The Importance of Route of Delivery - Hormone Restoration



Estradiol, Progesterone and Testosterone Therapies for Women The Importance of Route of DeliverySwallowing any hormone or hormone-like drug means that the entire dose must pass first through the liver, the primary organ of our biochemical metabolism. This causes 2 problems not seen with transdermal or parenteral delivery (e.g. subcutaneous injections and pellets): the hormone has an excessive effect on the liver and the liver has an excessive effect on the hormone; usually metabolizing it into other molecules, possibly rendering it completely ineffective (e.g. oral testosterone and progesterone). In general, the evidence supports transdermal or parenteral replacement over oral replacement for most steroid hormones, and for estradiol and testosterone in particular. Higher estradiol levels in the serum have a small pro-clotting effect. Oral estrogens in particular overdose the liver, increasing its production clotting factor proteins. This can promote deep vein thrombosis, pulmonary embolus, heart attack or stroke. Unlike oral estrogens, including oral estrogens, including oral estardiol, transdermal estradiol does not significantly increase markers of blood clotting risk, or risk of thrombosis. The risk of venous thromboembolic disease is 4 times greater with oral estrogens than with transdermal estradiol. In a large Danish cohort study, transdermal estradiol reduced heart attack risk by 40%, whereas no benefit was seen with oral estrogens.Estradiol also causes the liver to make several hormone-binding proteins, oral estradiol therapy exagerates this effect, causing the liver to make 2 times more sex-hormone binding globulin, and reducing free testosterone levels by half. Transdermal estradiol has only a minimal effect on SHBG levels. Oral Premarin produces large increases in thyroid-binding globulin, cortisol binding-globulin and sex-hormone binding globulin and decreases in free testosterone, while transdermal estradiol produces minimal changes. Oral estradiol increases activated protein C resistance, a marker for thrombotic risk, whereas transdermal estradiol does not. Oral estradiol increases C-reactive protein, a marker of inflammation, transdermal estradiol does not. Transdermal estradiol lowers blood pressure whereas oral CEE does not. Oral CEE reduces insulin sensitivity while transdermal estradiol improves insulin sensitivity and thereby helps prevent diabetes mellitus. Oral CEE and higher doses of oral estradiol increase the risk of gallbladder disease and cholecystectomy; transdermal estradiol does not. Oral estradiol is excessively metabolized by the liver into estrone, producing levels that are much higher than normal. All oral estrogens, even bioidentical estradiol, should be avoided. For a summary of known differences between oral estrogen—of all kinds—and trandermal estradiol, see Fig. 14. IGF-1 mediates many of the effects of growth hormone in the body. Oral CEE reduces hepatic IGF-1 production and serum IGF-1levels, whereas trandsdermal estradiol increases IGF-1 levels.Oral progesterone is almost completely metabolized by liver and inactivated. To get around this problem, Prometrium was developed and approved by the FDA in 1998. It delivers progesterone in a capsule filled with peanut oil to increase absorption by passing into the intestinal lymphatic system, bypassing the liver and entering the venous circulation directly. However, this is only partially effective and most progesterone is still metabolized in the liver, producing high levels of metabolites and greatly reducing the effectiveness of the capsule. The metabolites are measured as progesterone using non-specific immunoassay techniques, creating the false impression of high progesterone delivery. Only about 1/8th of the serum level measured is actually progesterone. Only liquid-chromatography-mass spectroscopy (LC-MS) can identify specific progesterone and other molecules. The metabolites can also produce drowsiness, flushing and nausea. The sedating effect can help with sleep if the capsule is taken at bedtime, but may leave residual sedation in the morning. Oral progesterone is quite ineffective—it cannot be used for luteal phase support in infertility treatments. Vaginal progesterone is much more effective for this purpose even though it produces much lower serum levels. What is measured with transdermal or vaginal delivery is mostly progesterone. When progesterone is measured in whole blood with LC/MS, only 80mg of progesterone applied to the skin produces the same 24hr whole blood progesterone levels as 200mg of oral Prometrium. Fortunately, Prometrium and its generics will dissolve when inserted vaginally at bedtime, providing much greater uterine and systemic effect. How to Restore Estradiol and ProgesteroneThe practice of BHRT for