Why Evolution is True is a blog written by Jerry Coyne, centered on evolution and biology but also dealing with diverse topics like politics, culture, and cats.
Today’s post comes from Joseph Shen, a pharmacology student in Chicago. He has guest-posted here once before (see link below), and this week sent a contribution on what he’s learned about puberty blockers. I am not a pharmacologist and haven’t checked all the claims in this post, so please do so yourself if you have concerns. Also I am not giving any medical advice here and am not responsible for whether people decide to take or not take these drugs.
Shen is worried about the overuse of puberty blockers in “affirmative care” by doctors and therapists who don’t know about possible side effects of these blockers or the fact that they haven’t been tested properly for their effects on blocking puberty.
Finally, there’s a felid lagniappe to this post that I’ve put below the fold.
Without further ado (and see the “Update” at bottom.
What a Student Pharmacist Thinks about Puberty Blockers
Joseph Shen
Hello readers, I have been on this website once before when Prof. Ceiling Cat (Emeritus) kindly shared my post about UIC’s mishandling of the Jason Kilborn controversy. What I didn’t mention at the time was that I am a pharmacy student. The ultimate role of the pharmacist is to optimize drug therapy, which means following best-practice guidelines, understanding side effects, and avoiding unnecessary therapies. You can see how this will connect to the transgender debate around puberty blockers.
I’m sure most readers here are familiar with articles giving critiques of puberty blockers like the one in the New York Times and the ones by Jesse Singal on his Substack site. While their content is good, I wanted to share with you how I viewed this topic through the lens of a pharmacist, focusing more on the drugs: what they are and how they are (mis)used. My goal is to inform you so that the next time you tell an affirmative care supporter that puberty blockers are not safe, they retort “what do you know about them?” or “why do you care that they need to be safe?”, you will have an answer.
Background Knowledge.
To understand drugs like a pharmacist, you must do a basic review of anatomy and physiology, specifically the hypothalamic-pituitary-gonadal (HPG) axis pictured here.
From Wikipedia
For anyone unfamiliar with this, the simplified version is that the hypothalamus releases gonadotropin-releasing hormone (GnRH) into the pituitary gland in front of it. The pituitary gland secretes two more hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates cells around immature ova and spermatozoa to help them mature. More importantly, LH triggers other cells nearby to synthesize progesterone, testosterone, and estrogens. This process triggers all the changes in puberty.
What, Exactly, are Puberty Blockers?
To block puberty, you have to interrupt the effects of the HPG axis. The most popular way is to inhibit the function of LH so that no hormones are synthesized. GnRH agonists are synthetic peptide molecules that mimic GnRH. They bind the same receptor and trigger the release of LH. At first, there is a release of LH and temporary increase in sex hormones. But after around 10 days, the stores of LH are depleted and desensitization reduces the number of receptors for GnRH, so releasing LH becomes harder. There are also GnRH antagonists: other synthetic peptides which bind the same receptors but don’t trigger any reaction, stopping the cycle immediately. While they work faster, these drugs are more costly and have more side effects, making them far less popular. When a person stops taking either class of drug, the HPG-axis resumes its cycles. This is what leads activists to claim that their effects are reversible. The cycles may resume on the molecular level, but that does not mean puberty will resume as normal on the bodily level.
Among GnRH agonists, just a few are used in most cases. Leuprolide is the most common drug in the class. It can be injected as a suspension into the muscle/fat every month, or it can be a biodegradable implant. Two other very similar drugs are goserelin and triptorelin, though they are available only as an implant and injection, respectively.
While known to the public as “puberty blockers” thanks to the controversy, GnRH agonists have several uses. They are first-line treatments for all stages of prostate cancer, depriving the tumor of growth-stimulating testosterone. They can also be used to treat endometriosis, in which uterine-like tissue grows somewhere else in the body, causing severe pain. Since that tissue is stimulated by sex hormones, GnRH agonists make it inactive. And during in vitro fertilization, a woman takes a dose to make sure she doesn’t ovulate early.
