Testosterone Replacement Therapy (TRT)
Testosterone is produced by both men and women but the amount produced by women is much smaller and the production comes from the adrenal glands. A decline in the testosterone level is associated with decrease in sex drive and libido in both sexes and this condition is commonly observed in those with Adrenal Fatigue. Testosterone replacement therapy (TRT) re-energizes the entire body, increases lean muscle mass, and reverses the fat accumulation and muscular atrophy characteristic of aging in normal people. Unfortunately, aggressive use of testosterone in Adrenal Fatigue can lead to over stimulation and eventually to adrenal crashes.
Pre TRT workups should include a complete history and physical examination, together with a battery of blood tests including male hormonal profile and cancer screening tests such as prostate specific antigen (PSA) to rule out any relative or absolute contraindications to testosterone replacement therapy. Various forms of synthetic testosterone have traditionally been used and these include oral, sublingual, intra-muscular injection, and trans-dermal patches. While these synthetic hormones have been widely used with beneficial effects, there are drawbacks to their use.
Oral synthetic preparations result in short-term elevation and undesirably high inter-individual and intra-individual variability of concentrations of testosterone. There are also commonly associated elevations of liver function tests and abnormalities at liver scans. Despite this, oral preparations still constitute about a third of prescriptions filled in the United States. Some common forms are pure testosterone, methyl testosterone, sublingual methyl testosterone and fluoxymesterone.
The injectable synthetic testosterone is etherified. It is safe, effective, and the least expensive androgen preparation available. When injected into a large muscle, it slowly absorbs and lasts longer, taking effect over several days to weeks. Injections eliminate the natural daily diurnal rhythm of testosterone production-high at night and early morning and low during the day. Testosterone enanthate and cypionate are forms commonly used and they have comparable pharmacokinetics. Both result in supra-physiologic concentration of testosterone for one to four days after injection. A satisfactory regimen is to administer 200 mg of one of these esters once every two weeks intramuscularly, but a more physiologic replacement therapy would be 100 mg of one of these on a weekly basis.
Trans-dermal synthetic TRT systems are perhaps the most commonly used and they come in scrotal and non-scrotal forms. Clinical studies have shown that both are effective forms of androgen replacement. The advantage of the scrotal form is that it produces high levels of circulating dihydrotestosterone (DHT) due to the high 5-alpha-reductase enzyme activity of scrotal skin and it requires shaving the scrotum. Inadequate scrotal size and adherence problems are limitations. Skin irritation does occur in those with sensitive skin. Non-scrotal skin patch’s advantage is that the serum testosterone concentration profile mimics the normal circadian variation observed in healthy young men. However, skin irritation is more common, with over 50 percent of users experiencing some form of site reaction sometime during treatment. Pretreatment with corticosteroid creams (not the ointment forms) has been shown to reduce the severity and incidence of skin irritation without significantly affecting testosterone absorption from the patch.
Testosterone replacement can have undesirable side effects, including frequent or persistent erections, nausea, vomiting, jaundice, ankle swelling, or virilization of the female sexual partner. Breast enlargement can also develop as testosterone can be converted to estrogen via the enzyme aromatase. More serious complications include water retention, liver toxicity, cardiovascular disease, sleep apnea and prostate enlargement. These side effect risks are relatively uncommon when the dosage is closely monitored to that found physiologically in the body.
Results of testosterone replacement may not be evident for several weeks. Impotence may not be corrected after several months of therapy despite improvement in other andropause symptoms. For these patients, evaluation for causes of erectile dysfunction other than hypogonadism due to andropause is indicated.
Close monitoring of serum testosterone levels should be carried out for patients on testosterone. Other signs, such as acne, increase in breast size, and tenderness should be checked. After one week or more of trans-dermal TRT, serum testosterone levels can be measured about 12 hours after patch application and the dosage can then be adjusted accordingly. For oral methyltestosterone therapy, no assays are available to monitor therapy. For patients on the injectable form, nadir testosterone levels should be obtained three to four months prior to the next injection.
The alternatives to testosterone includes the testosterone precursors, androstenedione and androstenediol, which are available in oral capsules or sublingual sprays.
While testosterone replacement is one of the most effective ways to boost energy, extensive workup should be conducted prior to its use. This hormone should not be used in people with normal testosterone levels. In the Adrenal Fatigue setting, testosterone replacement is seldom necessary as there are many more gentle nutrients available without the body being exposed to this strong androgen.
