HORMONE THERAPY: INTRODUCTION

<< RETURN TO Table of Contents

OBLIGATORY DISCLAIMER

This information was compiled by someone who is NOT a doctor and, in fact, has no medical training at all. It has been collected from multiple sources and referenced as to source whenever possible. Some sources are reputable medical authorities, others are questionable. The author of this HRT information makes no value judgements on the sources or their validity. However, the author does have personal experience with hormone therapy under physicians' supervision. It is strongly recommended that you do not use this information for the purposes of self-medicating with hormones as this can be dangerous - even deadly! Never take any prescription medications without consulting a doctor. This is for informational purposes only and this web site and its creator are not responsible for misuse or abuse of this information or any injury or harm that may result.

GENERAL INFORMATION

There is a lot of research being done on the effectiveness of HRT drugs. Unfortunately most of the recent studies that have made news headlines are referring to hormone therapy for post-menopausal women, and in many cases the sample groups were quite small. What implications, if any, these studies may have to HRT for transsexual or intersexed people remains unknown. Also, these studies looked exclusively at the synthetic HRT drugs and the data conclusions may not apply to bio-identical hormones at all (and likely do not).

Methods of Delivery/Administration

(in descending order of approximate efficiency in delivery into bloodstream)

Intramuscular injection - 100% efficient
Transdermal (patch, gel, or cream) - 90%
Sublingual troche [under tongue] or nasal spray - 80%
Oral - 10%

Understanding "Enteric Coatings"

There isn't just one enteric coating that is used industry-wide. There are many different formulations that are used for different applications (i.e., one for gelcaps, one for granules, another for tablets, etc.). Here's a link to one company that makes the coatings for pharmaceutical companies: www.idealcures.com/enteric-coating.html (where it says "weight gain" in their table, don't worry, they're talking about how much weight it adds to the pills coated with it). The entire purpose of these coatings is to allow them to survive through stomach acids - saliva isn't going to dissolve the coating, so for those who've planned to dissolve such pills under your tongue (sublingual administration), enteric coated pills won't work for that. You'd have to "breach the barrier" to absorb the medication sublingually (i.e., puncture the gelcap or crush the tablet). SOME will invariably go down your throat and into your stomach - and these coatings are usually added for a limited number of reasons. Either:

1. because the medication is likely to make your stomach upset if dissolved there.
2. to time-release the medication instead of all at once.
3. to target the medication to the small intestine.

Coated meds are usually labeled as being "Enteric Coated" or "Time Release" or "Targeted Medication" (or words to that effect). Some people are allergic to the coatings themselves and labeling regulations require the packaging indicate such coatings are present.

In addition to those studies, other research into the biochemical effects of HRT medications at the genetic level are also underway. This page will be updated with information as it becomes available.

The "Hormone Chain" Explained

One thing that is very difficult for people to understand is how the human body produces hormones. Before anyone considers purposely altering their hormone balance I feel it is important to know the way it's all supposed to work.

Steroids of the Adrenal Cortex

The adrenal cortex is responsible for production of three major classes of steroid hormones:

1. glucocorticoids, which regulate carbohydrate metabolism;
2. mineralocorticoids, which regulate the body levels of sodium and potassium; and
3. androgens, whose actions are similar to that of steroids produced by the male gonads.

The adrenal cortex is composed of three main tissue regions: zona glomerulosa, zona fasciculata, and zona reticularis. Although the pathway to pregnenolone synthesis is the same in all zones of the cortex, the structure of the tissues and enzymes present in each zone are distinct, with the exact steroid hormone product dependent on the enzymes present in the cells of each zone. Think of them like three factories all receiving the same raw materials but cranking out different product lines.

Gonadal Steroid Hormones

Although many steroids are produced by the testes and the ovaries, the two most important are testosterone and estradiol. These hormones are under tight control with short and long negative feedback loops to the brain regulating the secretion of follicle stimulating hormone (FSH) and leutinizing hormone (LH) by the pituitary gland and gonadotropin releasing hormone (GnRH) by the hypothalamus.

