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; doubly so owing to Familial pattern of hypophyseal dysregulation.

Table of contents

1. Counterindications/adverse interactions
2. Oestradiol cycles
3. Slow titration
4. Blood tests pre-HRT; normal total T and high SHBG pre-HRT
5. Acute thyroid downregulation
6. Familial pattern of hypophyseal dysregulation
7. References

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.

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, [3], [4], and Transdermal Oestradiol gel: temporary discontinuation.

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, Transdermal Oestradiol gel: temporary discontinuation.

Slow titration

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

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.

Acute thyroid downregulation

Given sufficiently high Oestradiol target levels/gradients (e.g. 25 pg/mL adrenal E2 pre-HRT, >=200 pg/mL E2 HRT, though this may very well apply at >=150 pg/mL) initiation of HRT via any route of administration induces acute thyroid downregulation, presumably via TBG modulation. The degree of downregulation should be significant enough to be of significance, reflecting well established sexual dimorphism in, inter alia, metabolism, but not anywhere near pathological, even during or after a period or repeated periods of "hormonal chaos" (stable pre-HRT TSH ~1.0-1.2 µUI/L, stable post-HRT initiation (across multiple regimens) TSH ~1.5-1.8 µUI/L, during/after "hormonal chaos": ~2-2.3 µUI/L.)
This is normally unlikely to be a problem but certainly bears mentioning and documenting, particularly as diet/lifestyle changes may be recommendable.

Familial pattern of hypophyseal dysregulation

A familial pattern of underlying systemic/dynamic hypophyseal dysregulation, possibly implicating the hypothalamus as well, expressing a diffuse range of genotypes and phenotypes may eventually express a genotype on the transsexual spectrum and potentially serve as a biomarker thereof. In the case of the author, the genotypes/phenotypes comprise:

1. maternal uncle: hypophyseal tumour
2. biological mother: moustache growth, androgynous facial anatomy, migraine, poor skin health, with an onset during puberty
3. the author of this document (pre-HRT phenotype, all resolved post-HRT:)
   
   1. The hypothyroidic syndrome (metabolic/digestive slowing, fatigue/low energy levels, cold/heat intolerance, flu-like symptoms (implicating mucosal tissue, histamine, the immune system,) cognitive dysfunction/DPR, slow wound healing, skin dryness, insomnia, catecholamine dysregulation suspected but very hard to differentiate, etc.)
   2. A diffuse range of symptoms for which currently no phenomenologically and empirically valid notion exists and which must hence be provisionally subsumed under the terms of gender incongruence, gender dysphoria/dysmorphia, or transsexuality presenting with, DPR, cognitive, affective, social cognitive, as well as sympathetic ("screaming brain") as well as parasympathetic ANS dysfunction/dysregulation, psychoticity, non-normative gender/sex identity development and a much larger range of primarily physiological systemic and often subtle dysfunctionality/dysregulation that defies differentiation and specificity, in particular wrt. the above mentioned hypothyroidic syndrome.

It bears emphasising that the dysregulation here most likely refers to decidedly non-linear phenomena that cannot be understood in a mechanistic manner and instead require a systemic approach that considers the hypothalamus-pituitary gland-... axes from a systems theoretical perspective and in terms of dynamic processes, implicating: timing, specific critical developmental windows, desynchronisation, homeostasis/balance, feedback, calibration, response curves, gain, set-points, receptor sensitivity/density, ratios of different receptor (sub)types, aberrant systemic reconfiguration in response to specific triggers (such as puberty onset,) etc.

It additionally bears mentioning that this complicates anything relating to HRT owing to the possibility of introducing additional instability to a regulatory system that is already prone to instability by itself, plus downstream across and beyond merely the HPG axis, and appears to also increase susceptibility to certain concentration curves (e.g. transdermal vs. injections) that would otherwise not matter.

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] 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"

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