Notice anything about these uses? They are all either short-term or used to correct a hormonal abnormality. What GnRH agonists are not well-supported for using is stopping normal onset of puberty, leaving the body in a developmental limbo. Leuprolide, in fact, has a shady history. Its initial approval by the FDA was based on very limited data, with some small sample sizes and short durations. Some post-market studies carried out after approval also had issues, with serious side effects such as bone disease omitted from a 2010 study. The poor literature means we can’t definitively predict what will happen when you start and stop using the blockers. Human bodies going through puberty are not tardigrades that will hibernate when the environment is hostile and later restart as if nothing happened. Pausing puberty is more like pulling on a Slinky: leave it stretched too long—and it may never slink again. With no big longitudinal studies, we just don’t know.
The thing most people want to hear about GnRH agonists are their side effects, and there’s a lot to discuss. Mainstream articles frequently mention poorer bone health. Sex hormones trigger the cartilage known as the growth plate in the femurs to grow and then turn to bone. They also maintain a balance between bone growth and breakdown. For someone on puberty blockers, the growth plate may not mature, and the balance shifts towards bone breakdown, both of which make fractures more likely. Sexual issues are another real possibility. The lack of sex hormones can reduce or eliminate development of libido in both trans boys and girls. What I haven’t seen discussed is what happened to many girls who were given leuprolide for years to delay puberty so that they grew taller. Decades later, these girls who had normal puberties and who have never been on other treatments developed osteoporosis, weak joints, and fibromyalgia. What reason is there to believe similar cases won’t happen with trans kids without normal puberties? Beyond that, leuprolide and the others currently carry warnings for increased risk of heart attacks, dizziness and fainting, and a host of other conditions, all based on thousands of cases of reported adverse effects—how can these drugs possibly be perfectly safe?
A Pharmacist’s Concerns
It confuses me why all the debate over these drugs rarely involves pharmacists, who are the drug experts. Doctors may know treatments, but it’s pharmacists who are more keenly aware when a drug therapy is lacking evidence.
Improper prescribing is a huge, pharmacist-specific concern. Contrary to popular belief, pharmacists don’t just fill prescriptions made by physicians without question. Pharmacists are required by law to exercise “corresponding responsibility” and dispense drugs only when they’re safe and appropriate. I see the transgender controversy as having some of the biggest potential for improper prescribing. Without solid guidelines and with influence from various organizations like WPATH, pharmacists are put into a bind. We can either sign off on unwarranted med orders or refuse to fill them and be condemned by societal and professional peer pressure. We will have to stand up for our profession by saying NO when decisions are not based on good science. It is our duty to stop potential harm to patients, sometimes even if it’s what they want.
Another pharmacist-specific concern erodes trust in modern medicine. Physicians live by the Hippocratic Oath, often condensed into the phrase “first, do no harm.” At times, doctors withhold information from patients to spare them emotional and psychological harm (e.g., giving “affirmative” advice without telling parents so that they can’t be obstacles). This causes doctors to butt heads with pharmacists who, in contrast, live by the Oath of a Pharmacist [side note: the 2021-2022 updated oath includes the line “I will promote inclusion, embrace diversity, and advocate for justice to advance health equity.”] We tend to emphasize patient autonomy, being truthful, and giving enough information for them to make rational choices. It is unethical to deceive patients about a drug’s safety to increase the likelihood of using that drug. This kind of behavior makes practicing medicine seem like it’s based on reckless opinion rather than on evidence from clinical trials. When patients think their doctor’s suggestions are just opinions, then all they need to refuse a suggestion is their own opinion—the same kind of opinion that could make them refuse vaccinations or turn to alternative medicine.
Conclusion
This controversy would not exist if there was simply enough evidence. But we can’t do large-scale, longitudinal studies because they’re ethically and practically impossible. Subjects would have to be prepubescent and started on these drugs for years with consent from their parents. No thinking parent would allow this. Studying only children who claim to have gender dysphoria seems like the clear next option. But sample sizes would be much smaller, and the zealous proponents of affirmative care don’t want to wait years and delay transition. Observational studies are the best we can do, and we know their results so far are not promising.
I genuinely sympathize with the young, dysphoric people who are in a catch-22. If they use blockers but then lose their dysphoria, they may incur irreparable damage to their bodies for nothing. If they wait until they’re sure they want to transition, but their bodies develop, they may never be satisfied with themselves. But when I choose patient safety over satisfaction, I’m doing it not out of malice but because I care enough to value their wellbeing.