Low levels of circulating sex hormone in the blood reduce feedback inhibition on GnRH (the long loop), leading to elevated FSH and LH. The pathway to sex hormones in both male and female gonadal tissue (i.e, sex organs) includes the production of androgens: androstenedione and dehydroepiandrosterone. Testes and ovaries contain an additional enzyme, a 17b-hydroxysteroid dehydrogenase, that enables androgens to be converted into testosterone.

IN MALES: LH binds to Leydig cells (in the testes), stimulating production of the principal Leydig cell hormone, testosterone. Testosterone is secreted to the blood and also carried to Sertoli cells (elsewhere in the testes) by androgen binding protein (ABP). In Sertoli cells the testosterone is converted into dihydrotestosterone (DHT). Testosterone and DHT are carried in the bloodstream to target tissues by a specific gonadal-steroid binding globulin (GBG)*. In a number of target tissues, the testosterone can be converted to DHT "on site." DHT is the most potent of the male steroid hormones, with an activity that is 10 times that of testosterone. Because of its relatively lower potency, testosterone is sometimes actually considered to be a "prohormone" (another name for a "hormone precursor").

Testosterone is also produced by Sertoli cells but in these cells it is regulated by FSH. FSH stimulates Sertoli cells to secrete androgen-binding protein (ABP), which transports testosterone and DHT from Leydig cells to the place in the testes where sperm are made, where the testosterone stimulates sperm production.

IN FEMALES: LH binds to Thecal cells in the ovaries, where it stimulates the production of androstenedione and testosterone. An additional enzyme known as aromatase is responsible for the final conversion of androstenedione and testosterone into the estrogens.

Aromatase activity is also found in Granulosa cells, but in these cells the activity is stimulated by FSH. Normally, Thecal cell androgens produced in response to LH diffuse to Granulosa cells, where Granulosa cell aromatase converts these androgens to estrogens.

As Granulosa cells mature they develop large numbers of LH receptors becoming increasingly responsive to the presence of LH, increasing the quantity of estrogen produced from these cells. Granulosa cell estrogens are largely, if not all, secreted into follicular fluid. Thecal cell estrogens are secreted largely into the bloodstream, where they are delivered to target tissue by the same globulin (GBG)* used to transport testosterone.

IN BOTH MALES & FEMALES: Aromatase is found in numerous tissues in both males and females, being especially prevelant in adipose (fatty) tissue, but also in muscular tissues. There it converts testosterone and androstenedione into estrogens. In males the conversion in adipose tissues are the principle source of estrogens.

5-alpha-Reductase (5-AR) is responsible in both males and females for the enzymatic conversion of Testosterone to DHT and Progesterone to Dihydroprogesterone (DHP). 5-AR occurs throughout the body but occurs in to forms. Type I (5-R1) is the primary form active in acne and sebaceous gland oil secretions in the skin but is most abundant in the liver where it catabolizes steroids. Type II (5-R2) is primarily expressed in target tissues for androgens, such as the prostate and seminal vesicles, though it has been found present in the oil around hair follicles as well.

*Another name for that globulin is "Sex Hormone Binding Globulin" (SHBG).

This info lifted from the Indiana State University Medical Biochemistry web site.

WARNINGS FOR EVERYONE

The important thing to keep in mind is that hormone therapies are tailored to the individual's body chemistry. A proper dosage for one person may not be the proper dosage for another person. That is why it is imparitive to have a doctor monitoring you and doing regular blood work.

Hormones are nothing to be taken lightly. They can potentially KILL you if they are misused!

BLOOD CLOTS

Here's some information about the risk factor (this is in relation to post-menopausal women, by the way, but I think it might be reasonable to assume that men might have at least a similar risk, if not more-so since cardiovascular problems are much more prevelant among the male population).

