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The Sperm-Count ‘Crisis’ Doesn’t Add Up
Reports of a decline in male fertility rely on flawed assumptions, a new study contends.
Male scientists have long waxed poetic on the contents of their testes. “Sperm is a drop of brain,” wrote the ancient Greek writer Diogenes Laërtius. Leonardo da Vinci drew the penis with a sperm duct that connected directly to the spinal cord. The 17th-century microscopist Antonie van Leeuwenhoek claimed that each sperm cell contained within it a folded-up human being waiting patiently to unfurl.
For nearly as long, scientists have fretted about sperm’s seemingly inevitable decline. Most recently, a series of alarming headlines — as well as a new book by an epidemiologist at Mount Sinai Medical Center in New York — warned that falling sperm counts might threaten the future of the human race. “It’s a global existential crisis,” said Shanna H. Swan, author of the book “Count Down.”
Most of these headlines can be traced to an influential 2017 meta-analysis by Dr. Swan and others, which found that sperm counts in Europe, North America, Australia and New Zealand had plummeted by nearly 60 percent since 1973. The authors screened 7,500 sperm-count studies from around the world, weeded out most of them and ultimately analyzed 185 studies on 43,000 men worldwide.
They called the decline a “canary in the coal mine” for waning male reproductive health worldwide. Today, the authors would revise that statement. “There is clear and present alarm now,” said Dr. Hagai Levine, an epidemiologist at Hebrew University-Hadassah School of Public Health and a co-author on the 2017 review, in an email. “The canary is in trouble now.” Dr. Swan, in the same email, agreed.
Now a group of interdisciplinary researchers from Harvard and the Massachusetts Institute of Technology contend that fears of an impending Spermageddon have been vastly overstated. In a study published in May in the journal Human Fertility, they re-evaluated the 2017 review and found that it relied on flawed assumptions and failed to consider alternate explanations for the apparent decline of sperm.
In an interview, Sarah Richardson, a Harvard scholar on gender and science and the senior author on the new study, called the conclusion of the 2017 review “an astonishing and terrifying claim that, were it to be true, would justify the apocalyptic tenor of some of the writing.” Fortunately, she and her co-authors argue, there is little evidence that this is the case.
The 2017 authors were “methodologically rigorous” when it came to screening sperm-count studies for quality and consistency, Dr. Richardson and her colleagues write. However, even the data that passed muster was geographically sparse and uneven and often lacked basic criteria like the age of the men. Moreover, its authors took for granted that a single metric — sperm count — was an accurate predictor of male fertility and overall health.
The connection sounds logical: Without sperm, there can be no conception. That’s why sperm count is one of the first metrics that fertility specialists measure to try to determine the cause of infertility in a couple. But beyond that truism, the science of sperm count is surprisingly slippery.
For starters, no one knows what an “optimal” sperm count is. The World Health Organization sets a range of “normal” sperm count as from 15 to 250 million sperm per milliliter. (Men produce about 2 to 5 milliliters per ejaculation.) But it isn’t clear that more is better. Above a certain threshold — 40 million per milliliter, according to the W.H.O. — a higher sperm count does not mean a man is more fertile.
“Doubling your sperm count from 25 to 50 million doesn’t double your chances,” said Allan Pacey, an andrologist at the University of Sheffield and the editor of Human Fertility. “Doubling it from 100 to 200 million doesn’t double your chances — in fact it flattens off, if anything. So this relationship between sperm count and fertility is weak.”
Germaine M. Buck Louis, a reproductive epidemiologist at George Mason University who studies environmental influences on human fertility, agreed that sperm count is a poor indicator of fertility. “We don’t see it predicting much of anything, especially in the context of a partner with a healthy female pelvis,” said Dr. Buck Louis, who was not involved in the sperm-count studies.
The authors of the 2017 study inferred that lower sperm counts equated to lower fertility — even though the sperm-count declines they documented all took place within the “normal” range, Dr. Richardson noted. “It’s similar to the whole conversation around testosterone — more is better, and more is manlier,” she said. “That’s really a point we make, that there is no known normal or baseline for average population sperm counts.”