I apologize if this sounds like a polemic. While I speak from the principles taught to me as a pharmacist, I speak only for myself. I hope this piece was at least somewhat engaging and not as dull as the actual lectures we all had to sit through to learn this. I’ll end on a high note. As is customary for a cat’s staff member, I must share pictures of my boss. They tell a comedy in 3 acts.
UPDATE:
One commentor (#9 below) correctly pointed out that I implied without evidence that physicians are frequently not discussing the risks of GnRH agonists with patients. This was wrong of me. What I should have written was that the medical field (at least in the U.S.) is largely supporting GnRH agonists regularly despite the lack of evidence for their safety, and not admitting to that. It is this air of support, not individual people, that concerns me. If and when individual physicians downplay the risks, then that is even more unethical; I’m certain that’s not the vast majority of doctors treating gender-dysphoric kids.
Here is the evidence for that support. The Endocrine Society (ES)’s 2017 guideline claims “pubertal suppression is fully reversible,” implying that long-term side effects are negligible. They “recommend,” (a strong statement) not “suggest,” (a weaker statement) that puberty suppression be used when indicated. They give a lukewarm review of the effects on bone and say next-to-nothing about brain development. Wikipedia conveniently lists the American organizations. that give position statements supporting GnRH agonists and/or the ES’s position. Position statements are not scientific evidence but carry scientific credibility in people’s minds.
This is exacerbated by mainstream media, in which articles from progressive-leaning venues (see here, here, and here) cite individual professionals who claim that puberty blockers are “well-studied, well-documented, and well-tolerated”, are “a benign medication”, and that the side effects are “not enough of a reason to allow a child … to continue going through puberty.” This small number of professional opinions (one of the lowest forms of scientific evidence) can shape what the public perceives to be the state of medicine. And again, it’s aways about what the doctors think in these articles, not the drug experts. Doctors are not always perfectly scientific and rational, needing pharmacists to help guide them with drug therapy. It’s just that no one in the media bothers speaking to a clinical pharmacist.
Guidelines are the starting-point resources for doctors before they make their own professional decisions. It is not a good thing when they hold poorly supported statements and when people are hesitant to challenge them because of social pressure. It is misleading at best and needs to be addressed with evidence and compassion, not instinctively calling critics transphobic.
[JAC: Read the story below the fold (click “read more”)]
Reader Fred sent me a photo that came from this tweet. Can you spot the bobcat in it? I’ll put the extracted picture below, and will post the reveal at noon Chicago time.
Please don’t put the answer in the comments so that others can search. But you can say whether you spotted it.
Reader Bruce Cochrane sent me this photo yesterday with an explanation:
In honor of the day [International Cat Day], I thought you might appreciate a picture of our international cat, Luna Mew. She is a refugee Burmese from Ukraine, brought to us by way of Hungary, Slovenia, Austria, The Netherlands, Boston, and finally the Cincinnati airport, where we met up with her “cat nanny”. She’s a wonderful little cat, and as she see, she loves playing with a feather on a stick while Rommel looks on.
He also added that he has eight cats.
When I asked whether this was related to the war, and what was involved in adopting a Ukrainian cat, Bruce wrote this:
Yes, this is definitely war related, and all the credit in the world goes to Burmese Cat Rescue of America (based in Minnesota) for orchestrating this. Apparently, Ukraine is home to a number of Burmese breeders, and they have been trying to get their cats to safety. In this case, there were a total of eight cats, mostly kittens from two litters. A total of 3-4 cat nannies flew to Vienna, where they picked up the cats for transfer to the states and their final destinations. And while in Europe, they got their initial shots and were neutered, so while the cost of this was substantial, it wasn’t as bad as the amount charged seemed to be. And after a few days of recovery and adjustments, she’s worked out terms with our other cats.
That’s a lot of work! When I asked Bruce whether less privileged moggies, like non-purebred cats, also get adopted, he said he’s trying to find out.
