Guest Post: What a student pharmacist thinks about puberty blockers

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.

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”)]

Years ago, we bought Scooter a cat bed. Turns out he doesn’t like the texture of fur, real or faux.

Instead, Scooter likes to sleep on my jackets, always preferring it to the bed. Maybe it’s my scent.

I naively thought that if I covered the bed with my jacket and slowly moved it off each night, he’ll get accustomed to sleeping on the cat bed. My experiment ended in predictable failure.

To this day, I have to always cover his bed with one of my recently used jackets so that he will sleep in it. The lesson learned is that it’s futile to compromise with a cat, because cats have no concept of compromise. And maybe that’s how it should be.