menopause is not monolithic. There are different schools of thought regarding how to test hormone levels, by what routes to deliver the hormones (oral, sublingual, transdermal, pellets, etc.), what hormone levels to achieve, and whether it is necessary to induce a withdrawal bleed (period) every month. Some BHRT practitioners rely solely on saliva tests to assess hormone levels, others use blood tests. What BHRT practitioners do generally agree upon is that they will prescribe only bioidentical molecules, they will prescribe progesterone to all women, and they believe that a woman should continue estradiol-progesterone replacement for life. I will provide my own assessment of these issues based upon the scientific literature and personal experience. SymptomsThe preliminary assessment of any woman includes taking a history, gathering of current symptoms and then testing to measure hormone levels. Since it takes a significant estradiol production to produce uterine bleeding, Symptoms occurring in a woman who is menstruating regularly are unlikely to be due to estradiol deficiency—although this is not always true. Hot flashes are the one symptom that most often causes a woman to seek hormone replacement. These can also be due to cortisol deficiency and to thyroid deficiency or excess. Indications for Progesterone Irregular menstrual cycles No periods—amenorrheaHeavy bleedingFibrocystic breast diseaseEndometriosis/adenomyosisEvery woman in menopauseEstradiol replacement therapyIf the woman is perimenopausal or menopausal and estradiol levels are low, I will always give them a trial of estradiol-progesterone therapy first to see if it eliminates the hot flashes. Vaginal dryness is a cardinal symptom of estradiol deficiency and is reliably resolved with replacement. I inquire about breast symptoms. Low estrogen levels will cause the breasts to feel soft and non-tender at all times, whereas episodes of breast fullness suggest that estradiol is being produced at times. Low estradiol levels can cause night sweats and/or poor sleep quality with frequent awakenings. It is difficult to fall back asleep. Low estradiol levels can cause a subtle depression and irritability also. On the other hand, if a woman has symptoms of high estradiol levels with inadequate progesterone (excessive breast tenderness, irregular heavy periods, etc.) then she will most likely benefit from cyclical or nightly progesterone. TestingBlood tests are the best way to assess pre-treatment levels and to monitor dosing. Symptoms are always the most important guide to dosing, but testing adds valuable additional information and can help one decide whether to try raising or lowering the dose. For instance, when there are no symptoms of estradiol excess, it’s possible that a patient will get more benefits with a higher dose. So often the only way to find the optimal dose is to produce some symptoms of estradiol excess, then lower the dose to eliminate those symptoms. I monitor patients with blood tests done approximately 12 hrs after the application of estradiol, progesterone and testosterone. Since this time is mid-way between the daily doses, it provides a good estimate of their 24 hr. average levels—particularly with transdermal application. Typically I have patients begin by applying the hormones at bedtime and then have their blood drawn in the morning. If they prefer to apply the hormones in the morning, I either have them do an afternoon test, at least 8 hrs after application, or I have them switch to bedtime dosing for 3 nights before the test for AM testing. AM testing is the norm for my patients as they are often taking thyroid hormone which must be tested in the AM prior to their daily dose. I have not found saliva testing to be useful for pre-treatment testing and it cannot be used at all to monitor estradiol, progesterone or testosterone levels on replacement therapy. Blood testing is covered by most persons’ insurance and so is easy to order and to obtain at low cost to the patients. Blood tests also provide the most accurate assessment of effective hormone delivery while on replacement therapy. Saliva testing can be accurate prior to hormone replacement, but cannot be used to monitor transdermal steroid hormone replacement. (see Appendix 4). For women on appropriate estradiol replacement, a serum level around 12 hrs after a dose will typically be in the follicular-phase range, usually between 30 and 100pg/ml. This level is sufficient to provide the health benefits of estradiol without causing symptoms of excess estradiol. Women do not need the higher estradiol levels seen at ovulation or in the luteal phase as these are for producing pregnancy, not for maintaining health. Progesterone levels on replacement are more difficult to interpret. Typical progesterone levels without replacement are under 1ng/ml. Progesterone