General notes concerning HRT

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]

Unless otherwise specified, the information provided on this page is based on the experience of the author of this document.
Interindividual variability applies.

General: counterindications/adverse interactions

• Any medication or substance in general which is metabolised by the enzyme Cytochrome P450 3A4 (CYP3A4) and of which, after taking into account bioavailability, average concentrations in serum in the µg/mL range are attained, such as Quetiapine IM and XR (Seroquel, etc.,) will interact with Oestradiol by significantly increasing serum levels relative to the same amount thereof if no Quetiapine were present and simultaneously, significantly lower levels of Quetiapine are also induced. This must be taken into account when titrating upwards or downwards either Oestradiol or the medication in question or both as well as when estimating target serum levels relative to any HRT dosage.
  
  This occurs both due to competition for the same enzyme by both Oestradiol and Quetiapine as well a difference in average concentrations of close to two orders of magnitude: in the case of Oestradiol, 100-200 pg/mL vs. in the case of Quetiapine, ~1-10 µg/mL given dosages of 100-350 mg p/d and an oral bioavailability of 9%.
  
  While this phenomenon is acknowledged and discussed in literature[1], it is not sufficiently well-known and particularly so in conjunction with HRT.
• Any medication or substance in general which significantly increases SHBG, be it in the short, if acutely, mid, or long term, given habitual use, is to be ideally avoided entirely or at least treated with great care, particularly when stability in HRT has not been attained, as this will affect Free Oestradiol and constitute significant endocrine disruption. This includes, most importantly, Alcohol[2], especially if acutely, and, though to a much lesser degree and indirectly, Caffeine Coffee[3]. As Insulin increases SHBG also, there is an argument to be made that a healthy diet devoid in particular of "junk food", etc. is ideally to be preferred.

General: Oestradiol cycles

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, [4].
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%.

General: slow titration

Please refer to Project "First Trans Person in Space": on insufficient HRT titration for an in-depth discussion of this topic.

General: bloodwork pre-HRT; normal total T and high SHBG pre-HRT

When starting HRT, it is very highly recommended - in general - that extensive blood testing be done in order to determine a long list of serum levels, representing the pre-HRT state, and particularly including total E2 and total T as well as SHBG.
A consistently high SHBG pre-HRT that is not accounted for by diet, lifestyle, medication, etc. in conjunction with normal T as well as, most likely, barrage of pervasive, (adult) life-long physiological as well as mental symptoms, may be indicative of partial Androgen Receptor Insensitivity, as T is supposed to downregulate hepatic SHBG expression; this can be tested for.

Transdermal Oestradiol gel: 1.28g pumps vs. 1.25g

An unnamed brand of transdermal Oestradiol gel is claimed by the manufacturer to produce 1.25g of gel upon pump activation. This is not the case, as anyone with a digital scale may confirm for themselves. Instead, 1 pump corresponds to ~1.28g of gel with fluctuation in the µg range. This must be taken into consideration when estimating how many pumps a single bottle contains, after substracting the very first "priming" pump.

It is advised to integrate weighing the bottle after priming and after each pump with a suitable digital scale into one's personal HRT protocol.

Transdermal Oestradiol gel: use pump gently

An unnamed brand of transdermal Oestradiol gel presents with an undocumented problem concerning its pump mechanism. If the pump mechanism is engaged with excessive force as opposed to gently, it will, given 2 pumps p/d, predictably and reliably break after about 21 days/3 weeks, at which point each pump will exceed 1.28g by a steadily increasing amount, as anyone with a digital scale may confirm for themselves.

It is advised to integrate weighing the bottle after priming and after each pump with a suitable digital scale into one's personal HRT protocol.

Transdermal Oestradiol gel: determining serum levels

Estradiol levels after the last dose with 1 mg/day transdermal estradiol gel applied to different amounts of skin area (200 cm2, 400 cm2, or as large as possible) in postmenopausal women.[5]

As seen above, transdermal Oestradiol gel of whichever brand or manufacturer will generally present with a concentration curve across time as opposed to (ignoring brief peaks) stable levels, such as is the case with oral Oestradiol. This must be taken into consideration when attempting to determine serum levels as follows:

1. Assay Cmax, e.g. the maximum or peak concentration at the 3 hour mark (Tmax.)
2. Assay Cmin, e.g. the minimum or trough concentration at the 12 hour mark (Tmin,) e.g. right before the next dose.
3. Calculate Cmean, e.g. the average concentration, by, based on Cmax, Tmax, Cmin, Tmin, finding the Area Under the Curve (AUC,)[6] utilising the logarithmic method (((c1 - c2) / (LN(c1) - LN(c2))) * (t2 - t1)) during the absorption phase (rising levels) and the linear method (1/2 * (c1 + c2) * (t2 - t1)) during the elimination phase (falling levels.) This yields the maximum total exposure during that time period which, when divided by that same time period, e.g. 24 hours, will yield the maximum average concentration.
   This is the most meaningful and important of the three pharmacokinetic parameters. Unless otherwise specified, any source specifying Oestradiol serum levels will refer to average concentration (Cmean.)
   
   A HRT AUC calculator is available on this website.

Transdermal Oestradiol gel: suboptimal concentration curve

Estradiol levels after the last dose with 1 mg/day transdermal estradiol gel applied to different amounts of skin area (200 cm2, 400 cm2, or as large as possible) in postmenopausal women.[5]

As seen above, transdermal Oestradiol gel of whichever brand or manufacturer will generally present with a concentration curve with a considerable peak-to-trough ratio and two peaks and two troughs p/d. It bears mentioning that this can be suboptimal for the same reason as with the concentration curve of Oestradiol Valerate.

Transdermal Oestradiol gel: temporary discontinuation

When discontinuing, wait for about two weeks, respecting cycle boundaries, before resuming and be mindful of severely hypogonadic menopausal Oestradiol levels - this implies hypothyroidism - as well as insufficient Testosterone suppression. This is purely based on experience, though time to steady state of transdermal Oestradiol gel - e.g. three days, though however much remains at trough will be very rapidly taken up in any case - as well as SHBG - e.g. five weeks, though stability after week two can usually be expected - are factors.

Transdermal Oestradiol gel: surface area

Estradiol levels after the last dose with 1 mg/day transdermal estradiol gel applied to different amounts of skin area (200 cm2, 400 cm2, or as large as possible) in postmenopausal women.[5]

Always use the smallest possible surface area when applying transdermal Oestradiol gel in order to maximise absorption.

References