Sperm count has other limitations as a metric. It takes around two months for stem cells in the testes to develop into new sperm, meaning that any single count is merely a snapshot of an evolving landscape.
“Something that’s going on in a man’s body one month may be totally different from what’s happening the next month, and the effects on sperm count might be changing also,” said Meredith Reiches, an author on the 2021 paper and a biological anthropologist at the University of Massachusetts, Boston
It also overlooks a vital piece of the infertility puzzle: women. Focusing only on the male metric leaves out key interactions between sperm, the female reproductive tract and the egg. “It’s very important, actually, to look at the couple,” said Dr. Bradley D. Anawalt, a reproductive endocrinologist at the University of Washington School of Medicine.
In her book, Dr. Swan suggests that sperm counts have plummeted largely due to the rise of endocrine disruptors, a class of hormone-mimicking chemicals found in everything from shampoo to TV-dinner packaging. (She also cites lifestyle factors like obesity, alcohol, and smoking.) Dr. Swan has shown in previous studies that exposure to these chemicals in utero can alter male and female sexual development.
Dr. Richardson and her co-authors suggested an alternative explanation: Perhaps sperm levels naturally rise and fall over time and within populations. The question has not been explored by reproductive researchers and cannot be answered easily, as global sperm counts before 1970 are largely unknown.
There are other possible explanations, as well. Sperm-counting is a tricky business and notoriously prone to human error, Dr. Pacey said. (“I say it from the point of view of someone who spent 30 years counting sperm and knows how difficult it is,” he added.) In a 2013 review article, he noted that as methodologies for counting had improved and been standardized since the 1980s, sperm counts had appeared to fall. In other words, it may simply be that earlier scientists were overcounting sperm.
Dr. Swan and Dr. Levine agreed that exploring these alternative hypotheses was important, so that threats to reproductive health could be established and prevented. “We showed evidence for decline, and raised alarm,” Dr. Levine wrote in an email. “We need to study the causes, including the unlikely possibility of non-pathological decline.”
There was one point that every author agreed on: Men’s reproductive health matters. And until now, it has been surprisingly neglected.
Male infertility contributes to at least half of all cases of infertility worldwide. Yet historically, women have shouldered most of the blame for the inability to conceive. And with the rise of reproductive technologies like in vitro fertilization, women’s bodies are the ones that have been meticulously measured and tracked by reproductive medicine.
As a result, science still lacks basic knowledge when it comes to sperm, said Rene Almeling, a sociologist of medicine and author of “GUYnecology: The Missing Science of Men’s Reproductive Health.” For instance, just this year, researchers reported for the first time that sperm swim in a corkscrew motion, rather than undulating like eels.
“We have built up such a medical infrastructure around the fertility and reproductivity of women’s bodies that we haven’t asked some of the basic questions about men’s reproductive health,” Dr. Almeling said. “There is just so, so much basic research still to be done about sperm.”
The main qualities of sperm that infertility specialists look at nowadays — how many, what shape and how they swim — have not changed in the past 40 years, said Dr. Abraham Morgentaler, a urologist and founder of Men’s Health Boston.
Dr. Morgentaler, who worked at a semen analysis lab at Beth Israel Deaconess Medical Center in the 1980s, attributes this stagnation to the rise of I.V.F. and other reproductive technologies, which have become frontline treatments for almost any male factor fertility problem. “It almost doesn’t even matter what’s wrong with the sperm,” he said.
These knowledge gaps radiate out to all bodies. In fact, Dr. Swan said part of her motivation for writing the book was that she wanted to see the public — men and women — become more proactive about their reproductive health.
“It’s invisible,” she said. “People don’t talk about it. You talk about, ‘Oh, I’ve got a high cholesterol measure,’ or ‘My blood pressure’s up.’ But you never would say, ‘My egg count is down,’ or ‘My sperm count is down.’”
