Project "First Trans Person in Space"[1]: on insufficient HRT titration

DISCLAIMER: The information provided on this page is offered as is for general educational purposes only. I am not a medical professional, and nothing here should be interpreted as medical advice, diagnosis, or treatment guidance. Endocrine care, hormone therapy, and any related decisions involve medical risk and should be discussed with a qualified healthcare provider. By using this information, you acknowledge that any actions you take are entirely your own responsibility, and you agree that I am not liable for any outcomes, consequences, or damages resulting from your use or interpretation of this material.[0]

The problem: insufficient titration

This document proposes that all HRT protocols fail to account for the pattern of continuous change in (at least) Oestradiol serum levels observed in endogenous puberty and insufficiently titrate and overdose by severely violating physiological constraints on titration of (at least) Oestradiol as present in endogenous puberty[2], where changes in average concentrations are constrained to 1-3 pg/mL per each cycle[2], and hence result in:

1. Lack of efficacy due to inadequate rates of transcription for the effective induction of a phenotypal shift wrt. secondary sexual characteristics.
2. Lack of efficacy due to probable failure to effectively induce changes in methylation patterns additionally preventing a phenotypal shift, at the level of epigenetics.
   This phenomenon is documented in [3].
3. Needlessly adverse physiological inasmuch as mental side effect profile during at least an initial time period of 28-35 days owing to overdosing (including but not limited to: nausea, digestive and metabolical symptoms, "hot flashes"/thermoregulation, excessive energy levels and thyroid upregulation, insomnia, affective instability, fatigue/"mind fog", etc.)

The solution: the puberty protocol

As a potential solution, this document proposes a protocol of very slow titration mimicking endogenous puberty that intends to optimise for the highest safely available rates of transcription, significantly induce changes in methylation patterns, and eliminate all adverse side effects associated with unsafe rates of titration as follows:

• Assuming:
  10 mg/mL Oestradiol Cypionate, SC or IM, 7 day schedule
  5-10 mg p/d Cyproterone Acetate or, ideally, any GnRH-ergic antiandrogen
  Caveat: the 10 mg/mL Oestradiol Cypionate is likely to require custom prescriptions as 40 mg/mL is often the lowest available concentration.
  With Cyproterone Acetate as an antiandrogen, insufficient T suppression is unfortunately to be expected up until a certain Oestradiol threshold, corresponding to about 50 pg/mL in the case of the author; if the <50 pg/mL range is to be explored, this will require an individualised solution.
• Stabilise on 50 pg/mL E2 (Cmean,) assuming sufficient T suppression at that level for 1-2 cycles.
• Apply steady increments of 0.01 mL/10 µL corresponding to increases of +5-10 pg/mL[4] in average concentration every 1-2 cycle, subject to cycle length, taking into account the max. 6 weeks time to steady state of Oestradiol Cypionate and max. 5 weeks time to steady state of SHBG as well as potential thyroid response
  Caveat: considering endogenous puberty, this may still constitute insufficiently slow titration - if so, 5 mg/mL Oestradiol Cypionate should address this potential problem.
• Corresponding to +25-50 pg/mL per year and assuming a target of ~200 pg/mL, a simulated exogenous puberty spanning ~3-6 years.
  Caveat: there may exist a highly favourable dose-response relationship in the 25-50 pg/mL range, being as +5 pg/mL relative to 25 pg/mL is 1/5th, whereas +5 pg/mL relative to 50 pg/mL is 1/10th, etc.
• Going to SPAAAAAAAAAAAAAACE
  Caveat: there is no air in space.

Rationale

It is firstly to be observed that:

1. In endogenous puberty, for which a large body of sound data is available, the average concentration of Oestradiol as well as Testosterone is not stable across time and instead gradually rises from puberty onset to puberty peak in the form of a gradient, constrained to, in the case of Oestradiol, ~1-3 pg/mL per every ~28-35 day cycle.
   