One of the causes of the disruptions of sleeping patterns for people suffering from Adrenal Fatigue and aging is the reduction in the nightly release of melatonin by the pineal gland. Many people have discovered that bedtime doses of melatonin will restore their ability to have a sound and peaceful night’s sleep. This helps not only with sleep onset insomnia (difficulty in falling asleep), but also sleep maintenance insomnia (waking up at night and unable to fall back to sleep).
Melatonin levels are known to decline drastically with age. Since melatonin and FSH appear to be antagonistic in women, the same relationship may be true for men. It has been postulated that melatonin may even act to normalize (lower) gonadotropin levels. It is one of the few substances that have repeatedly been shown to extend the maximum life span of experimental animals. While low doses of melatonin (0.5 to 6 mg) act as a natural sleeping pill, high doses of melatonin (20 mg or more) have excellent anti-oxidative properties and are being used commonly in alternative medicine circle to fight breast cancer. Because of its ability to cross the blood brain barrier, melatonin is also a highly effective compound that can fight cancer that has metastasized to the brain or in treating other neurodegenerative diseases such as Parkinson’s Disease or Alzheimer’s Disease.
The exact dosage of melatonin varies greatly among people as the dosage curve is not linear. This is especially true in Adrenal Fatigue. Trial and error is therefore the best method. A higher dose does not mean more potency as some people may feel better with a smaller dose. To normalize sleep and the bio clock, a good dosage to start is 0.5 to 1 mg and this should gradually be increased if there are no adverse side effects.
A slight disorientation and dizziness may be experienced for the first few hours after waking up when melatonin treatment is first started. This hangover sensation should go away after a few nights of melatonin use. If it persists, a reduced dose is recommended. Some people require as much as 60mg to before it begins to work. This is contraindicated in pregnant or nursing mother, children, women trying to conceive, people who are on prescription steroids or who have mental illness, severe allergies, or immune system cancers such as lymphoma.
There are a few rules for the effective use of melatonin. Firstly, always take this hormone just before bedtime. If you take it earlier in the day, it may disrupt sleeping and waking cycles. Those who wake up with a hangover may wish to take it earlier in the evening instead of at bedtime.
Estrogen and progesterone work in synchronization with each other as checks and balances to achieve hormonal harmony in both sexes. It is not the absolute deficiency of estrogen or progesterone but rather the relative dominance of estrogen and relative deficiency of progesterone that is main culprit in Adrenal Fatigue. Let us examine this in more detail.
While sex hormones such as estrogen and progesterone decline with age gradually, there is a drastic change in the rate of decline during the perimenopausal and menopausal years for the women in these two hormones.
From age 35 to 50, there is a 75% reduction in production of progesterone in the female body. Estrogen, during the same period, only declines about 35%. By menopause, the total amount of progesterone made in the body is extremely low, while estrogen is still present in the body at about half its pre-menopausal level. With the gradual drop in estrogen but severe drop in progesterone, there is insufficient progesterone to counteract the amount of estrogen in our body. This state is called Estrogen Dominance.
Estrogen Dominance affects about half the women in the United States. It is caused by an imbalance between ‘the stimulating hormone’ estrogen and ‘the calming hormone’ progesterone and is the cause of many metabolic dysfunction symptoms. Many women in their mid-thirties, most women during perimenopausal (mid-forties), and essentially all women during menopause (age 50 and beyond) are overloaded with estrogen and at the same time suffering from progesterone deficiency because of the severe drop in physiological production during this period. This is further compounded by stress and the environment, both of which result in the body’s overall estrogen load. The end result – excessive estrogen relative to progesterone is a condition we call estrogen dominance.
What is so bad about estrogen dominance? It is the root cause of a myriad of illnesses. Conditions associated with this include fibrocystic breast disease, PMS, uterine fibroids, breast cancer, endometriosis, infertility problem, endometrial polyps, PCOS, auto-immune disorders, low blood sugar problems and menstrual pain, among many others.
Estrogen dominance and Adrenal Fatigue are closely related. One of the hallmarks of Adrenal Fatigue Stage 3B is the presence of Estrogen Dominance. When the adrenals are stressed, their response is to increase cortisol output and this requires more progesterone, a precursor. Cortisol output rises in Stage 1 and Stage 2 of Adrenal Fatigue. As adrenal weakness advances, cortisol output will begin to decline after peak production cannot be sustained and the adrenal glands become tired. The body’s increased need for cortisol depletes the progesterone levels. As more progesterone (and also pregnenolone) is shunted or sequestered to make cortisol, less is available to balance off the estrogen. As a result, there is a relative increase in estrogen in the body compared to progesterone during Adrenal Fatigue, further compounding any pre-existing Estrogen Dominance.
