HRT – A look under the hood.

This post will be pinned as an independent page, it’s more of a research effort I did 2 years ago, and I thought I’d compile it for those who interested on the works of sex hormones in general and HRT in specific ..

It’s only built based on a logical order in my head ..

Review and corrections to any information hereunder are always welcome.

1   Endocrine system

The pituitary gland (often called the master gland) is located in a small bony cavity at the base of the brain. A stalk links the pituitary to the hypothalamus, which controls release of pituitary hormones. The pituitary gland has two lobes: the anterior and posterior lobes. The anterior pituitary is glandular.

fig 1

The endocrine system in females and males.

The hypothalamus contains neurons that control releases from the anterior pituitary. Seven hypothalamic hormones are released into a portal system connecting the hypothalamus and pituitary, and cause targets in the pituitary to release eight hormones.

 

fig 2fig 3fig 4fig 5

The location and roles of the hypothalamus and pituitary glands.

Growth hormone (GH) is a peptide anterior pituitary hormone essential for growth. GH-releasing hormone stimulates release of GH. GH-inhibiting hormone suppresses the release of GH. The hypothalamus maintains homeostatic levels of GH. Cells under the action of GH increase in size (hypertrophy) and number (hyperplasia). GH also causes increase in bone length and thickness by deposition of cartilage at the ends of bones. During adolescence, sex hormones cause replacement of cartilage by bone, halting further bone growth even though GH is still present. Too little or two much GH can cause dwarfism or gigantism, respectively.

Hypothalamus receptors monitor blood levels of thyroid hormones. Low blood levels of Thyroid-stimulating hormone (TSH) cause the release of TSH-releasing hormone from the hypothalamus, which in turn causes the release of TSH from the anterior pituitary. TSH travels to the thyroid where it promotes production of thyroid hormones, which in turn regulate metabolic rates and body temperatures.

Gonadotropins and prolactin are also secreted by the anterior pituitary. Gonadotropins (which include follicle-stimulating hormone, FSH, and luteinizing hormone, LH) affect the gonads by stimulating gamete formation and production of sex hormones. Prolactin is secreted near the end of pregnancy and prepares the breasts for milk production. .

2   Steroid and non-steroid hormones

2.1  Nonsteroid Hormones

Nonsteroid hormones (water soluble) do not enter the cell but bind to plasma membrane receptors, generating a chemical signal (second messenger) inside the target cell. Five different second messenger chemicals, including cyclic AMP have been identified. Second messengers activate other intracellular chemicals to produce the target cell response.

 

fig 6fig 7fig 8fig 9

The action of nonsteroid hormones.

2.2  Steroid Hormones

The second mechanism involves steroid hormones, which pass through the plasma membrane and act in a two-step process. Steroid hormones bind, once inside the cell, to the nuclear membrane receptors, producing an activated hormone-receptor complex. The activated hormone-receptor complex binds to DNA and activates specific genes, increasing production of proteins.

fig 10fig 11

 

2.3  Testosterone, Estrogens, And progesterone

2.3.1  Testosterone

In Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–6 months of age.[13][14] The function of this rise in humans is unknown. It has been speculated that “brain masculinization” is occurring since no significant changes have been identified in other parts of the body.[15] It is interesting to note that the male brain is masculinized by the aromatization of testosterone into estrogen, which crosses theblood–brain barrier and enters the male brain, whereas female fetuses have alpha-fetoprotein, which binds the estrogen so that female brains are not affected.

Pubertal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males, these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood.

 

Higher levels of testosterone were associated with periods of sexual activity within subjects, but between subjects testosterone levels were higher for less sexually active individuals.

2.3.2  Estrogens

While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. They promote the development of female secondary sexual characteristics, such as breasts, and are also involved in the thickening of the endometriumand other aspects of regulating the menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important to the maturation of sperm[13][14][15] and may be necessary for a healthy libido.[16] Furthermore, there are several other structural changes induced by estrogen in addition to other functions.

2.3.3  Progestogens

2.3.3.1 Female indications

Progestins are used in a variety of different forms of hormonal contraception, including birth control pillsimplants, and the intrauterine devices.[2][3]

In women, progestogens are commonly used to prevent endometrial hyperplasia from unopposed estrogen during hormone replacement therapy. They also used to treat secondary amenorrheadysfunctional uterine bleeding and endometriosis.[2][3]

In a normal menstrual cycle, declining levels of progesterone triggers menstruation. Norethindrone acetate and medroxyprogesterone acetate may be used to artificially induce progestogen-associated breakthrough bleeding.[5]

2.3.3.2 As antiandrogens

Main article: Antiandrogen

In addition to their progestogen properties, some progestins are antagonists of the androgen receptor, and can be used clinically as antiandrogens. Examples include chlormadinone acetatecyproterone acetatedienogestdrospirenonemegestrol acetatenomegestrol acetate,[6] andnorgestimate.[7] Care must be taken as to which progestin is used however, as various others, such as levonorgestrel,[8] norgestrel,[9] norethisterone,[8] norethisterone acetate,[8] and medroxyprogesterone acetate,[10] conversely have androgenic properties.