NEW YORK, March 14, 2000 (Reuters) -- Women who take estrogen after menopause have a greater risk of developing blood clots in the legs or lungs in the first year of hormone use, a new study suggests. The association holds true whether a woman takes estrogen by pill or patch, alone or in combination with other hormones, or in high or low doses. However, the risk drops sharply after the one-year mark. After that, a hormone-user appears to be at no greater risk of blood clots than other women, according to the report in the March 15 issue of the British Medical Journal.

Overall, a woman has a 1.3 in 10,000 risk of developing such clots, which can be life-threatening if they lodge in the lungs. A woman's risk of clots rises to roughly 3 to 4 in 10,000 if she is taking estrogen, reported researchers from Madrid and Barcelona, Spain. When used for extended periods, estrogen replacement therapy (ERT) is thought to greatly lower the risk of heart disease and the bone-thinning disorder, osteoporosis. In the short term, ERT can help reduce menopausal symptoms, such as hot flashes and night sweats.

While estrogen does increase the risk of uterine cancer, most women also take progestin, a hormone that helps to reduce that risk. The new study included 292 women, aged 50 to 79, who were diagnosed with lung or leg clots. The researchers compared the women to 10,000 other randomly selected women the same age. Overall, women have four to five times greater risk of developing a clot in the first 6 months of taking hormones, and a three times greater risk at 6 to 12 months of taking estrogen. Other risk factors for such clots include a history of varicose veins, removal of both ovaries, obesity, and smoking. A leg clot, or deep vein thrombosis, is characterized by pain, swelling and warmth, and discoloration of the skin on the affected leg. A lung clot can cause shortness of breath, chest pain and fever.

What can you do to prevent the possibility of blood clots? Well, don't smoke, make sure to excercise regularly, and eat right. If there is a history of coronary problems in your family, you're most likely a contender for cardiovascular problems as well and should take that into consideration. A couple aspirin a day is supposed to be healthy and prevent clotting because it acts as a blood thinner, but NEVER start an aspirin therapy without consulting a physician first!

LIVER DAMAGE

The liver is the largest organ inside your body and it performs over 500 functions and is the primary "detox" center of your body, seperating the good stuff from the bad stuff and then passing on the good stuff to the rest of the body while sending the bad stuff to the gall bladder and kidneys for further processing and disposal (that is a VERY simplistic version of the process, by the way). And that literally means EVERYTHING that winds up in your blood or stomach - alcohol, pesticides on foods you eat, chemicals absorbed through your skin, fumes inhaled, etc. We live in a VERY toxic world, and your liver is putting in a lot of Over Time just trying to deal with it. Even things we normally don't think of as "toxic" can be if the liver is overworked or malfunctioning. A high protein diet can, for example, lead to unwanted Amonia in your bloodstream (it is a byproduct of metabolizing proteins). Too much amonia in the blood can lead to dementia, among other things. Okay, now that the scare is on and you're ready to live in a bubble, you should also know that the liver can do it's job even when 80% of it's tissues are damaged. That doesn't mean you shouldn't care what you do to it, though.

As part of its "detox duties" it also has to deal with a number of hormones. For example, it is supposed to clear out extra insulin. If it doesn't, the insulin remains in circulation and continues to do its job of lowering blood sugar. Failure to dispose of adrenaline (the "fight" or"flight" hormone) after it has outlived its usefulness may lead to chronic irritability and temper explosions.

All products absorbed through digestion initially pass through the liver. THIS is why ingested hormones CAN POTENTIALLY damage the liver. The liver is supposed to take care of "excess" hormone production. Ideally, if you are trying to infuse your system with hormones, you want them to make a complete circuit through your body, bonding to receptors along the way, BEFORE the blood gets to the liver. Otherwise there are just too many hormones for the liver to deal with. But it is also important to consider WHICH hormones actually do damage. It is well-documented that synthetic anabolic steroids or testosterone derivitives damage the liver. I had difficulty understanding exactly HOW they damage it, but I gathered that the enzymes employed in breaking down the "natural" hormones into harmless compounds often "accidently" break synthetics down into toxic substances that cause cellular-level damage. But what abodut estrogen? In some cases, even as little as two or three weeks of use have been documented to ruin the ability of the liver to detoxify natural estrogen. The livers of women on B vitamin/protein deficient diets may have difficulty metabolizing estrogen to non-toxic estriol, leaving it instead in the form of liver toxic estradiol. Estradiol is the form associated with hyper emotional states including explosive temper and obsessive-compulsive tendencies (essentially, PMS).