cream at my typical dose of 100mg/ml nightly, produce low serum levels at 12 hrs (usually just 2 to 4 ng/ml). Sublingual progesterone tablets produce serum levels that vary greatly, between 2ng/ml up to 15ng/ml at 12 hrs. The best serum test of any steroid hormone is the free hormone level—which indicates how much of the hormone is free in the serum and thus able to get into the cells of the body. The vast majority of the hormone in the serum (>95%) is not free but bound to proteins and thus not able to contact cell walls. The amounts of these binding proteins can vary greatly between patients naturally and due to other factors, thus total serum levels can be quite misleading. Only recently have free estradiol levels become available. However, I typically order the total estradiol because of its lower cost, as I am adjusting the dose by symptoms anyway. I do order the free estradiol level to solve problems and in women that I know have high SHBG levels. Oral T3 thyroid replacement, either with liothyroinine or NDT, raises SHBG due to its first-pass effect on the liver. Estradiol and Progesterone RestorationBased upon the history, symptoms and test results, I decide whether estradiol and progesterone, or progesterone alone are indicated. Improvement in or resolution of key symptoms is proof that a deficiency existed and has been corrected. The goal, as in all hormone restoration, is to eliminate all symptoms of hormone deficiency while producing no symptoms of hormone excess. Serum levels tested at appropriate times are helpful, but not as sensitive or as specific to the patient as are symptoms. replacement therapy needs to be individualized—not just the dose but also the route of delivery, time of delivery, etc. The goal is to produce the best clinical effect in a way that is convenient for the patient. I present the choice of hormone restoration to every patient as a trial—to see if in fact it helps eliminate symptoms and improves their quality of life. They can decide if they want to continue the hormone. I do of course also inform them of the health benefits of restoring the hormone and the health problems expected with not restoring the hormone. I have learned to have patients start only one hormone at any given time, and wait a minimum of 5 days before adding a 2nd hormone. Given the misinformation and controversy surrounding the hormone restoration and compounding pharmacies; and given our perverse civil liability-malpractice system and physician-oversight by state medical boards, I have every Symptoms/signs of Estradiol Excess Breast/nipple tendernessVaginal spotting/bleedingFluid retentionExcessive emotionality, cryingHot flashesExcessive vaginal secretionspatient sign a detailed consent form (see this under “Forms” at my website). I recommend that every physician do the same for any hormonal therapy that is not the “standard practice” as advocated by drug-company funded professional organizations. There are FDA-approved progesterone and estradiol products. Estradiol comes in pills patches, gels, and a vaginal ring. The transdermal estradiol products are acceptable, but I do not prescribe them much for several reasons. They often come in fixed low-dose formulations, adjusting the dose is not easy, and their cost is high. Some products cost $200/mo. or more; usually the co-pays are more than a compounded estradiol cream, which can cost as little at $10/mo. The least expensive FDA-approved estradiol products are the generic patches, but again often the dose, even of the highest-strength patch, is insufficient. Women also often have inadequate adherence of the patches or skin reactions to the adhesive. Estradiol gels, unlike creams, can have a drying effect on the skin that many women do not like. There is no FDA-approved estradiol and progesterone combination product; the combinations products with estradiol contain a progestin instead. If pharmaceutical corporations really want to help women by providing convenient and physiological BHRT, I suggest that they develop once-weekly, subcutaneously injectable preparations containing various proportions of estradiol, progesterone, and testosterone. This will be more convenient and will eliminate the sex hormone contamination of the environment that occurs when people wash off hormones that were applied to their skin. I know that women will find this acceptable as I’ve found it easy to teach men to do weekly subcutaneous injections of long-acting testosterone cypionate and enanthate preparations. FDA-Approved Bioidenticals Estradiol patches (Climara,Vivelle, etc.)Estradiol gel (Estrogel, Divigel, ElestrinEstradiol vaginal ring (Femring) Progesterone capsules (Prometrium)Progesterone vaginal gel (Crinone)Testosterone gel (Androgel) (not approved for women)For estradiol replacement, I typically start a woman on a compounded