Desogestrelnorgestimategestodenedienogest, and etynodiol diacetate have little or no androgenic effects.[9][11][12] Moreover, dydrogesterone[13]and nestorone[14] lack any androgenic effects.

2.3.3.3 As antigonadotropins

Progestogens, similarly to the androgens and estrogens through their own respective receptors, inhibit the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via activation of the progesterone receptor. This effect is a form of negative feedback on thehypothalamic-pituitary-gonadal (HPG) axis that the body uses to prevent sex hormone levels from becoming too elevated.[15][16][17] Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects,[18] and progestins in sufficient amounts can markedly suppress the body’s normal production of progestogens, androgens, and estrogens, as well as, in theory, neurosteroids.[17] As such, some of the more potent progestins, including chlormadinone acetate,[16] medroxyprogesterone acetate,[19] megestrol acetate,[18] nomegestrol acetate,[20]and norethisterone acetate[21] are sometimes used to suppress sex hormone levels in a variety of androgen and estrogen-associated conditions. Examples of indications include treating sex hormone-sensitive cancers (e.g., breast cancer), suppressing precocious puberty and puberty intransgender youth, and reducing sex drive in sex offenders and individuals with paraphilias or hypersexuality.

Progesterone itself is not employed as an antigonadotropin, as it can function as a prohormone to androgens and estrogens,[22] especially at the relatively high doses that would be necessary to achieve sufficient antigonadotropic action.[22][23][24]

2.3.3.4 Cachexia

Further information: Cachexia

In many people suffering from solid malignancy, especially gastric and pancreatic cancer, high doses of certain progestins can be employed to improve appetite and reduce wasting. In general, they are used in combination with certain other steroids such as dexamethasone. Their effects take several weeks to become apparent, but are relatively long-lived when compared to those of corticosteroids. Furthermore, they are recognized as being the only drugs to increase lean body mass. Megestrol acetate is the lead drug of this class for the management of cachexia, andmedroxyprogesterone acetate is also used.[25][26]

 

3   Secondary sex characteristics

3.1  Males

In males, testosterone directly increases size and mass of musclesvocal cords, and bones, deepening the voice, and changing the shape of the face and skeleton. Converted into DHT in the skin, it accelerates growth of androgen-responsive facial and body hair, but may slow and eventually stop the growth of head hair. Taller stature is largely a result of later pubertyand slower epiphyseal fusion.

3.2  Females

In females, breasts are a manifestation of higher levels of estrogen; estrogen also widens the pelvis and increases the amount of body fat in hips, thighs, buttocks, and breasts. Estrogen also induces growth of the uterus, proliferation of the endometrium, and menses.

  • Enlargement ofbreasts and erection of nipples.[4]
  • Growth ofbody hair, most prominently underarm and pubic hair
  • Greater development of thigh muscles behind thefemur, rather than in front of it
  • Widening ofhips;[5] lower waist to hip ratio than adult males
  • Smaller hands and feet than men
  • Elbows thathyperextend 5-8° more than men[6]
  • Rounder face
  • Smaller waist than men
  • Upper arms approximately 2 cm longer, on average, for a given height[7]
  • Changed distribution in weight and fat; moresubcutaneous fat and fat deposits, mainly around the buttocksthighs, and hips
  • Labia minora, the inner lips of the vulva, may grow more prominent and undergo changes in color.[8]

4   Prostate

4.1  Function

4.1.1  Male sexual response

During male ejaculation, sperm is transmitted from the ductus deferens into the male urethra via the ejaculatory ducts, which lie within the prostate gland. It is possible for men to achieve orgasm solely through stimulation of the prostate gland, such as prostate massage or receptive anal intercourse.[17][18][19]

4.1.2  Secretions

Prostatic secretions vary among species. They are generally composed of simple sugars and are often slightly acidic. In human prostatic secretions, the protein content is less than 1% and includes proteolytic enzymesprostatic acid phosphatasebeta-microseminoprotein, and prostate-specific antigen. The secretions also contain zinc with a concentration 500–1,000 times the concentration in blood.

4.1.3  Regulation

To function properly, the prostate needs male hormones (androgens), which are responsible for male sex characteristics. The main male hormone is testosterone, which is produced mainly by the testicles. It is dihydrotestosterone, a metabolite of testosterone that regulates the prostate.

4.2  Prostate and MTF SRS

Since the size and the function or prostate is regulated and solely controlled by testosterone, going under hormonal therapy will mean atrophy of the prostate.

