option now exists. "I'm sure it will work for others," she says.
Obesity is a risk factor for worse outcomes for a variety of medical conditions ranging from cancer to Covid-19. Most experts attribute it simply to underlying low-grade inflammation and added weight that make breathing more difficult.
Now researchers have found a more direct reason: SARS-CoV-2, the virus that causes Covid-19, can infect adipocytes, more commonly known as fat cells, and macrophages, immune cells that are part of the broader matrix of cells that support fat tissue. Stanford University researchers Catherine Blish and Tracey McLaughlin are senior authors of the study.
Most of us think of fat as the spare tire that can accumulate around the middle as we age, but fat also is present closer to most internal organs. McLaughlin's research has focused on epicardial fat, “which sits right on top of the heart with no physical barrier at all,” she says. So if that fat got infected and inflamed, it might directly affect the heart.” That could help explain cardiovascular problems associated with Covid-19 infections.
Looking at tissue taken from autopsy, there was evidence of SARS-CoV-2 virus inside the fat cells as well as surrounding inflammation. In fat cells and immune cells harvested from health humans, infection in the laboratory drove "an inflammatory response, particularly in the macrophages…They secreted proteins that are typically seen in a cytokine storm” where the immune response runs amok with potential life-threatening consequences. This suggests to McLaughlin “that there could be a regional and even a systemic inflammatory response following infection in fat.”
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
The macrophages studied by McLaughlin and Blish were spewing out inflammatory proteins, While the the virus within them was replicating, the new viral particles were not able to replicate within those cells. It was a different story in the fat cells. “When [the virus] gets into the fat cells, it not only replicates, it's a productive infection, which means the resulting viral particles can infect another cell,” including microphages, McLaughlin explains. It seems to be a symbiotic tango of the virus between the two cell types that keeps the cycle going.
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
Macrophages are mobile; they engulf and carry invading pathogens to lymphoid tissue in the lymph nodes, tonsils and elsewhere in the body to alert T cells of the immune system to the pathogen. Perhaps some of them also carry the virus through the bloodstream to more distant tissue.
ACE2 receptors are the means by which SARS-CoV-2 latches on to and enters most cells. They are not thought to be common on fat cells, so initially most researchers thought it unlikely they would become infected.
However, while some cell receptors always sit on the surface of the cell, other receptors are expressed on the surface only under certain conditions. Philipp Scherer, a professor of internal medicine and director of the Touchstone Diabetes Center at the University of Texas Southwestern Medical Center, suggests that, in people who have obesity, “There might be higher levels of dysfunctional [fat cells] that facilitate entry of the virus,” either through transiently expressed ACE2 or other receptors. Inflammatory proteins generated by macrophages might contribute to this process.
Another hypothesis is that viral RNA might be smuggled into fat cells as cargo in small bits of material called extracellular vesicles, or EVs, that can travel between cells. Other researchers have shown that when EVs express ACE2 receptors, they can act as decoys for SARS-CoV-2, where the virus binds to them rather than a cell. These scientists are working to create drugs that mimic this decoy effect as an approach to therapy.
Do fat cells play a role in Long Covid? “Fat cells are a great place to hide. You have all the energy you need and fat cells turn over very slowly; they have a half-life of ten years,” says Scherer. Observational studies suggest that acute Covid-19 can trigger the onset of diabetes especially in people who are overweight, and that patients taking medicines to regulate their diabetes “were actually quite protective” against acute Covid-19. Scherer has funding to study the risks and benefits of those drugs in animal models of Long Covid.
McLaughlin says there are two areas of potential concern with fat tissue and Long Covid. One is that this tissue might serve as a “big reservoir where the virus continues to replicate and is sent out” to other parts of the body. The second is that inflammation due to infected fat cells and macrophages can result in fibrosis or scar tissue forming around organs, inhibiting their function. Once scar tissue forms, the tissue damage becomes more difficult to repair.
Current Covid-19 treatments work by stopping the virus from entering cells through the ACE2 receptor, so they likely would have no effect on virus that uses a different mechanism. That means another approach will have to be developed to complement the treatments we already have. So the best advice McLaughlin can offer today is to keep current on vaccinations and boosters and lose weight to reduce the risk associated with obesity.
Air pollution can lead to lung cancer. The connection suggests new ways to stop cancer in its tracks.
Forget taking a deep breath. Around the world, 99 percent of people breathe air polluted to unsafe levels, according to data from the World Health Organization. Activities such as burning fossil fuels release greenhouse gases that contribute to air pollution, which could lead to heart disease, stroke, asthma, emphysema, and some types of cancer.