estradiol cream of strength 3mg/0.5ml (6mg/ml). I usually ask that it be put in a 3ml syringe designed for topical use. (See the next chapter for a discussion of pharmacy compounding). The syringe has marks at every 0.1ml. Of course any device to deliver the cream is fine if it allows the woman to finely adjust the dose of the cream. If they have been estradiol-deficient for some time, they will be initially very sensitive to the hormone. The most likely symptom of initial sensitivity is breast/nipple tenderness. So I have them start with a low dose of 0.1ml (1 line) applied to face at bedtime and tell them to increase the dose of to 0.3ml as tolerated. They can lower the dose or keep it low in order to minimize breast tenderness. I have them add progesterone nightly after they have been on 0.2 ml of estradiol for several days. I have women begin by applying the estradiol cream to their face at bedtime. They can apply other creams afterwards—which likely further increases the absorption of the estradiol. Estradiol increases collagen formation in the body in general, and even more so where it is applied, so it helps counteract the weakening and wrinkling of skin of the face that occurs with aging. Absorption from facial skin is also very good, so the dose can be lower than if applied elsewhere. Some women get acne-form changes on their face with applying the estradiol there. In which case they can apply it to the neck which also has good absorption. If they want to apply it elsewhere—like shoulders or inner thighs, they will need higher doses. Estradiol cream can also be applied to the genital skin—the inner labia, clitoris and vaginal opening. It is very highly absorbed there and can produce maximal improvement in vaginal dryness and atrophy. However, it can also promote uterine stimulation more than when applied elsewhere, and so cause more bleeding problems. For some women, a good solution is to apply a small amount of the total daily dose to the inner genital skin. There is a large variation between persons in their absorption of transdermal estradiol. A sufficient dose of estradiol should definitely eliminate hot flashes and restore vaginal moisture. The dose should be lowered if there is persistent breast fullness/tenderness or vaginal bleeding. In some women, hot flashes can worsen with starting estradiol replacement, even though it is clearly needed. In my experience, this is either just a temporary adjustment problem, or a sign of insufficient cortisol. First I will try having them lower the estradiol dose, providing them with a weaker cream if needed. They can then often gradually increase the dose to good replacement levels. With applying any hormone to the skin, it is essential to rub it in well, until dry, and then to wash one’s hands. It is important to avoid transfer of the hormones to other persons. For women applying estradiol to their face, this means they should have allow a dog to lick their face overnight, nor routinely have face-to-face contact with a child or spouse during that time. If they cannot avoid such contact, then can apply the estradiol to the neck or elsewhere, or apply it in the AM instead and wash it off by evening. Hormones should not be applied to elbow areas or below since the hormone entering the circulation from these areas will spuriously increase serum tests when blood is typically draw from a vein in the elbow area. Relatively low levels of progesterone reduce mitoses (cell division) in the endometrium, but higher levels are necessary to induce withdrawal bleeding and endometrial secretory transformation. So the induction of amenorrhea with a relatively low dose of progestone is all that is needed to provide protection against uterine cancer. For progesterone replacement my typical starting approach is to use a compounded 100mg sublingual tablet at bedtime. This is a large dose for sublingual delivery and much more effective oral Prometrium and its generics. Oral progesterone is only about 10% bioavailable, its absorption is doubled if taken with food. One must work closely with a compounding pharmacy to make sure that the tablets are pleasant to taste and dissolve in a reasonable amount of time. Sublinguals should not be overly sweetened or flavored as this increases salivation and the amount of hormone swallowed rather than absorbed directly in the the bloodstream through the oral mucosa. Some of the sublingual progesterone will be swallowed and the liver will produce sedating metabolites, but less so than with oral capsules. These metabolites have the beneficial effect of sedation and so can improved sleep, which is a frequent problem for menopausal women. I find laboratory testing less helpful for progesterone than with any other hormone. After the bedtime sublingual dose, serum progesterone levels a very high—higher than youthful