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.

Table of contents

1. General: counterindications/adverse interactions
2. General: Oestradiol cycles
3. General: slow titration
4. General: blood tests pre-HRT; normal total T and high SHBG pre-HRT
5. Transdermal Oestradiol gel: 1.28g pumps vs. 1.25g
6. Transdermal Oestradiol gel: use pump gently
7. Transdermal Oestradiol gel: determining serum levels
8. Transdermal Oestradiol gel: suboptimal concentration curve
9. Transdermal Oestradiol gel: temporary discontinuation
10. Transdermal Oestradiol gel: surface area
11. Transdermal Oestradiol gel: steady state
12. References

General: counterindications/adverse interactions

• Any medication or substance in general which is metabolised by the enzymes Cytochrome P450 3A4 (CYP3A4) and/or Cytochrome P450 1A2 (CYP1A2) 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, owing to CYP3A4 upregulation, significantly lower levels of Quetiapine are also induced relative to a male endocrine phenotype.
  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.
  If transdermal Oestradiol gel is used and hence, twice daily, Quetiapine, when taken once daily and at night will additionally induce asymmetry in the morning Oestradiol curve vs. nocturnal Oestradiol curve such that the nocturnal curve's Cmax, Cmin, and Cmean will be significantly higher than those of the morning curve.
  
  The difference in serum levels appears to roughly correspond to 15-20 pg/mL Cmean Oestradiol for each 25 mg of Quetiapine, based on multiple data points given varying Quetiapine dosages.
  
• 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.

General: Oestradiol cycles

It bears mentioning that exogenously driven Oestradiol 35-day cycles with distinguished pseudo-follicular, pseudo-ovulatory peak, pseudo-luteal, as well as PMS/PMDD phases 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 emergent dynamics resulting from interactions between Oestradiol levels/curves and (inter alia) Oestrogen Receptor (ER) populations (density) as well as their sensitivity and the housekeeping thereof (e.g. enzymes) within each cell, being as Oestradiol is responsible in conjunction with ERs for making more ERs, constituting an autoregulatory feedback loop exhibiting hysteresis within a larger intracellular regulatory network with considerable inertia, see, inter alia, [4], [7], and the temporary discontinuation section in this document.

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%.

In case of sufficient, especially pervasive, damage to cycle structure and subsequent recovery of stable Oestradiol inputs wrt. average serum levels as well as concentration curves, cycles may either temporarily lose coherence (highly pathological) and/or degrade to a cycle length of 7 days (equally pathological) for, on average, at least 7 iterations (e.g. 7 weeks,) followed, most likely, by an increase to a cycle length of 14 days (pathological, but much less problematic) for up to 2 iterations (e.g. 4 weeks in total,) and then recovery, back to the original (non-pathological) cycle length of 35 days. In case of failure to recover stable Oestradiol inputs, this process will continue oscillating indefinitely and maladaptively entrain these erratic patterns and eventually go on to adversely affect downstream systems, such as the thyroid gland and require, as soon as possible, temporary discontinuation.

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: blood tests 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 between four to five weeks, taking cycle boundaries into account, before resuming and be mindful of both severely hypogonadic menopausal Oestradiol levels as well as, given insufficient Testosterone suppression, gradually rising Testosterone levels, though SHBG being slow to respond is helpful here, and, eventually, well into the 2nd month, hypothyroidism; being as there is no reservoir effect with transdermal Oestradiol gel, any Oestradiol remaining at trough, irrespective of time to steady state, will be gone within an hour at most, at which point endocrine Oestradiol will be strictly adrenal on the input side.

With regard to the time period required to wait for: two weeks (11.5 days): crashes after day 17.5), three weeks (18.5 days): crashes after week #5, at least four weeks (32 days): stable after one cycle, according to experimental evidence. It would appear probable that this is both a function of SHBG stability (steady state after max. 5 weeks) as well as compound ER state, e.g. ER population (density) in each cell as well as sensitivity and all factors relating to ER housekeeping from transcription/translation to activation and elimination and all factors significantly affected by (effective) Oestradiol.

Furthermore, the presumed Oestradiol-driven ER density/sensitivity oscillations (cycles) appear to be only loosely coupled to their Oestradiol inputs and present with a considerable degree of hysteresis, e.g. they will maintain their internal state even if the external signal in its original state is absent for an unknown time period that may or may not correspond to between four-five weeks and may indeed be much longer, with the possibility of cycles gradually becoming more and more protracted, as observed in menopause and the phenomenon of cycles persisting after a hysterectomy.

For a general overview that does not specifically focus on ERs, refer to [7].

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.

Transdermal Oestradiol gel: steady state

The documented maximum time to steady state parameter of transdermal Oestradiol gel of three days is incorrect. Oestradiol, acting as a transcription factor, significantly induces CYP3A4, effectively increasing clearance/elimination relative to a masculine phenotype. Given a half life of between 1-6 days, this process should take no more than about two weeks to complete at most, before which, however, steady state is not achieved.

References

[0] (courtesy of ChatGPT)

[1] The association between hormones and antipsychotic use: a focus on postpartum and menopausal women - PMC
Do women need a change in dose of prescription drugs with onset of menopause? Time to find out | BMC Medicine | Full Text

[2] inter alia:
Sex hormone-binding globulin in non-cirrhotic alcoholic patients during early withdrawal and after longer abstinence
Alcohol consumption in relation to plasma sex hormones, prolactin and sex hormonebinding globulin in premenopausal women

[3] inter alia:
Coffee and Caffeine Consumption in Relation to Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Postmenopausal Women - PMC
Caffeine Upregulates Hepatic Sex Hormone‐Binding Globulin Production by Increasing Adiponectin Through AKT/FOXO1 Pathway in White Adipose Tissue - Briansó‐Llort - 2020 - Molecular Nutrition & Food Research - Wiley Online Library

[4] Kloosterboer, Helenius; Schoonen, Willem; Verheul, Herman (2008). "Breast Cancer". The Oncologist.
17 (1): 343–366. doi:10.3109/9781420058734-19. ISBN 978-1-4200-5872-7. PMC 3267821. PMID 22234628.
"Steroid deprivation, for instance, can have a major impact on the growth stimulation by E2. Estrogen sensitivity can be increased easily by four log-units or more (Masamura et al., 1995; Chan et al., 2002) (Fig. 1). This effect may be explained, at least partly, by a 100-fold higher level of ER(s) (Zajchowski et al., 1993), but coactivator sensitivity as well as the degree of phosphorylation of transactivation factors (TAF-1 and/or TAF-2) may also be crucial."

Downregulation of Estrogen Receptor Gene Expression by Exogenous 17p-Estradiol in the Mammary Glands of Lactating Mice
Estradiol-induced down-regulation of estrogen receptor. Effect of various modulators of protein synthesis and expression
Janus kinase 2--a novel negative regulator of estrogen receptor α function"

[5] (from Pharmacokinetics of estradiol - Wikipedia)

[6] Principles of Pharmacokinetics - Holland-Frei Cancer Medicine - NCBI Bookshelf
Area under the curve (pharmacokinetics)

[7] Melvin E. Andersen and Hugh A. Barton - Biological Regulation of Receptor-Hormone Complex Concentrations in Relation to Dose-Response Assessments for Endocrine-Active Compounds