Thank Ceiling Cat: two readers came through with photos when the tank was empty. Today’s lot comes from Leo Glenn, who sends photos from Costa Rica. His captions are indented, and you can enlarge the photos by clicking on them.
Here are some more photos from my recent trip to Costa Rica.
There are four species of monkeys in Costa Rica: the Central American squirrel monkey (Saimiri oerstedii), the Panamanian white-faced capuchin (Cebus imitator), Geoffroy’s spider monkey (Ateles geoffroyi), and the mantled howler monkey (Alouatta palliata). As we were spending most of our time in parks and nature preserves, we were hopeful that we would see at least one of the species. It came as quite a surprise to us, then, that while we saw no monkeys in any of the nature preserves, a family of mantled howlers moved Into the trees next to our rental house and spent around 45 minutes eating, lounging, and playing. It was an amazing experience.
Like cats, they were masters at relaxing in the most precarious of positions.
We enjoyed watching them use their prehensile tails to move among the branches, sometimes hanging from them to reach the choicest leaves, which make up 75% of their diet.
Another species that we were hoping to catch a glimpse of was a coatimundi. And just as we pulled into the Monteverde Cloud Forest Reserve, a South American coatimundi (Nasua nasua) strolled right across the parking lot.
Coatimundis, known locally as pizotes, are members of the family Procyonidae, the same family as raccoons, and they share many of the same traits. Unlike the more nocturnal raccoons, however, coatimundis are diurnal.
In the cloud forest, we came upon a nest of red-tailed stingless bees (Trigona fulviventris). Our guide said that the honey they produce is inedible, but it has been used traditionally for medicinal purposes. I couldn’t find any information on that, but I did read that the sticky resin they make to build their nests has been used by fishermen to caulk leaks in their canoes. Another occasion when I wished I had a longer lens.
A tree fern (Cyathea holdridgeana). I was particularly excited to see this, as I have been obsessed with paleontology since I was a child. Tree ferns, along with Lycopods and Horsetails, were the predominant “trees” in ancient forests, before our current trees evolved. This particular species grows at elevations of 2400-2800 m, much higher than most other tree ferns in Central America. I believe we were at around 2100 m on this tour.
A colorful group of caterpillars. I was unable to determine the species, but they appear to be a moth in the genus Euglyphis.
And finally, our rental house came with a cat [Felis catus], whose name was Linda.
Linda asking to be let in.
Below: Linda’s favorite activity, after we let her in (other than begging for something to eat). She was 17 years old, and growing deaf. Her meow was loud enough to wake the dead (something she liked to do at five in the morning outside our bedroom window). But she was otherwise spry and hale. Of course we fell in love with her.
Today we have part 3 of Tony Eales’s safari to Botswana (see parts 1 and 2 here and here, and we have one more to go: from Victoria Falls). Tony’s captions are indented, and you can enlarge his photos by clicking on them.
Safari Part III
Ok, enough elephants and hippos. We all know what WEIT fans are here for: cats and owls.
The first cats were ones that worked at the Sedia Riverside Hotel. One specialised in breakfast clean up, the other in small bird control.
But of course, what you go to Africa for are the big cats. and the first and most wonderful we saw was an adult female leopard (Panthera pardus):
We found out about her position from another safari car and when we got to her position there were at least half a dozen other cars all trying to get a position to see her. She had taken an impala kill into a thick bush and was eating part of it:
When she had had her fill, she came out and lay in the grass and cleaned herself. We were a bit annoyed with one particular safari company that had many cars there and seemed to be coming in far too close and blocking other peoples’ views. Despite all this the leopard acted as if the cars didn’t exist only occasionally looking up briefly when a car restarted its engine. All the cats, leopards and lions, that we saw treated the cars as beneath their concern, unworthy of any attention:
We got the story from some other guides that they believed that this leopard had cubs hidden somewhere. Because our camp was very close by we were able to stay after all the other cars had left and got some great views before she wandered off after sunset, presumably to see her cubs or get water.
