As part of my research when questioning prior to starting Hormone Replacement Therapy (HRT), I read the international guidelines on trans healthcare of the time. Since then I also may have attended an endocrinology session at EPATH earlier this year. You know, the big international transgender healthcare conference that was in Ireland. The one that not a single Irish doctor attended.
So while I am obliged to point out that I am not a medical professional and you should not consider anything in this article as medical advice, I may have picked up one or two things. As WPATH SoC v8 says, many trans people find themselves “having to educate [Health Care Professionals] to be able to receive adequate care”.
GnRH Blockers
I’d like to first look at a paper written by National Gender Service (NGS) staff and draw your attention to this definition in Table 1:
The reference there is to the 2017 Endocrine Society Guidelines, which you may remember from a previous article are referenced in the NGS’s Model of Care. However the term “GnRH blocker” does not appear anywhere in its 35 pages. And only one sentence of that definition is substantially taken directly from the text.
As someone who has read more than a few pieces of medical literature on trans healthcare, it feels a bit off. Almost as though the authors are not fully familiar with the area. Let me explain why.
Firstly, the term “GnRH blocker” to me would usually indicate something that blocks the GnRH receptor. Such medications exist and are called GnRH antagonists. However, they’re not the more common GnRH agonists/analogs which are used by the NGS and have a different mechanism. In addition, the 2017 Endocrine Society Guidelines only mention GnRH agonists/analogs. You’re probably more familiar with the more colloquial term puberty blocker for all of these medications. It feels like the terms puberty blocker and GnRH agonist might have been mashed together without appreciating that the resultant term could be taken to have a different meaning.
Secondly, this talks about inhibiting the production of testosterone and oestrogen, which is an imprecision that always irks me a bit. This is the case as while testosterone is a specific chemical, oestrogen is a category of chemicals. In this context saying either oestrogens or mentioning oestradiol in particular would feel more correct. The 2017 Guidelines use different terms depending on the context. And the only place in which both are mentioned alongside each other has “testosterone and estradiol”. Estradiol and oestradiol are the US and UK spelling respectively.
Thirdly, the “specific gender goals” makes it seem that the use of GnRH agonists is rare in adults. They are in fact are the preferred way to stop the gonads producing testosterone in transfemme people and much more rarely in transmascs such as where testosterone alone is insufficient to stop periods.
This paper is part of a doctoral thesis and I don’t think it’s a big deal that the primary author missed a few of the finer details unrelated to the main thrust of the paper, especially given I gather they had only been involved with the NGS for around a year when this was written.
However, I would expect a deeper understanding of trans endocrinology from two of the co-authors — Dr. Karl Neff and Dr. Donal O’Shea — both of whom provided a final review prior to submission of the paper and failed to pick up on these. As you may recall from previous articles, Dr. Neff is the Consultant Endocrinologist and Clinical Lead of the NGS while Dr. O’Shea is a Consultant Endocrinologist who has had trans patients since the 1990s.
A Little Antagonising
The next paper of interest by NGS staff covers some of the patients that the NGS saw in 2020. This paper once again uses the term GnRH blocker, and also mentions Zoladex, the NGS’s preferred GnRH agonist/analog:
Again this wording comes across as saying that Zoladex blocks GnRH analogs rather than it being a GnRH analog.
Now you may feel I’m beating a dead horse here, being unnecessarily antagonistic and over-focusing on wording that’s only a tad muddled. The real antagonism can be found in the Results section of the Abstract:
This is a clear error in terminology, as I’ve never heard of GnRH antagonists being used by the NGS, only GnRH agonists are listed the NGS’s internal endocrine documents, and the paper itself mentions that the GnRH agonist Zoladex is the most common treatment.
Once again this paper has as co-authors Dr. Neff and Dr. O’Shea, both of whom commented on the drafts, and then read and approved the final manuscript. So neither of the NGS’s most senior endocrinologists spotted this error right in the abstract of the paper.
Blocker Therapy
How did this error happen? From reading the “Recommendations for Endocrine Care in the National Gender Service” I have a theory. There are three versions of this document from the following years: 2020, 2022, and 2023. Here’s the section on Blockers from the 2020 1.0 version which predates both of the above two papers:
It would appear that when the NGS says “Blockers” they specifically mean suppressing the gonadotropins. This terminology does not appear in the 2017 Endocrine Society Guidelines nor am I familiar with this usage from other literature such as WPATH.
Some endocrinology is required for context. GnRH controls the production of the gonadotropins including Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH). LH and FSH, among other things, control how much testosterone and estradiol that the gonads produce. How GnRH agonists work is by overloading GnRH receptors so that they stop working (known as downregulation), much less LH/FSH are produced, and the gonads produce far less testosterone and estradiol.