luteal levels—for several hours. By 12 hrs, however, levels may be low-luteal again. This is a kind of pulse-therapy and the high-levels pulses seem to proved the body with sufficient progesterone to last for 24hrs. Ultimately the progesterone dose has to be adjusted by symptoms. If I’m unable to eliminate estrogen dominance symptoms by lowering the estradiol dose—if the lower doses cause estradiol deficiency symptms to return, then I will increase the progesterone dose or have a women insert the subligual tablets or capsules vaginally at bedtime. Vaginal progesterone has both greater systemic effects and particularly greater effects on the uterus. Some women have uterine conditions (e.g. submucosal fibroids, adenomyosis, polyps, etc.) that make them very susceptible to bleeding on estradiol therapy. For many of these women, only vaginal progesterone will allow them to replace estradiol without bleeding. Transdermal progesterone cream can also be used. I typically prescribe 100mg/ml and have the woman apply 1ml to the chest and breasts, abdomen, or inner thighs at bedtime. Only a small fraction of this dose is absorbed, but it avoid the first pass effect altogether. In my experience 100mg by cream is not as effective as 100mg subingually to control bleeding or breast tenderness. If women prefer the cream, the dose can be increased as needed to achieve good clinical effect. For premenopausal or perimenopausal women with early breakthrough bleeding and/or heavy bleeding and cramping, I will always search for and correct hypothyroidism. Sufficient thyroid hormone can normalize menses and can greatly reduce bleeding and cramping. If thyroid levels are not the problem, I will use progesterone supplementation to prevent the build-up of the uterine lining and thereby reduce bleeding and cramping. First, one can try the most physiological approach—taking progesterone daily only during the luteal phase—from ovulation to just before the next period is expected. The dose can be as little as 100mg sublingually at bedtime, or increased if needed to 100mg twice-daily. If luteal-phase progesterone dose not work sufficiently well, she can just take the progesterone every night and stop it when a period starts, restarting it when the bleeding has stopped. Taking progesterone throughout the month this way has maximal anti-estradiol effects and minimizes uterine lining build-up. The physician can prescribe progesterone, in any dose needed, without fear of harmful effects. Progesterone is not known to harm a woman’s health, at any dose or any serum levels. During pregnancy, progesterone levels are many times those that are seed at their peak in the luteal phase of a menstrual cycle. Excessive progesterone may cause some unpleasant symptoms—sedation and gastrointestinal relaxation. Progesterone’s effect on the GI system may produce constipation or reflux. Progesterone counteracts estradiol, so an excessive progesterone/estradiol ratio may cause estradiol deficiency symptoms even if estradiol levels are good. In perimenopause, women can have very high estradiol levels at times, with almost no progesterone. This produces the excessive breast tenderness and bleeding seen in many perimenopausal women. Physicians should prescribe as much progesterone as is needed to reduce the breast and uterine symptoms. Sufficient progesterone effect, with vaginal delivery if needed, would prevent most hysterectomies that are performed in perimenopause for heavy bleeding. Presently physicians are afraid to provide sufficient progesterone because of the mistaken belief that progesterone has the same deleterious effects as many progestins do. (See next chapter.)To Bleed or not to BleedIf women want to continue to menstruate after menopause., they can with the right cyclical use of estradiol and progesterone. Estradiol must be taken alone for 2 weeks, then progesterone added for 2 weeks—in a sufficient dose to change the uterine lining and prevent bleeding until the progesterone is stopped. This typically requires higher estradiol doses and twice-daily progesterone dosing for the last two weeks. The estradiol dose can be the same each day, but can also be lower in the first two weeks and higher in the second two weeks to mimic a normal cycle and pervent breakthrough bleeding. At the end of the 4 week cycle, stopping the progesterone and/or lowering the estradiol dose causes sloughing of the lining. However, this is not a true menstrual cycle but only an imitation of a cycle. It is just a building up and the sloughing off of the uterine lining. As mentioned early, the purpose of the menstrual cycle is reproduction first, a women’s health second. In my opinion, a woman needs only a certain daily levels of estradiol and progesterone for her health needs. When estradiol and progesterone are taken together daily and in proper