The next day we came back early and saw a hyena, presumably attracted by the kill, run off. we went to the thicket but the impala was gone. Then we heard jackals yelping nearby:
We followed their gaze and found the female eating again, this time in high grass. As more cars turned up we decided to head off:
We came back in the afternoon and found a different scene. Now the adult female was laying out on a high mound near a tree. And in that tree was a young male:
The story we gleaned from others was that this male was her cub from last year. He had come to participate in the meal and she had chased him up the tree. He was no longer going to get handouts now that she had new cub. If he moved at all she growled and ran at the tree climbing halfway up the trunk to keep him in place. It was hard not to anthropomorphise his expression as confused and sad as he watched her with fixed gaze as she eventually wandered off:
The next cats we saw was a small pride of lions (Panthera leo), a female, two young male brothers and two cubs. we were the first to spot them and got wonderful views of them playing and interacting:
In the end we saw approximately 30 lions in the trip both in Momei and Chobe and I can’t put up all the shots I got this nice one of a young male in Chobe:
There isn’t much wildlife in these photos by Athayde Tonhasca Júnior, but a lot of history and travel, so they qualify as “wildlife”. His notes are indented, and you can enlarge his photos by clicking on them.
Phoenicians, Greeks, and Minoans (Cretans) were very fond of octopuses. This 1500-1450 BC vase is one of many pieces of octopus-themed pottery in the Cyprus Museum (Nicosia) and museums from all over the Aegean region. Scholars have offered countless explanations for this Octopoda-fixation.
Today’s rich and famous stuff their homes with art objects, but the Romans had mosaics as symbols of status. They were created by artisans specialised in assembling tesserae (a tessera is a small tile made of ceramic, stone or glass). The Mosaics of Paphos from 3rd-4th century AD were discovered in 1962 when a farmer accidentally unearthed one of them while ploughing his field. They are part of Paphos archaeological complex, an UNESCO World Heritage site.
This mosaic depicts the duel between Theseus and the Minotaur in the Labyrinth of Crete. Theseus is holding a club and grabbing a horn of the Minotaur, who has fallen to his knees. The scene is framed by successive decorative zones that symbolize the Labyrinth.
Nicosia, the Cypriot capital, is not particularly photogenic. But many houses have lovely, old-fashioned porticos.
This street divides Lefkoşa (North Nicosia, on the left) and Lefkosia (South Nicosia), both surrounded by Venetian walls. Nicosia was the capital of the unified island until 1974, when Turkey invaded Cyprus. Now Lefkoşa is the capital of the Turkish Republic of Northern Cyprus (TRNC), a ‘country’ recognised by nobody except Turkey, and Lefkosia is the capital of the Cyprus republic. The pillboxes on the right side are pocked by bullet marks, reminders of the vicious fighting in 1974.
The United Nations Buffer Zone, known as The Green Line. This 180 km-long no man’s land divides Cyprus from the Turkish occupied area. The Green Line is patrolled by a UN force and an army of mangy cats.
Cyprus version of Berlin’s Checkpoint Charlie: you show your passport to a bored Cypriot guard, walk 50 m past dilapidated & empty buildings, show your passport to a bored Turkish guard, and officially leave Europe. The Turkish side is jam-packed with shoppers with an eye for bargain luxury-branded merchandise, possibly genuine handbags, shoes, clothes and assorted tat. There’s no need to change currency: traders are more than happy to take Euros instead of the ailing Turkish Lira.
The Green Line is not a Berlin Wall reincarnation, but it saw its share of activists arrested or shot. Today the Line’s greater danger is being shouted at by a UN soldier for the illegal act of photographing their shabby military installations. Notice the white-and-blue Greek colours, which are meant to rub the Turks the wrong way.
The Liberty Monument to celebrate independence from Britain in 1960. Liberty stands above two members of EOKA (National Organisation of Cypriot Fighters) opening the prison gates to free rebels, civilians and the clergy. Unfortunately there was no room in the monument for remembering the hundreds of Turkish-Cypriots murdered by EOKA, whose war cry was ‘first the British and then the Turks’. About 90 EOKA members were killed during the insurgency (a few were tortured in prison by the British forces), while nearly 500 British & Turkish-Cypriots, including policemen, medics and civilians, were murdered. One man’s freedom fighter is another man’s terrorist.