Dr. Richardson agreed that the impact of reproductive toxins on fertility deserved further investigation. “To say that we think these are alarmist and apocalyptic claims, and they’re not well founded, is not to say that we think it isn’t an important research agenda,” she said. “There is a need to center on men’s reproductive health and understand their bodies as reproductive and as porous to the environment as anyone’s bodies.”
What Are Puberty Blockers?
Recent conservative legislation has targeted a class of drugs used to treat transgender adolescents. But what do these drugs actually do?
When Sebastian Liafsha came out as transgender in middle school, his mother, Heather, jumped into research mode.
Ms. Liafsha, a registered nurse in Lexington, S.C., put together a three-inch-thick binder packed with printouts of various laws, medical guidelines, pharmaceutical records and more. It was there that she would record the dates and details of Sebastian’s puberty blocker injections every three months for two and a half years, starting at age 14.
As a child who had never truly understood himself to be a girl, female puberty felt like an obstacle on Mr. Liafsha’s journey to manhood.
For Mr. Liafsha, now 19, puberty blockers not only paused the development of unwanted secondary sexual characteristics like breasts and a menstrual cycle, they gave him and his family time to continue his social transition (the process of presenting and living as the desired gender) and prepare for any future medical interventions.
“Before he started his transition, there were just a few months where puberty hit him, and he was off the wall,” Ms. Liafsha recalled. “He became really depressed.”
Puberty blockers helped to increase Sebastian’s confidence and happiness as an adolescent, which Ms. Liafsha likes to illustrate by pointing to her son’s life in the theater. In middle school, she said, he had always hidden in the ensemble, but by 10th grade — after two years on puberty blockers — he had flourished into a leading man.
Lately, puberty blockers have become a subject of debate in state legislatures, as lawmakers across the country introduce bills to limit health care options for transgender youth. Legislators in Arkansas already passed such a law, although Gov. Asa Hutchinson vetoed it last month. Arkansas conservatives argued that “the risks of gender transition procedures far outweigh any benefit at this stage of clinical study on these procedures.” But medical experts say that’s not the case.
Among the significant benefits of puberty blockers are a reduction in suicidal tendencies, which are often high in transgender adolescents, and a reduced need for expensive gender-affirming operations as adults. But while puberty blockers are commonly referred to as “fully reversible,” more research is needed to fully understand the impact they may have on certain patients’ fertility. There is also little known about the drugs’ lasting effects on brain development and bone mineral density.
Transgender youth have been the focus of new laws in states including Mississippi and Idaho, and pending in many others, designed to restrict their participation in sports — but this debate is largely separate from the discussion of puberty blockers.
Because the use of puberty blockers in transgender kids is still relatively new, the information is developing.
Here is a roundup of what experts know so far.
What are puberty blockers?
Puberty blockers are medications that suppress puberty by halting the production of estrogen or testosterone. They can stop transgender kids from experiencing the effects of puberty that may not align with their gender identities. Medically, the class of medications are called gonadotropin-releasing hormone agonists, or GnRH agonists. They are approved by the Food and Drug Administration to treat precocious puberty — puberty occurring at an unusually early age — so when they are prescribed to treat transgender youth, it’s considered an off-label use.
“Off-label,” the American Academy of Pediatrics noted in a 2014 statement, “does not imply an improper, illegal, contraindicated or investigational use” — it merely refers to the process of F.D.A. approval.
The medications may be given as shots in a doctor’s office every one, three or six months, or as an implant which lasts for about a year. Dr. Jessica Kremen, a pediatric endocrinologist for Boston Children’s Hospital’s Gender Multispecialty Service, noted that patients and families may prefer the convenience of the implants or six-month shots.
“It depends a lot on what is obtainable through a patient’s insurance,” Dr. Kremen said. Insurance companies are reluctant to cover off-label drug treatments, and implants can run up to approximately $45,000 per implant out of pocket, while shots cost can cost thousands of dollars per dose.
“That often determines which form we ended up using,” Dr. Kremen said. “But they all work well, as long as you administer them on time.”