balance, there is little build-up of the uterine lining, and so no need to have a period to shed the lining. The one potential benefit of cycling the hormones is that is could induce a sloughing of the breast duct epithelium which may have a further anti-cancer effect. This should be studied further. I’m not yet convinced that this effects occurs with cyclic estradiol/progesterone therapy, or that that it is significant enough to justify the inconvenience of bleeding for the rest of a woman’s life. Most women do not want to have bleeding after menopause. Troubleshooting Estradiol-Progesterone TherapyIt is important to remember, again, that bioidentical hormones have the expected effects in the human body. They have no side effects. Understanding this allows the physician to solve and fix problems that arise during BHRT. Any negative symptoms or problems with estradiol-progesterone restoration must be due either:Excessive or inadequate dosingWrong method of deliveryAn imbalance with other hormonesSensitivity to an inert component of the hormone productAn underlying disease or disorder that is worsened by a hormoneFor instance, women with underlying breast or uterine pathologies may not tolerate the stimulatory effect of any estradiol restoration. The inability to tolerate any estradiol or progesterone may be due to cortisol deficiency. With any symptoms that are possibly due to excessive estradiol effect in the breasts or uterus or elsewhere the first intervention should be to lower the estradiol dose. If a lower dose produced estradiol-deficiency symptoms, then one should raise the dose and increase the delivery of progesterone. It taking oral progesterone, increase the dose, switch to sublingual at the same dose, or take the progesterone vaginally. Bleeding and Uterine Cancer SurveillanceSpotting and bleeding are not uncommon on replacement therapy and I tell every woman with a uterus that it still works and bleeding is possible, but will not persist with proper dose adjustment. The primary concern of any gynecologist is to rule out uterine cancer in any women with bleeding after menopause. Standard practice guidelines call for a transvaginal ultrasound and uterine biopsy for any bleeding after menopause. This does not apply to a woman taking hormones since they are not estradiol-progesterone deficient. Such procedures are warranted only if a women spots/bleeds with any doses of estradiol and progesterone or if she continues to bleed after stopping the hormones for a couple months. Likewise, gynecological guidelines call for a uterine biopsy if a trans-vaginal ultrasound shows that the uterine lining is >5mm in thickness. This again only applies to women who are estradiol-progesterone deficient in menopause. The uterine lining is much thicker than this cyclically in menstruating women, and there is no evidence to suggest that this guideline should be applied to women on EP therapy as they have premenopausal progesterone levels. Bleeding can occur for several reasons. A women who has only recently stopped having menstrual bleeding for a few months may have a thickened uterine lining due to incomplete shedding with the last bleed or due to estradiol production since the last bleed. When she takes progesterone, the uterine lining is destabilized and sloughs off. This is a therapeutic result. Bleeding that occurs after some weeks on EP therapy may still be due to initial uterine lining thickness. I will typically have the woman stop both hormones to encourage a complete shedding of the lining. When all bleeding has stopped for a day or two, I have her restart the estradiol and progesterone at the same doses. If bleeding recurrs, I have her stop the hormones again, and then restart with a lower estradiol dose (less by 0.1ml). If she feels worse on the lower estradiol dose (has symptoms of estradiol deficiency), I’ll have her raise the dose to the previous level and change the progesterone dose/delivery to provide more progesterone effect in the uterus. Occasionally a woman who has had no bleeding for many months Testosterone Replacement in WomenHow much testosterone, what levels and effects, are best for a woman? That is a complicated and very personal question. Testosterone acts on a continuum from lower to higher levels. One study found that the serum testosterone level in women with no acne, hirsutism, or menstrual dysfunction was only 14.1 pg/ml. Higher levels were found with increasing hirsutism and menstrual dysfunction. The authors suggested an upper limit of 28ng/dl to exclude “hyperandrogenemia (usual range 0-95ng/dL). More testosterone will increase hairiness in women and in men, the question for each woman, however, is at what level they will have the best compromise between the benefits of testosterone supplementation and the negative effects. Excessive testosterone