Continuing to read, some surgeons do remove the prostate as part of SRS operation, others don’t, and they just retain it to maintain the sensational function of it.

Since it doesn’t produce any male hormones (it rather consumes it), and the fact it will just undergo atrophy, it’s not of a major concern.

5   Brain meets body

5.1  Blood-Brain Barrier

The blood-brain barrier (BBB) separates the central nervous system (CNS) from the peripheral tissues. However, this does not prevent hormones from entering the brain, but shifts the main control of entry to the BBB. In general, steroid hormones cross the BBB by transmembrane diffusion, a nonsaturable process resulting in brain levels that reflect blood levels, whereas thyroid hormones and many peptides and regulatory proteins cross using transporters, a saturable process resulting in brain levels that reflect blood levels and transporter characteristics. Protein binding, brain-to-blood transport, and pharmacokinetics modulate BBB penetration. Some hormones have the opposite effect within the CNS than they do in the periphery, suggesting that these hormones cross the BBB to act as their own counterregulators. The cells making up the BBB are also endocrine like, both responding to circulating substances and secreting substances into the circulation and CNS. By dividing a hormone’s receptors into central and peripheral pools, the former of which may not be part of the hormone’s negative feed back loop, the BBB fosters the development of variable hormone resistance syndromes, as exemplified by evidence that altered insulin action in the CNS can contribute to Alzheimer’s disease. In summary, the BBB acts as a regulatory interface in an endocrine-like, humoral-based communication between the CNS and peripheral tissues.

5.2  Mechanisms for Translocation

fig 12

Mechanisms for translocation across the BBB of hormones and their messages between the brain and blood. The role of barrier prevents substances from crossing the BBB as exemplified by steroids that are protein bound. Permeability of the BBB is often by way of transmembrane diffusion as exemplified by unbound steroid hormone or by way of transporters as exemplified by leptin. The cells forming the BBB are themselves targets of circulating substances as exemplified by the many effects that insulin has on brain endotheial cell function. The cells that form the BBB are themselves endocrine-like in that they can secret substances into the blood or into the brain as exemplified by IL-6 secretion by brain endothelial cells. Relay is a special feature arising from the unique separation of brain endothelial cells into luminal and abluminal membranes and allows the BBB cell to receive an input on one membrane and to secrete from the other as exemplified here by adiponectin acting at the luminal membrane to alter secretion of IL-6 from the abluminal membrane. Extracellular pathways (data not shown) can be used by albumin and by very large and stable proteins (antibodies, erythropoietin) to gain access to the CNS.

fig 13

6   Feminizing Hormone Therapy

6.1  Why take feminizing hormones?

Starting feminizing hormones is a huge step on the path to aligning mind and body for trans women. They alter mood and body, and as the WPATH (World Professional Association for Transgender Health) SOC (Standards of Care, Version 7) points out:

Hormone therapy can provide significant comfort to patients who do not wish to make a social gender role transition or undergo surgery, or who are unable to do so (Meyer III, 2009).

Obviously, most people who socially transition also take feminizing hormones.

The comfort referred to above is related to physical and emotional changes that hormones drive.

6.2  What about anti-androgens?

Anti-androgens are mainly needed to stop/slow down Testosterone and how it affects our bodies, there’re different types of anti-androgens that can be used during HRT, the following diagram is a simple graphical representation of how testosterone is produced.

fig 14

Few types of anti-androgens.

GnRH inhibitors; aka GnRH antagonists, are mainly used to inhibit the secretion of GnRH, hence preventing the entire production of FSH, and LH, preventing the entire production of testosterone by testes, but also can be used to stop ovulation and the production of natural Estrogen, GnRH antagonists are also used to pause/stall puberty for young trans folks, and to treat hormone-sensitive tumours.

Progesterones; its mostly famous cyproterone acetate (aka Androcur, as well as other commercial brands), directly inhibit the production of FSH/LH, and hence effectively preventing the testes from producing testosterone, since it’s used to inhibit the production of FSH/LH, it’s also used to treat hormone-sensitive tumours.

Weak anti-androgens bind to testosterone, and binding as well to the testosterone receptors in target cells, so it’s practically racing the testosterone molecules to the target cells blocking the reception of testosterone, and hence preventing the related masculinizing effects.

Also another type of weak anti-androgens, is Finastride, which as described earlier prevents the metabolism of testosterone to its more potent version (DHT), and it’s also used to treat male baldness.

Anti-androgens are not required for feminizing hormones to be effective, but as described below, this will vary from person to person. In general though, the lower the testosterone level, the more effective estrogen will be in driving physical changes, which is why estrogen is most often paired with an anti-androgen.

Personally, I believe that the best anti-androgen is Estrogen itself. Maintaining a steady high-enough, near natural level, will automatically produce the negative feedback needed to signal the body to stop producing more FSH/LH, hence stopping the testosterone production.