How do they work?
Typically, in puberty, gonadotropin-releasing hormone helps to produce follicle-stimulating hormone (FSH) and luteinizing hormone (L.H.). In people assigned female at birth, these hormones prompt the ovaries to make estrogen, which promotes processes like breast growth and menstruation. In people assigned male at birth, they prompt the testes to make testosterone, which promotes processes like facial hair growth and a deepening of the voice.
Puberty blockers disrupt the production of FSH and L.H., therefore blocking the production of estrogen or testosterone. As a result, transgender adolescents do not continue to develop unwanted secondary sexual characteristics — transgender boys do not develop breasts and transgender girls do not develop facial hair, for example.
Puberty blockers do not stop an early stage in sexual maturation called adrenarche, which can cause acne, the growth of underarm and pubic hair and body odor.
Who can get puberty blockers?
Although parents might think they should start puberty blockers very young, so that a child never has to experience any physical changes associated with the unwanted gender, experts say it’s better to wait at least until the early stages of puberty have started. Dr. Stephen Rosenthal, medical director of the child and adolescent gender center for U.C.S.F. Benioff Children’s Hospitals, was a co-author of the Endocrine Society’s 2017 guidelines for transgender health care. He recommended starting puberty blockers when breast budding or the enlargement of the testes has begun, at the earliest.
That’s because Dr. Rosenthal does not recommend puberty blockers for prolonged use outside of the normal window of puberty. They restrict the functioning of the gonads, which may lead to adverse health effects. The longer blockers are used past the typical start of puberty — generally age 14, at the latest — the greater the possible risk.
When blockers are initiated in the early stages of puberty, Dr. Rosenthal typically suggests that his patients stop using them by age 14. At that point, patients, with their families and their doctors, can determine whether to introduce hormones that help them develop according to their gender identity or resume puberty in the gender assigned at birth.
Dr. Rosenthal further recommended that before starting blockers, children be evaluated by a mental health professional and determined to have gender dysphoria. He said families should also undergo a thorough process of informed consent, during which they are educated about the potential effects of blocking puberty — including adverse ones.
The World Professional Association for Transgender Health’s guidelines for medical care suggest that “before any physical interventions are considered for adolescents, extensive exploration of psychological, family and social issues should be undertaken.” Professionals emphasized mental health care as an integral part of the process.
What are the benefits?
Treatment with puberty blockers may improve the mental health of transgender adolescents, who are at high risk for suicide. A 2020 study found lower odds of lifetime suicidal ideation in transgender adults who wanted to take puberty blockers and were able to access this treatment. Another recent study showed similarly positive effects: transgender adolescents receiving puberty blockers had less “emotional and behavioral problems” than transgender adolescents recently referred to care, and also reported rates of self-harm and suicidality similar to those of their non-transgender peers. A 2020 study of 50 transgender adolescents indicated that puberty blockers and gender-affirming hormone treatments, or both, could positively impact quality of life and decrease depression and suicidal ideation. A 2014 study found that 55 young transgender adults who used puberty blockers, took gender-affirming hormones and had gender confirmation surgeries were able to “resolve” their gender dysphoria and showed overall well-being “in many respects comparable to peers.”
Because puberty blockers halt the development of secondary sexual characteristics, transgender adolescents who take them before gender-affirming hormones may also be able to avoid future gender-affirming procedures. For instance, transgender men who don’t develop breasts wouldn’t have reason to have mastectomies, while transgender women who don’t develop masculine facial features might no longer choose to have facial feminization surgery.
What are the risks?
Puberty blockers are largely considered safe for short-term use in transgender adolescents, with known side effects including hot flashes, fatigue and mood swings. But doctors do not yet know how the drugs could affect factors like bone mineral density, brain development and fertility in transgender patients.
The Endocrine Society recommends lab work be done regularly to measure height and weight, bone health and hormone and vitamin levels while adolescents are taking puberty blockers.