Most women with Stage 3B Adrenal Fatigue or higher invariably suffer from Estrogen Dominance as a result. Those women who suffer from one condition tend to have the other condition to some degree. Because the symptoms are similar, Estrogen Dominance, when prominent, can mask the underlying Adrenal Fatigue, which then is overlooked. Clinicians can be misled into believing that the root problem is Estrogen Dominance when in fact it is Adrenal Fatigue in disguise. Administration of hormone replacement, natural or otherwise, may give temporary relief but it will normally fail over time if adrenal recovery is not first given the primary focus. Conversely, symptoms of Estrogen Dominance tend to subside when optimum adrenal health returns.
Another common reason for low progesterone levels is the anovulatory cycle (a menstrual cycle in which there is no ovulation). In Adrenal Fatigue, the body’s emergency repair system is activated but priority is given to metabolic balance to keep the basic bodily functions, such as blood pressure and blood sugar, stable. Reproductive functions are considered to be low priority at this point and accordingly, ovulation can be temporary shutdown. In fact, many women under high stress will have irregular menstrual cycles and amenorrhea for this reason. Without the ovulation, there is no corpus luteum to make additional progesterone for the cycle. The lowered progesterone level leaves the women with an excessive estrogenic effect due to the deficiency of progesterone.
Estrogen Dominance can also be caused by excessive estrogenic stimulation from other sources. As Adrenal Fatigue progresses (with the exception of adrenal failure), weight gain is usually the norm as the body tries to slow down metabolism to conserve energy. When this happens, excessive fatty tissues are accumulated and fat cells will make estrogen and this estrogen will in turn cause fatty tissue growth. Both Estrogen Dominance and Adrenal Fatigue will lead to excessive estrogen and relative progesterone deficiency.
Those who are on birth control pill as well as those who are exposed to environmental estrogen-like compounds called xenoestrogen may compound that problem. Chemicals that mimic estrogen can be found in many plastics and they can enter the food chain when microwaving food in plastic dishes or when plastic wraps and containers are used. These estrogen-like compounds can also come from eating non-organic food as livestock are typically given potent estrogenic substances (‘super-estrogens’) to make them more grow faster.
Estrogen also increases thyroid-binding proteins in the bloodstream. Thyroid blood test results may therefore be normal although there may be insufficient free thyroid hormone in the tissues, resulting in a state of sub-clinical or secondary clinical hypothyroidism.
When estrogen levels are high, the adrenal cortex will fail to respond to signals from the brain. A woman with Estrogen Dominance may have adequate levels of total cortisol in her bloodstream and blood tests of total cortisol may be well within the normal range. However, her free available cortisol level may be low. Since only free cortisol can pass through cell membranes and activate the receptors inside the cell, the effectiveness of cortisol is blunted at the cellular level.
Synthetic progesterone called Progestin is sometimes prescribed to combat such deficiency by conventional physicians but this can make matters worse. Progestin is similar to progesterone but acts differently from progesterone because it is molecularly different. Our bodies cannot convert the Progestin into cortisol to help the adrenals or convert them into any other hormonal compounds as we can with bio-identical progesterone. Progestin can also be highly toxic and hard to break down in those people suffering from advanced Adrenal Fatigue, leading to a built-up of toxic metabolites in the body.
Reducing estrogen overload is an important clinical goal in Adrenal Fatigue recovery. Healing the adrenals indirectly helps improve this by allowing more progesterone to be available to offset the estrogen. Direct help to the estrogen-progesterone balance will indirectly support the adrenals by making more progesterone available for cortisol production. Both go hand in hand. In addition, progesterone itself has a toning down, calming and sleep supporting effect which will further help to restore the stressed adrenals.
The easiest way to restore balance to Estrogen Dominance is with natural progesterone which is different from the prescription Progestin mentioned above. There are different ways to take progesterone and they can the women differently. There are many delivery systems available, but for most women, the low dose topical form is most inexpensive and works well. However, the right dosage and time are the keys and this is especially true in the case of Adrenal Fatigue. Wrong dosage or timing can make Adrenal Fatigue condition worse and may even trigger adrenal crashes. People who are in low clearance state which is characteristic of Adrenal Exhaustion need to be especially careful. For these people, even normal physiological dose may be too much for the body to handle. The temptation to overcome Estrogen Dominance may be great, especially if the clinical symptoms are severe but it is always best to heal the adrenals first as much as possible and delay the administration of natural progesterone until the body becomes ready. The stronger the body, the better it is able to tolerate natural progesterone and the stronger the liver will be to metabolize the chemical.