The Liberty monument was erected in 1973, one year before the Turkish invasion. The bullet impressions above the heads of these statues are mementos of those turbulent times. It all started when the right-wing military usurped power in Greece, and the humourless, moustachioed colonels winked the go-ahead to the Greek-Cypriots dreaming of enosis (union with the Greek motherland). Union happened in Crete, but Turkish-Cypriots were not keen on pan-Hellenism. Turkey moved in to defend its brethren, thousands were killed, and many thousands living on the wrong side of the island were displaced.
You see more Greek flags than Cypriot flags in the streets of Nicosia. The enosis aspiration may not have died, which will keep the Turks wary of Cyprus’ reunification.
What did the British ever do for Cyprus? A decent postal service, for one thing. To disguise their colonial past, the traditional red pillar-boxes were painted yellow. But the Royal Cypher (George Rex) was kindly preserved.
Sign in a Nicosia restaurant: One of the penalties of refusing to participate in politics is that you end up being governed by your inferiors—Plato.
A Gothic church from 1360 in Gazimağusa (Famagusta) on the Turkish-occupied northern coast. Converted to a mosque in 1572, the Brits finally put the building to good use by changing it to a wheat warehouse. Famagusta was established during the Byzantine era by refugees from the island of Salamis (in today’s Greece) fleeing Arab raiders. The city prospered under the Lusignans (French crusaders who ruled Jerusalem, Cyprus and Armenia at various times between 12th and 15th c.), and reached its zenith with the influx of Christian merchants and craftsmen after the fall of Acre to the Saracens in 1291. The Catholic Church ban on economic ties with the infidel was an even better windfall: Famagusta, strategically positioned to face the Middle East, became a major commercial hub for the whole eastern Mediterranean. And you thought modern international relations were complex.
The Turkish and Turkish-Cypriot flags over the Venetian walls surrounding Famagusta. The town was blocked by the Ottomans in 1570, but the vastly outnumbered Venetian defenders held out for ten months. Their commander, Marcantonio Bragadin, agreed to surrender after being promised that civilians could leave the city and his soldiers could sail for Crete. But when the Ottoman commander Mustafa Paşa learned his opponents were so few, he lost his rag. He ordered the killing of several Venetian officers and the remaining Christians. Bragadin had his ears and nose cut off, and after several weeks of’ imprisonment, he was flayed alive. His skin was stuffed with straw and sent to the sultan in Constantinople. The treatment of Bragadin supposedly motivated the Venetians to victory at the Battle of Lepanto, which stopped Ottoman expansion in the Mediterranean. Eventually a Venetian pinched Bragadin’s skin and smuggled it to Venice, where it rests in the Basilica di San Giovanni e Paolo. The tall buildings in the distance are in the ghost town of Varosha. Once the heart of Famagusta’s tourism, the town was evacuated and fenced off after the 1974 Turkish invasion.
Severios Library’s inspiring front (Nicosia).
No boring “High Street” or “Station Road” in Cyprus or Greece.
Another charming portico in Nicosia.
From Jerry: Since it’s Caturday, I want to add that Cypress may be the site where we have the first evidence of domesticated cats (9,500 years ago). Here’s the Wikipedia entry:
Historians previously accounted Egypt as the earliest site of cat domestication due to the clear depictions of house cats in ancient Egyptian paintings about 3,600 years old. However, in 2004, a Neolithic grave was excavated in Shillourokambos, Cyprus that contained skeletons, laid close to one another, of both a human and a cat. The grave is estimated to be 9,500 years old, pushing back the earliest known feline-human association significantly. The cat specimen is large and closely resembles the African wildcat (Felis silvestris lybica), rather than present-day domestic cats.
Here’s a photo of the site and a reconstruction from National Geographic (captions are theirs). I put the arrow to show the cat skeleton. Text from Nat. Geo.:
The complete body of the animal was buried in a small pit at about twenty centimeters from the human grave. The tomb, particularly rich in offerings in comparison to other graves known from this period in Cyprus, suggests that the individual had a special social status. Τhis grave certainly bears witness to relationships between humans and cats in the 8th millennium B.C., not restricted to the material benefit of humans but also involved in spiritual links.
The cat is buried together with its “master”, 3D reconstruction of the Early Aceramic Neolithic grave of Shillourokambos.