A handful of studies have underscored low bone mineral density as a potential issue, though a 2020 study posited that low bone mineral density may instead be a pre-existing condition in transgender youth. Treatment with gender-affirming hormones may theoretically reverse this effect, according to Endocrine Society guidelines.
The impact of puberty blockers on brain development is similarly hazy. The Endocrine Society guidelines point to two studies: A small one published in 2015 showed that the drugs did not seem to impact executive functioning (cognitive processes including self-control and working memory), while a 2017 study of rams treated with GnRH agonists suggested chronic use could harm long-term spatial memory. (Of course, rams are not humans.)
The effects of puberty blockers are often referred to as “fully reversible,” including in both the Endocrine Society and WPATH guidelines, because of evidence showing that girls treated for precocious puberty were still able to undergo normal puberty and have children later in life.
While much of the data gleaned from precocious puberty treatments are applicable to transgender patients, Dr. Kremen said, “you’re asking a different question for precocious puberty than you are for a transgender child” when it comes to fertility. Halting puberty at its onset and then later starting gender-affirming hormones — a typical course for some transgender adolescents — may affect the ability to have children, she said. The Endocrine Society advises clinicians to counsel patients on “options for fertility preservation prior to initiating puberty suppression in adolescents.”
It is also worth noting that Lupron, one of the drugs widely used as a puberty blocker, has been reported to have long-term adverse effects in women who used it to treat precocious puberty. Women have reported issues including depression, bone thinning and chronic pain.
Puberty blockers may also impact future gender-affirming surgeries for transgender women. A recent study showed that transgender women who began puberty blockers at the start of puberty were 84 times more likely to require abdominal surgery if they wanted to pursue gender-affirming surgery. Because tissue from the penis and testes is used to construct a neovagina, and puberty blockers prevent the growth of those organs, material from the colon or omentum may need to be used.
An in-depth conversation detailing puberty blocker treatment and all its potential effects is an essential part of any transgender adolescent’s care. Specialists are eager for more research, but for now, they say the apparent benefits outweigh the hypothetical risks.
“Medications are rarely without side effects,” Dr. Kremen said. “That is usually not enough of a reason to allow a child, who is telling you that they’re extremely distressed by the pubertal changes that they’re seeing, to continue going through puberty.”
“Knowing what we do know, these medications have enormous benefits for the population that we care for,” she added.
Women Report Worse Side Effects After a Covid Vaccine
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Women Report Worse Side Effects After a Covid Vaccine
Men and women tend to respond differently to many kinds of vaccines. That’s probably because of a mix of factors, including hormones, genes and the dosing of the shots.
- March 8, 2021, 11:44 a.m. ET
On the morning that Shelly Kendeffy received her second dose of the Moderna Covid-19 vaccine, she felt fine. By afternoon, she noticed a sore arm and body aches, and by evening, it felt like the flu.
“My teeth were chattering, but I was sweating — like soaked, but frozen,” said Ms. Kendeffy, 44, a medical technician in State College, Pa.
The next day, she went to work and surveyed her colleagues — eight men and seven women — about their vaccine experiences. Six of the women had body aches, chills and fatigue. The one woman who didn’t have flu symptoms was up much of the night vomiting.
The eight men gave drastically different reports. One had mild arm pain, a headache and body aches. Two described mild fatigue and a bit of achiness. One got a headache. And four had no symptoms at all.
“I work with some very tough women,” Ms. Kendeffy said. But “clearly, us women suffered a severity of the side effects.” She felt better after 24 hours, and is thrilled she got the vaccine. “I wouldn’t change a thing, because it sure beats the alternative,” she said. “But I also didn’t know what to expect.”
The differences Ms. Kendeffy observed among her co-workers are playing out across the country. In a study published last month, researchers from the Centers for Disease Control and Prevention analyzed safety data from the first 13.7 million Covid-19 vaccine doses given to Americans. Among the side effects reported to the agency, 79.1 percent came from women, even though only 61.2 percent of the vaccines had been administered to women.