   This is of significance as endogenous puberty is the only known and empirically studied mechanism by which a phenotypal shift wrt. secondary sexual characteristics significant enough to produce either - generally - the masculine or the feminine mode in the bimodal phenotype constituting biological sex is induced in a non-pathological fashion. This implies that sufficiently high rates of transcription are induced and maintained as part of this process, as is manifestly evident from the observed phenotypal shift.
2. There is a pervasive pattern in a significant body of anecdotal evidence, found on e.g. Reddit, of lack of efficacy of HRT in trans women and trans men of all ages, with all routes of administration, average and/or peak and/or trough serum levels, duration of HRT, etc. pp.
   This is expressed either in the form of observed efficacy during a brief initial time period (months) or none at all at any point, even years, and that upon cessation of HRT for a time period of 2-4 weeks and continuation of HRT, this may be temporarily alleviated (keywords: HRT doesn't work/not working, HRT stops/stopped working, HRT etc.)
   
   It must be emphasised here that dismissing anecdotal evidence is not an option as data of higher quality is simply not available since, bluntly spoken, nobody talks to trans people. Hence, it is obligatory to comb all the available anecdotal data for the very strongest signal on the basis of the predicate of pervasiveness. Equally so, it bears reminding that HRT is itself entirely experimental "frontier science" and that evidence, data, models, studies, protocols, guidelines, etc. are far more often than not of a speculative rather than empirical nature, in great part for systemic reasons.
   Hence, if a pervasive pattern of lack of efficacy of HRT and that the current standard practices and conventions by which HRT is administered, whichever they be, do not work for a large number of people exists in the data that is available, it cannot be dismissed a priori on grounds of data quality on both ethical inasmuch as epistemological grounds.
   

It is hence to be argued that sufficiently, sustained high rates of transcription correlate with gradients of gradually rising average concentrations of Oestradiol across time - "stable instability" - as opposed to specific fixed serum levels or even ranges thereof that are maintained stably across time. It would appear that little in the way of a rate of transcription beyond the basal is to be gained from a state of hormonal homeostasis, such as would be expected from stable serum levels, whichever they be, and much from a state of continually disrupted hormonal homeostasis, as long as this be constrained to a safe range of rate of change, as it is in endogenous puberty, where the necessary rate of transcription is observed.

Effective Oestradiol levels are to be seen as a function of both Free Oestradiol and Oestrogen Receptor (ER) density and/or sensitivity in target cells as well as the corresponding gradient ("how much Oestradiol across how much time with what kind of curve/gradient?"); the intricate dynamics of ERs with regard to down/upregulation of sensitivity and density by factors of up to 100x and 10,000x, among with other factors, in response to specific Oestradiol curves is documented in, inter alia, [5].

Though an at once entirely separate and yet also related matter, it bears mentioning that exogenously driven Oestradiol cycles exist, as observed by the author of this document and in the form of a pervasive pattern in a sufficiently large amount of anecdotal evidence on Reddit, etc. The mechanism behind this is unknown though it would appear likely that the culprit is to be found in the above mentioned ER dynamics as well as ER housekeeping within each cell, being as Oestradiol is responsible in conjunction with ERs for making more ERs, constituting a feedback loop internal to each cell, see, inter alia, [5].
As observed by the author of this document, there exists a constraint on rate of change that is lower than 200% given any average concentration, e.g. an increase from 50 pg/mL to 100 pg/mL (e.g. +50 pg/mL) is excessive and will dangerously impact cycle structure; being as the constraint in endogenous puberty is +~1-3 pg/mL per cycle, it is likely to be significantly lower than 200%.

References

Finally, the GAHT model provided a unique opportunity to determine the proportion of previously published sex-specific differences on autosomal chromosomes that are sensitive to hormonal influence post puberty. In total, GAHT affected 3% of all sex specific autosomal DMPs, but 15.8% of age-associated sex specific DMPs (Fig 6; Yusipov et al. 2020). This indicates that sex-specific DNA methylation that is present throughout life, from birth to adulthood, is hard-wired and determined by genetic and developmental programs, and not susceptible to change in response to hormones. The second conclusion from this analysis is that puberty-associated changes in DNA methylation can be induced in adults.

• Approximate Comparable Dosages of Estradiol by Different Routes - Transfeminine Science
• estradiol pharmacokinetics playground - estrannaise.js