There has been some controversy regarding which form is best to take the progesterone. Physicians tend to favor oral form (Prometrium), which is a prescription medication. Since around 80% is broken down by the liver, to get a 20mg blood level dose, you will need to take a 100mg capsule. This places an extra burden on the liver as it is the clearance center for this hormone. Most with Adrenal Fatigue are already stressed and in low clearance state to begin with and this overload of oral progesterone may trigger adrenal crashes when the liver is being overwhelmed sub-clinically. Blood level tends to be short lasting and as a result, it may require splitting the original dose into 2 doses daily to get a more even or stable blood level throughout the day/night. In short, oral form of progesterone is not recommended for those suffering from Adrenal Fatigue.
Troche (soft tablets you dissolve under your tongue) is another option. It is less convenient than a capsule but less messy than a cream overall. To get the physiological level of 20mg, you need a 20mg troche. Some people don’t like sucking on a tablet for the 1-2 minutes it takes to dissolve. Blood level tends to be short lasting and it may require splitting the original dose into 2 doses daily to get a more stable blood level throughout the day/night. Furthermore, it is also expansive.
Topical progesterone cream is the most common and it comes in a variety of concentrations. The best for people suffering from Adrenal Fatigue is the low-dose over the counter form. To get a 20mg blood level, you need to apply 20mg. Progesterone is lipophilic and it likes to stay in a fatty environment, allowing us to modulate the rate of release. Application to an area such as the abdomen with a thick fatty layer will slow the release. Application to an area such as the wrist or a thin fatty layer would lead to faster release. Cream tends to be a bit messy, but for most women, this is the best alternative overall and the least expensive. For best results, one needs to rotate the site of application to allow the skin to refresh itself. Many over the counter brands are available and they vary greatly in quality. Topical progesterone cream tends to release slowly over hours, days, or weeks from fatty tissue deposits. If used correctly, a steady blood level of progesterone can be achieved better with cream than by any other practical method. Those in Adrenal Fatigue will do much better with the topical form of progesterone as compared to other forms.
Women suffering from Adrenal Fatigue should be especially careful of high potency progesterone cream which is commercially available because it can trigger adrenal crashes. Even normal potency cream may sometimes be too much for those suffering from Adrenal Fatigue.
As with most hormones, too much can cause problems. In the case of Adrenal Fatigue, even a small amount below physiological amount can be a big problem. In addition to intolerance and sensitivity, too much progesterone is actually counterproductive. Chronically high dose of progesterone over many months will eventually cause progesterone receptors to turn off, reducing its effectiveness and may lead to toxic side effects. Some possible side effects include:
- An anesthetic and intoxicating effect such as slight sleepiness. Excess progesterone down-regulates estrogen receptors, and the brain’s response to estrogen are needed for serotonin production. When this happens, simply reduce the dose until the sleepiness goes away.
- Some women report paradoxical Estrogen Dominance symptoms for the first week or two after starting progesterone. It is also common for those who have been deficient in progesterone for years, in the initial application of progesterone, to experience some water retention, headaches Bland swollen breasts. These are symptoms of Estrogen Dominance, but paradoxically they are exhibited in the initial stages of progesterone application, as the estrogen receptors are being re-sensitized by the progesterone and “waking up”. This usually goes away by itself and is not a sign of toxicity.
- Edema (water retention). This is likely to be caused by excess conversion to deoxycortisol, a mineralocorticoids made in the adrenal glands that causes water retention.
- Candida. Excess progesterone can inhibit anti-Candida white blood cells and this can lead to bloating and gas.
- Lowered libido. Excess progesterone blocks the conversion of testosterone to DHT. This primarily happens to men.
- Excessive progesterone can also lead to the increase in androgen production and ultimately an increase in estrogen production within the adrenal hormonal synthesis pathway as the body shunts the excessive progesterone to these other hormones.
It is important to be as accurate as possible when applying progesterone cream. The best low dose progesterone cream should contain 1.7% of progesterone and yield 20 mg of progesterone per application. The simplest application method is through the use of a metered pump that measures the exact amount (20 mg), each time the pump is pressed. Progesterone is best absorbed where the skin is relatively thin and well supplied with capillary blood flow. Areas such as face, neck, upper chest and inner arms are good areas for application. Spread out to as big an area as possible for maximum absorption and allow for as much time as possible for absorption. Therefore, bedtime application is best if you are applying it once a day. Twice a day application is best but it may be too troublesome for most people. Lastly, rotate to different areas to avoid saturation in any one particular site.