What I suspect happened is that the NGS somehow ended up with “blockers” as jargon specific to themselves. This became “GnRH Blockers”, possibly related to the common term puberty blockers. Finally this imprecision resulted in the incorrect “GnRH antagonist” being used when “GnRH agonist” was meant.
Suppressing the Gonadotropins
But wait, there’s more. The 2020 1.0 version also includes some other options for blockers, with some explanatory text:
This explanatory text was removed by the 2023 3.0 version, which lists four options for suppressing gonadotropins, of which Bicalutamide is new in that version:
Those familiar with the use of these medications in trans healthcare will immediately be intrigued.
First Cyproterone can indeed suppress the gonadatropins, among other effects, so that’s fine. Spironolactone is where things start to get dicey. Although while it can reduce testosterone levels, it does not do so by affecting the gonadotropins. Its effectiveness as an anti-androgen is more down to it being an androgen receptor antagonist. The androgen receptor is what testosterone and other androgens bind to to take effect.
I’ll take a moment to give a simplified explanation of what agonists and antagonists are. Your cells have receptors, which are like locks. An agonist is a key which can turn the lock and activate the receptor. The agonist may be the one your body produces itself or a synthetic chemical, an analog, that is able to activate the receptor. An antagonist or blocker, in contrast, gunks up the lock, so that nothing can turn it and activate the receptor.
Bicalutamide doesn’t suppress the gonadotropins, nor does it reduce testosterone levels. It is instead an antagonist of the androgen receptor.
Finasteride doesn’t suppress the gonadotropins, nor does it reduce testosterone levels. In fact it can increase testosterone levels. It is what’s called a 5α-reductase inhibitor, meaning it inhibits the conversion of testosterone to the more potent dihydrotestosterone (DHT) which affects hair loss. In a paper which is cited by WPATH SoC v8 on the matter, it is unclear whether 5α-reductase inhibitors are needed in transfemmes once testosterone levels have been lowered.
So three of the medications that the NGS has down as meant to suppress the gonadotropins don’t do so, two of them don’t suppress testosterone, and one of them doesn’t even help with general feminisation.
While we don’t know what training is provided to the NGS staff on top of this document, this issue of terminology looks like it might be going a bit beyond a single incorrect word in a research paper. One ponders if there may be more of a systemic issue. I would personally expect at least a warning that Bicalutamide and Finasteride do not reduce testosterone levels.
Barry’s or Lyons
The regular blood tests that the NGS requires of their patients should catch medications not having the expected effect on testosterone levels compared to GnRH agonists. So, naturally, we can check the section named “Initiating and Modifying Hormonal Therapy: Oestrogen” for what the internal NGS guidelines are. There is a target range mentioned for oestrogen (not oestradiol of course, the chance of running the wrong blood test keeps you on your toes) but none for testosterone. In fact the only ranges mentioned for testosterone are for trans mascs.
A sample letter to a GP relegates the hormone blood tests to “Other routine blood work”:
The only special warnings given are for extra kidney monitoring for Spironolactone, and in older versions of the document liver monitoring for Finasteride and Cyproterone.
It kind of looks like the NGS doesn’t check that testosterone levels are suppressed. And while they request LH and FSH blood tests, there’s nothing about checking them either. So in addition to not covering how some of these medications work significantly differently to their usual preference of Zoladex, they may not catch issues such as GnRH agonists not working as expected or insufficient dosing of Spironolactone.
The closest thing to monitoring testosterone levels for trans femmes is the suggested question to patients of “How are things going with your hormones?”.
The NGS Model of Care (MoC), which Dr. O’Shea co-authored, informs us that
And among the International Clinical Guidelines provided in the MoC are the 2017 Endocrine Society Guidelines.
Dr. O’Shea definitely appears to be a fan of international guidelines. In a radio interview earlier this year he said “every time I’ve gone with something obesity related, they listen to your opinion. And you guide clinical care in line with international best evidence. Here, every time we’ve gone along to say this isn’t safe, we’ve been told stop saying that.”
In a 2022 email Dr. Neff indicates that these are still in use:
What wisdom do these much lauded 2017 Endocrine Society Guidelines have for us?
The guidelines the NGS’s Clinical Lead consider a “main reference point” strongly recommend regularly monitoring testosterone and to keep it under 50ng/dL (that’s around 1.7 nmol/L in the units commonly used here in Ireland) for transfemmes.
No version of the NGS’s internal endocrine recommendations mention this.
Of course I’m sure that this is the only part of the 2017 Endocrine Society Guidelines that the NGS don’t follow.
Due to downsizing, Jes Black (she/it) can only afford threeshadowing.