“The burden of disease attributable to air pollution is now estimated to be on a par with other major global health risks such as unhealthy diet and tobacco smoking, and air pollution is now recognized as the single biggest environmental threat to human health,” wrote the authors of a 2021 WHO report.
The majority of lung cancer is attributed to smoking. But as pollution levels have increased, and anti-smoking campaigns have discouraged smoking, the proportion of lung cancers diagnosed in non-smokers has grown. The CDC estimates that 10 to 20 percent of lung cancers in the U.S. currently occur in non-smokers.
The mechanism between air pollution and the development of lung cancer has been unclear, but researchers at London’s Francis Crick Institute recently made an important breakthrough in understanding the connection. Lead investigator Charles Swanton presented this research last month at a conference in Paris.
Pollution awakens mutations
The Crick Institute scientists were able to identify a new link between common air pollutants and non-small cell lung cancer (NSCLC). They focused on pollutants called particulate matter, or PM, that are 2.5 microns wide, narrower than human cells.
Most cancer diagnosed in non-smoking people is NSCLC, but this type of cancer hasn’t received the same research attention as more common lung cancers found in smokers, according to Clare Weeden, a cancer researcher at the Crick Institute and a co-author of the study.
“This is a really underserved and under-researched population that we really need to tackle, as well as lung cancers that occur in smokers,” she says. “Lung cancer is the number one cancer killer worldwide.”
In the past, some researchers believed air pollution caused mutations that led to cancer. Others believed these mutations could remain dormant without any detriment to health until pollutants or other stressors triggered them to become cancerous. Reviving the latter hypothesis that carcinogens may activate pre-existing mutations, instead of directly causing them, the Crick researchers analyzed samples from 463,679 people in the UK and parts of Asia, noting mutations and comparing changes in gene expression in mice and human cells.
“The mutation can exist in a nascent clone without causing cancer,” says Emilia Lim, a bioinformatics expert and a co-first author of the Crick study. “It is the carcinogen that promotes a conducive environment for this one little clone to grow and expand into cancer. Through our work, we were able to revive excitement for this hypothesis and bring it to light.”
The study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
Other researchers had previously identified a link between mutations in certain genes that control epidermal growth factor receptors, or EGFR mutations, and the development of NSCLC. In a 2019 study of 250 people with this type of cancer, about 32 percent had the mutation. Women are more likely to have EGFR mutations than men.
Not everyone who has the EGFR mutation will develop lung cancer. Respirologist Stephen Lam studies lung cancer at the BC Cancer Research Centre in Vancouver, Canada, but was not involved in the Crick Institute research. He says the study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
More exposure leads to inflammation and lesions
The Crick researchers found that an excess of PM 2.5 in the air sparked an inflammatory process in cells within the lung. This inflammation set the stage for NSCLC to develop in people and mice with existing EGFR mutations.
The researchers also exposed mice without EGFR mutations to PM 2.5 pollution—an experiment that couldn’t be ethically conducted in humans—to link pollution exposure to NSCLC. The mice experiments also showed that NSCLC is dose-dependent; higher levels of exposure were associated with higher number of cancerous lesions forming.
Ultimately, the study “fundamentally changed how we view lung cancer in people who have never smoked,” said Swanton in a Crick Institute press release. “Cells with cancer-causing mutations accumulate naturally as we age, but they are normally inactive. We’ve demonstrated that air pollution wakes these cells up in the lungs, encouraging them to grow and potentially form tumors.”
Preventing cancer before it begins
Targeted therapies already exist for people with EGFR mutations who’ve developed NSCLC, but they have many side effects, according to Weeden. Researchers hope that making more definitive links between pollutants and cancer could help prevent people with EGFR or other mutations from developing lung cancer in the first place.
Along those lines, as an additional component of their study presented last month, the Crick researchers were able to prevent cancer in mice that had the EGFR mutations by blocking inflammation. They used an antibody to inhibit a protein called interleukin 1 beta, which plays a key role in inflammation. Scientists could eventually use such antibodies or other therapies to make a drug treatment that people can take to stop cancer in its tracks, even if they live in highly polluted areas.
Such potential could reach beyond lung cancer; in the past, Crick and other researchers have also found associations between exposure to air pollution and mesothelioma, as well as cancers of the small intestine, lip, mouth, and throat. These links could be meaningful to a growing number of people as climate change intensifies, and with increases in air pollution from fossil fuel combustion and natural disasters like forest fires.
Plus, air pollution is just one external condition that can flip the switch of these inflammatory pathways. Identifying a link between pollution and cancer “has wide ramifications for many other environmental factors that may [play] similar roles,” Weedon says. She hopes that the Crick study and future research in this area will offer some hope for non-smokers frustrated by cancer diagnoses.