Nearly all of the rare anaphylactic reactions to Covid-19 vaccines have occurred among women, too. C.D.C. researchers reported that all 19 of the individuals who had experienced such a reaction to the Moderna vaccine have been female, and that women made up 44 of the 47 who have had anaphylactic reactions to the Pfizer vaccine.
“I am not at all surprised,” said Sabra Klein, a microbiologist and immunologist at the Johns Hopkins Bloomberg School of Public Health. “This sex difference is completely consistent with past reports of other vaccines.”
In a 2013 study, scientists with the C.D.C. and other institutions found that four times as many women as men between the ages of 20 and 59 reported allergic reactions after receiving the 2009 pandemic flu vaccine, even though more men than women got those shots. Another study found that between 1990 and 2016, women accounted for 80 percent of all adult anaphylactic reactions to vaccines.
In general, women “have more reactions to a variety of vaccines,” said Julianne Gee, a medical officer in the C.D.C.’s Immunization Safety Office. That includes influenza vaccines given to adults, as well as some given in infancy, such as the hepatitis B and measles, mumps and rubella (M.M.R.) vaccines.
The news isn’t all bad for women, though. Side effects are usually mild and short-lived. And these physical reactions are a sign that a vaccine is working — that “you are mounting a very robust immune response, and you will likely be protected as a result,” Dr. Klein said.
But why do these sex differences happen? Part of the answer could be behavioral. It’s possible that women are more likely than men to report side effects even when their symptoms are the same, said Rosemary Morgan, an international health researcher at the Johns Hopkins Bloomberg School of Public Health. There’s no vaccine-specific research to support this claim, but men are less likely than women to see doctors when they are sick, so they may also be less likely to report side effects, she said.
Still, there’s no question that biology plays an important role. “The female immune response is distinct, in many ways, from the male immune response,” said Eleanor Fish, an immunologist at the University of Toronto.
Research has shown that, compared with their male counterparts, women and girls produce more — sometimes twice as many — infection-fighting antibodies in response to the vaccines for influenza, M.M.R., yellow fever, rabies, and hepatitis A and B. They often mount stronger responses from immune fighters called T cells, too, Ms. Gee noted. These differences are often most robust among younger adults, which “suggests a biological effect, possibly associated with reproductive hormones,” she said.
Sex hormones including estrogen, progesterone and testosterone can bind to the surface of immune cells and influence how they work. Exposure to estrogen causes immune cells to produce more antibodies in response to the flu vaccine, for example.
And testosterone, Dr. Klein said, “is kind of beautifully immunosuppressive.” The flu vaccine tends to be less protective in men with lots of testosterone compared with men with less of the sex hormone. Among other things, testosterone suppresses the body’s production of immune chemicals known as cytokines.
Genetic differences between men and women may also influence immunity. Many immune-related genes are on the X chromosome, of which women have two copies and men have only one. Historically, immunologists believed that only one X chromosome in women was turned on, and that the other was inactivated. But research now shows that 15 percent of genes escape this inactivation and are more highly expressed in women.
These robust immune responses help to explain why 80 percent of autoimmune diseases afflict women. “Women have greater immunity, whether it’s to ourselves, whether it’s to a vaccine antigen, whether it’s to a virus,” Dr. Klein said.
The size of a vaccine dose may also be important. Studies have shown that women absorb and metabolize drugs differently than men do, often needing lower doses for the same effect. But until the 1990s, drug and vaccine clinical trials largely excluded women. “The drug dosages that are recommended are historically based on clinical trials that involve male participants,” Dr. Morgan said.
Clinical trials today do include women. But in the trials for the new Covid vaccines, side effects were not sufficiently separated and analyzed by sex, Dr. Klein said. And they did not test whether lower doses might be just as effective for women but cause fewer side effects.
Until they do, Dr. Klein said, health care providers should talk to women about vaccine side effects so they are not scared by them. “I think that there is value to preparing women that they may experience more adverse reactions,” she said. “That is normal, and likely reflective of their immune system working.”
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