relugolix (Orgovyx) new orally active GHRH antagonist (medical castration)

[aklurker (imported)]

Folks considering chemical castration as a trial prior to seeking surgical castration may be interested to hear that a new orally active gonadotrophic hormone releasing hormone (GHRH) antagonist, relugolix (Orgovix), has just been approved by the FDA on 18 Dec 2020. The FDA approved its use only in adult males with hormone responsive advanced prostate cancer, but it is likely to be prescribed "off label" for other folks such as males with desires for male to female or male to eunuch (like me) gender transition.

Let me summarize three general approaches to medical castration. The first approach was the use of testosterone/hydroxytestosterone receptor antagonists such as cyproterone (Androcur) that directly block the interaction of testosterone with its receptors in tissues like the prostate and skin (i.e., beard growth). The problem with these agents is that they also block the pituitary feedback mechanism, leading to increased pituitary secretion of follicle stimulating hormone (FSH) and leutenizing hormone (LH) that stimulate the testes to increased secretion of testosterone and are actually associated with higher serum levels of testosterone. Though the effect of the increased testosterone on target tissues is blocked, there is increased conversion of testosterone to estrogens, leading to problems such as gynecomastia. There is also some suggestion (though the data on this are pretty thin) that the use of testosterone receptor blockers is associated with an increased frequency of psychiatric side effects such as mood disorders and depression than is seen with the other two classes of agents used to achieve medical castration.

The second class of agents is the group of gonadotrophic hormone releasing hormone (GHRH) agonists such as luprolide (Lupron), an analogue of GHRH. In normal physiology, GHRH is released by the hypothalamus in pulses that stimultate the pituitary to release follicle stimulating hormone (FSH) and luteinizing hormone (LH), and these in turn, in males, stimulate the testes to secrete more testosterone. It might seem as though this is going in the wrong direction for medical castration. But in fact when GHRH is increased in continuous fashion (as mimicked by luprolide), after a brief initial increase in testosterone it turns off further pituitary secretion of FSH and LH, thereby shutting down testosterone production by the testes. Luprolide is an injectable medicine typically given by injection every three months. These agents are now the most frequently used methods for medical castration.

The third class of agents is the direct GHRH receptor antagonists. These agents directly block the GHRH receptor in the pituirary resulting in sharp drops in secretion of FSH and LH, thereby blocking the release of testosterone from the testes. Up until now, the only member of this class was degarelix (Firmagon), another injectable medicine that needs to be injected once monthly. But now, as noted above, relugolix (Orgovix) has been approved in the US by the FDA. This is an oral medicine taken as a once a day pill.

Both these latter two classes of medicines are very effective in achieving medical castration. I have used degarelix for about a year, and it reduced my serum testosterone from a normal level of about 400 ng/mL to about 5 ng/mL (!!) within a couple of weeks. A castrate level of testosterone is < 50 ng/mL, and a profound suppression of testosterone is a level < 20 ng/mL. The only mild adverse systemic effect that I experienced with the degarelix was some mild hot flashes for the first month or two. (I don't count the other expected consequences of medical castration to be adverse effects!) But the degarelix injection contains an additive that is designed to prolong the release of the active agent over the month between injections. Unfortunately for me (and about 40% of other men taking degarelix) this agent is somewhat inflammatory, so the the injection site stayed quite tender for the whole month. I am planning to switch now to relugolix, the oral pill, which will not have this annoying side effect.

A major advantage of the GHRH receptor antagonists over the GHRH agonists is that the latter are associated with an increased risk of cardiovascular events such as heart attacks and strokes. This is not seen with the GHRH receptor antagonists. Further, as discussed above, there appears to be less risk of adverse psychiatric effects (< 10% incldence of mood disturbances). Another advantage of the GHRH antagonists is the they appear to be completely reversible at least when they are taken for only up to a year. So if a eunuch "wannabe" has an adverse effect or discovers that he doesn't like being a medical eunuch, he can stop the medicine and anticipate that he will recover a normal testosterone level and normal male functioning within a few months.

Please understand, readers, that you should not take any of the above as "medical advice." While I am pretty well informed about these issues, I am not in a position to give any medical advice. "Please consult your own personal physician before considering use of any of these agents, etc." Incidentally, let me confirm that I have no relationship of any sort with Myovant (the company that makes relugolix) and that nothing above should be taken as coming from Myovant.

Finally, however, submitting this message gives me the opportunity to say that I am obviously interested in being a eunuch, whether by medical or surgical means. I would be happy to discuss the above with any other members of the Eunuch Archive.

aklurker

[dreamwatcher (imported)]

most expensive way I think. in China, Degarelix 120mg*2 will cost 1300usd

[clueless (imported)]

Although it's useful to have as many methods of chemical castration as possible so one can review their options, I can't see this drug being financially viable until at least a few years. If you look at second generation anti androgens such as abiraterone acetate, enzalutamide, apalutamide and darolutamide, although all have been FDA approved for prostate cancer, none are within an affordable range. Darolutamide for example costs $10,000 a month.

[fhunter]

Darolutamide for example costs $10,000 a month.

So it is cheaper to get orchidectomy, than to use it long term. Interesting.