The main problem with taking hormones orally is that the hormones are passed into the liver as part of the process of digestion. Not only will some of the hormones be destroyed in the process, the liver is designed to deal with small amounts of "left overs" and will be inundated by the large amount of hormones - some of which will likely be liver-toxic and cause cellular damage to the organ. Whatever the liver can't handle will ultimately be washed out the "downstream" side of the liver into the cardiovascular circuit where the hormones will be pushed all around the body, binding to receptors as they go, before the blood returns to the liver. The problem with this scenario is that it is the REVERSE of the process for hormones produced within the body.

So, obviously, if you are going to have estrogen passing through your liver BEFORE it gets into the rest of your bloodstream, you'd avoid liver-toxic (i.e., liver damaging) effects if the hormones were "ESTRIOL" in form instead of "ESTRADIOL." Estriol is available and is also the main component of a supplement knowns as "Tri-Est" (Triple Estrogen) which is 80% Estriol, 10% Estradiol, and 10% Estrone. M2F Transsexuals report unsatisfactory feminization from estriol, as it is a relatively weak cell stimulator (i.e., it doesn't stimulate the growth of breast tissue as much as estradiol or estrone).

So how much is too much? That's unknown and would vary person to person and also depend on the concentrations of consumed. One thing you can do to mitigate this problem is to take estradiol transdermally (patch, lotion, or gel), sublingually (under the tongue), nasally (there is a spray available), or by intramuscular injection. All of those methods allow the hormone to enter the bloodstream first which means there is better efficiency and only waste product hormones will go through the liver in much smaller amounts.

I have had great difficulty in determining exactly how damaging elevated estradiol levels may be to one's liver. A recent study published in Oncology: International Journal of Cancer Research and Treatment a hospital-based case controlled study of male liver cancer patients in Greece looked specifically at the phenomena of elevated estradiol levels in such patients. It looked at 98 cancer patients and 111 control cases. It had been claimed that the elevated estradiol levels may have been responsible for the liver damage, however that claim was not supported by this study. When the researchers compensated for the fact the cancer patients' livers were compromised, and therefore incapable of dealing with steroid hormones efficiently, the conclusion was that the elevated estradiol levels were a consequence of the liver damage, not the cause of it. [ source ]

Part of the difficulty in determining what the actual liver damage risk is posed by estradiol is that there are too many variables to simply say you have X% chance of harming your liver if you take oral estradiol. If your liver is already compromised by pre-existing liver disease, or you have a predisposition to liver-related complications, or if you mega-dose (as mentioned above) thus consuming "toxic" levels, you're obviously going to have a far greater risk than someone without such factors.

See the section on Progesterone below for liver toxicity information regarding that hormone.

MOOD SWINGS & DEPRESSION

Hormones also alter your brain chemistry. This can lead to wild mood swings, uncontrollable emotional outbursts, and in some people HRT can cause severe depression or suicidal tendencies. If you are taking HRT medications and experience any of these side-effects you should discuss them with your physician as they indicate a negative reaction to the drugs. There may be alternatives you could take that would be better tolerated. MANY gender patients commit suicide and some of those deaths may have been attributable to HRT medications.

USE OF HRT DRUGS WITH ANTI-DEPRESSANTS/ANTI-ANXIETY MEDICATIONS

It is extremely common for gender patients to be concurrently using an anti-depressant medication with their HRT drugs. What doctors are NOT telling their patients, and is (to the best of my knowledge) generally not stated in the prescribing or patient information for the drugs, is the possible negative interactions between anti-depressant and hormone replacement therapy medications.