Here is a sample rotational application protocol:
- Day 1 morning: Apply to the right side of the back of the neck.
- Day 1 before bed: Apply to the left side of the back of the neck.
- Day 2 morning: Apply to the right wrist area, with palm facing up.
- Day 2 before bed: Apply to the left wrist area, with palm facing up.
- Day 3 morning: Apply to the underside of the right upper arm.
- Day 3 before bed: Apply to the underside of the left upper arm.
- Repeat this cycle from day 4 onwards. In other words, day 4 will be the same as day 1, and day 5 will be the same as day 2, etc.
Practically speaking, the best gauge for the ideal dose should not be determined by any laboratory test alone. It is important to rely on the relief of symptoms when figuring out the ideal dose. The right dose is the dose that works. This is especially critical in Adrenal Fatigue. Always start only after adrenal functional reserve is well established. Start with a small dose if in doubt and slowly scale up under professional guidance.
The following are general recommendations for topical progesterone cream application that may need to be modified in specific situations:
Women in premenopausal – still ovulating:
- Direction for those on no hormonal supplementation: Count the day the period begins as the first day. Apply 20mg (one full pump when properly dosed) of natural progesterone every day from day 12 to day 26. Those with longer cycles may wish to use from day 10 to day 28. Begin the cream after ovulation that usually occurs about 10 to 12 days after your period begins. If bleeding starts before day 26, stop applying the progesterone cream and start counting up to day 12, and start again.
Women in perimenopausal (still menstruating with menopausal symptoms and/or PMS but not ovulating):
- Directions: Count the day the period begins as the first day. Apply 20 mg of natural progesterone (one full pump when properly dosed) from day 7 to day 27. If your period begins early, stop using Progesterone cream while you are bleeding.
Women in menopause (not menstruating):
- Directions for those who are not on estrogen replacement therapy: Choose a calendar day, such as the first day of the month. Apply 20 mg of natural progesterone (one full pump when properly dosed) of natural progesterone daily from day 1 to 25. Let the body rest for the rest of the month. If a woman has not been taking progesterone for a number of years, the body-fat progesterone is probably low. In this case, double up on the application for the first 2 months, and return to normal physiological dose thereafter.
Estrogen represents an entire family of female related hormones and consists of three components: E1 (estrone), E2 (estradial), and E3 (estriol). E1 is the most potent and carcinogenic. E3 is the most gentle and in fact has anti-cancer properties. In the body, these hormones exist in perfectly balanced proportions. The amount of E3 is highest, while E1 is lowest. Estrogen is manufactured primarily in three places of the body: ovaries, adrenal glands, and fat cells. Your chances of Estrogen Dominance increase if you are overweight.
Receptor dysfunction can also trigger Estrogen Dominance. This is more commonly seen in skinny women that are not under any apparent stress but are clinically symptomatic. Because estrogen deficiency or dominance can produce similar symptoms, estrogen replacement, whether it is natural or synthetic, needs to proceed with care.
Most women who have Adrenal Fatigue are in a state of Estrogen Dominance due to progesterone deficiency. This is made with women who are also overweight. Symptoms consistent with excessive estrogen such as PMS, endometriosis, fluid retention, depression, fibrocystic breast disease are commonly associated the Ovarian-Adrenal-Thyroid Axis Imbalance characteristic of women who are in Stage 3B Adrenal Fatigue.
The best way to normalize Estrogen Dominance is through the use of natural progesterone. From time to time, a woman can present with the all too familiar symptoms of Estrogen Dominance, but in fact she is estrogen deficient. This is usually more prevalent in women with normal or below normal weight. The physiology is unclear, but may be related to receptor site or transport dysfunction. Enhancing liver function also can be helpful.
As mentioned earlier, symptoms of estrogen deficiency can be similar to Estrogen Dominance. Those with these symptoms occurring from day 4-14 of menstrual cycle should be on the alert for estrogen deficiency if they fit the weight distribution profile. Estrogen replacement can be of great relief once the woman’s adrenal function has been stabilized. Because estrogen is metabolized by the liver, the majority of those with advanced Adrenal Fatigue will concurrently have weak liver function and slow clearance. Aggressive use of estrogen when the liver and adrenals are not normalized can actually make the Adrenal Fatigue condition worse off and may trigger adrenal crashes.
© Copyright 2012 Michael Lam, M.D. All Rights Reserved.