6.3  What physical changes will feminizing hormones bring?

Feminizing hormones drive female secondary sex characteristic development and decrease male secondary sex characteristics. In general, this means breast growth and fat redistribution to a more female pattern and loss of muscle mass/strength, impotence, and sterility.

The following table, adapted from the SOC, highlights most physical changes. Time ranges are estimates based on published and unpublished clinical observations.

Effect Expected onset Expected maximum effect
Body fat redistribution 3-6 months 2-5 years
Decreased muscle mass/ strength (dependent upon amount of exercise) 3–6 months 1–2 years
Softening of skin/decreased oiliness 3–6 months Unknown
Decreased libido 1–3 months 1–2 years
Decreased spontaneous erections 1–3 months 3–6 months
Male sexual dysfunction Variable Variable
Breast growth 3–6 months 2–3 years
Decreased testicular volume 3–6 months 2–3 years
Decreased sperm production Variable Variable
Thinning and slowed growth of body and facial hair (full hair removal only possible with electrolysis and/or laser) 6–12 months More than 3 years
Male pattern baldness No regrowth, loss stops 1–3 months 1–2 years

Effects will be highly variable from person to person. The SOC is clear on this (emphasis added):

The degree and rate of physical effects depends in part on the dose, route of administration, and medications used, which are selected in accordance with a patient’s specific medical goals…and medical risk profile. There is no current evidence that response to hormone therapy…can be reliably predicted based on age, body habitus, ethnicity, or family appearance. All other factors being equal, there is no evidence to suggest that any medically approved type or method of administering hormones is more effective than any other in producing the desired physical changes.

 

6.4  The limits of knowledge

There is no clear scientific consensus on how dosages and formulations affect physical or emotional outcomes or rate of changes. Also, while some changes (such as breast tissue growth) are permanent even if hormones are stopped, it is impossible to predict the tipping point at which hormonally-driven changes would revert to a pre-feminizing hormones state, if at all.

What this means in practical terms is that dosage and formulation prescriptions are really best guesses by the doctor based on the medical history and condition, that the patient may need to change one or both to drive desired physical changes, and that even then you may not achieve your desired outcome.

Just as everyone’s transition is different, everyone’s response to hormones will be different from everyone else. Everyone should listen to their own bodies and evaluate information from the doctor before making any changes.

The risks of feminizing hormones

Taking hormones significantly increases the risks and likelihood of potentially life-threatening illnesses. These risks are compounded if one’s having pre-existing risk factors such as age, family history, or an existing condition.

The risks include:

Some of these risks are life-threatening. Carefully consider if the risk of premature death is worth it.

What are typical dosing ranges and formulations?

Often, feminizing agents are prescribed along with an anti-androgen, but it is not required. The following table is adapted from Jamie Feldman & Joshua Safer (2009):Hormone Therapy in Adults: Suggested Revisions to the Sixth Version of the Standards of Care , International Journal of Transgenderism, 11:3, 146-182.

As always, discuss dosages and risk factors with your doctor.

Type General dosage range Class/use
Oral estradiol 2.0–6.0 mg/day Feminizing agent
Transdermal estradiol patch 0.1–0.4 mg twice weekly (some brands are weekly dosing) Feminizing agent
Injected estradiol valerate 5–30 mg every 2 weeks Feminizing agent
Injected estradiol cypionate 2–10 mg every week Feminizing agent
Spironolactone 20–400 mg/day Anti-androgen
Cyproterone acetate 50–100 mg/day Anti-androgen
Goserlin acetate 3.75 mg SQ monthly Anti-androgen
Finasteride 5 mg/day Anti-androgen
Dutasteride 0.5 mg/day Anti-androgen
Medroxyprogesterone 10–40 mg/day Feminizing agent
Micronized progesterone 100–200 mg/day Feminizing agent

 

6.5  What emotional changes will feminizing hormones bring?

Given the fact that Testosterone and Estrogen are both steroid hormones, they do cross the Blood-Brain Barrier, meaning they’re bound to have impact on how our brains work, so indeed I do believe that sex hormones and HRT will certainly have impact on mood, emotions, even the way we think, how we react to events, and perceive the world surrounding us.

Also anti-androgens, like GnRH antagonist and cyproterone acetate, since they cross the Blood-Brain Barrier, they tend to have some negative side effects like possible depression.

I have been unable to find any clinical studies of the emotional impacts of feminizing hormones. Everything is anecdotal or accepted “community wisdom”. It is also hard to disentangle the relief of starting hormones, which many consider an emotionally significant step in transition, from their actual effects.

In general, many report feeling calmer in general, and for those who self-report with anxiety or depression, some may notice a lessening or cessation of symptoms. For some, emotional range and response becomes wider and more intense. Dosages and formulations seem to impact emotional response, so pay close attention in the weeks when you start or change either.

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