ESTROGEN - acts upon neurotransmitters in the same way as MAOI anti-depressants by increasing 5-HT-2 serotonin receptor binding as well as activating additional serotonin receptors and the overall concentration of serotonin. It also increases norepinephrine binding to receptors and the turnover (breakdown and replacement) rate for norepinephrine.

PROGESTERONE - acts upon neurotransmitters in a similar manner to SSRI anti-depressants. It inhibits re-uptake of serotonin by receptors and also inhibits the breakdown of the neurotransmitter thus increasing concentrations of it. Progesterone also increases the serum levels of norepinephrine but inhibits binding of it to receptors. Synthetic progestins appear to have a similar chemical action on neurotransmitters and have been directly linked to HRT-associated depression.

As a quick primer on these neurotransmitters:

Serotonin - low levels of activity (absorbtion) are associated with depression, high levels of activity are association with anxiety disorders. SSRI's increase the amount of serotonin by inhibiting how much the body can act on the body via receptors. For those with a naturally low amount the increase in intracellular concentration can alleviate depression. For those with a naturally high amount the inhibition of the receptors prevents some of the concentrated amount from acting on the body, reducing anxiety.

Norephinephrine - one of the metabolites of dopamine, this chemical is part of the body's system for responding to stress. Low levels of norepinephrine are associated with sluggishness, mental stress, and depression while high levels increase heart-rate, respiration, and increase energy levels (sometimes leading to nervousness or anxiety).

Serotonin and Norepinephrine levels are apparently linked and, in a healthy individual, are kept in balance to prevent episodes of depression or anxiety. The fluctuations in hormone levels experienced by women during their cycle (and the drop in hormones at menopause) adversely affect BOTH of these neurotransmitters, leading to mood disorders. SSRI and MAOI drugs prescribed to treat depression and anxiety problems also affect BOTH serotonin and norepinephrine levels.

Few transgendered people seem to be aware of the MAOI and SSRI effects of estrogen and progesterone, nor are they aware of potential adverse interactions between their HRT and anti-depressant/anti-anxiety medications. If you were taking an MAOI or SSRI for depression or anxiety before beginning HRT you may need to adjust your dosage once you are taking hormones (I'm inclined to say you'll probably have to reduce it, but you should talk to your doctor first). If, after you've been on HRT for a while, you are experiencing anxiety or depression an adjustement to your HRT regimen may be in order, and as a last resort the addition of an MAOI or SSRI.

Depression and anxiety disorders plague the majority of transgendered people, for which many are taking either SSRIs or MAOIs. Evidence suggests that the suicide rate alone among trangendered people is a whopping 50 percent* (* see update info Morbidity & Mortality) and the author of this site has to now wonder how many of those suicides were chemically induced because patients (or even their doctors) were unaware of the action hormone therapy has on serotonin and norepinephrine. Since estrogen, progesterone, SSRIs, and MAOIs do not appear to be listed as counterindications in patient and prescribing information, even though they act on the same neurotransmitters, seems a horrible oversight.

PERMENANT STERILITY & SEXUAL DYSFUNCTION

For biological males taking female hormones there is a risk of permenant sterility. This can happen rather quickly (some reports say in as little as three weeks), but is generally considered irreversible after six months of hormone use. This effect may be reversible before that timeframe however, and some are capable of reviving fertility even after the six month mark. Individual reaction to hormones, which medications are used, and quantity will all be factors. The author of this site strongly recommends that those who are concerned about losing fertility and/or sexual function reconsider medicating with hormones altogether. If your plans include having a child of your own, M2Fs should consider banking sperm and F2Ms storing eggs before beginning a counter-sexual hormone therapy. F2Ms and M2Fs will also need to consider that post-operatively they will not have a womb and any use of the stored eggs or banked sperm would require a surrogate (if you're lucky that might be your girlfriend or wife).

<< RETURN TO Table of Contents