for a given woman can cause excessive dark facial hair, oily skin, body odor, frontal scalp hair loss, and acne. Higher levels can cause deepening of the voice and clitormegaly. How a woman responds to higher testosterone varies remarkably. Some women will experience excessive facial hair or acne with any attempt to increase their testosterone level, others can live with well-above-range levels with no hyperandrogenic symptoms at all. What is consistent is that the higher a women’s testosterone levels are, the greater her energy, physical stamina, muscle strength and libido. Testosterone Replacement I start with 2mg/0.2ml cream, 0.1ml (1 line) applied inner labia at bedtime.Best absorption, improved libido and vaginal moistureIf excess acne or facial hair lower dose. If not tolerated labially, use higher strength/amount to inner thighs or back of knees (no local hair growth)12 hr. serum total testosterone usually high, but free testosterone is half of upper range. DHT may be high—not routinely testedBeyond Normality: Hormonal Solutions for WomenThe restoration of hormones lost in menopause is itself a choice to go against Nature and its compromise for female reproduction. There is more that can be done to improve women’s lives, in accordance with their choices regarding their well-being, ferility and functionality. I believe that women should have endocrine choice—I think that most would agree. Nature has given them a hormonal system optimized by the requirements of our species to produce and feed infants and then provide care for children. We live in a different world now. Women want to be equal to men in most important ways—but they don’t have the hormonal system for it. They have far lower testosterone levels than men—1/10th those of men. Because of this they are at a serious disadvantage when they compete with men in the workplace. Their lower muscle strength practically excludes them from many jobs (construction, auto repair, plumbing, lumberjacking, etc.). Even if the job does not require much physical strength, their lower testosterone levels also leave them with lower mental and emotional stamina, making it harder for them to handle sustained stress, including the stress of white-collar jobs. (Lower cortisol levels also play a role here as discussed). Testosterone optimization can help them live the kind of lives they want to life. Some may want and tolerate free testosterone levels above the female reference range (0-2.2pg/ml), but below optimal the male range (18-26pg/ml). In a study of weekly testosterone injections in oophorectimized women, doses that produced trough free testosterone levels well above the reference ranges, women had improved vitality, muscle strength and sexual function with little unwanted hyperandrogenic effects. The highest dose of 25mg/week produced trough free testosterone levels of 39pg/ml, well above the upper limit for women of 7.2pg/ml, but at the bottom of the male ref. range of 35-155pg/ml). If women desire the benefits of higher-than-natural testosterone levels, they should be allowed that choice. They can decide what androgenic changes they are willing to tolerate for the benefits they get with higher testosterone levels. Sufficient testosterone alone my suppress their menstrual cycle, further improving their functionality at all times and treating serious premenstrual disorders. Testosterone appears safe at any dose/level in women. Even giving women male levels of testosterone with injections (female-to-male transsexuals) is not associated with any increase mortality, breast cancer, vascular disease, or other major health problems. Male levels of testosterone suppress ovulation and reduce proliferation in the breasts and endometrium, suggesting a possible protective effect against cancer in these organs. No increase in breast cancer or mortality has been seen in M-to-F transsexuals.Hormonal therapy might help prevent breast cancer later in life. Since pregnancy protects against breast cancer, women who are not planning on pregnancy for many years after menarche could be offered high doses of estradiol and progesterone for a few months (a pseudopregnancy).Appendix 1. Estriol, OTC Progesterone Cream, Saliva Testing, and the Wiley ProtocolDue to the advice of Dr. Jonathan Wright, a pioneer in bioidentical hormone replacement and natural scientific medicine, prescribers often include estriol and estrone in compounded bioidentical hormone therapy. Based upon a study performed in his own laboratory, Dr. Wright asserted that premenopausal women had very high estriol levels—between 200 and 2400 pm/ml—much higher than their estradiol levels., However, subsequent studies have contradicted his assertion, finding estriol levels of only 7 to 11pg/ml in menstruating women, and of 6pg/ml in postmenopausal women., Compares the levels of this weak estrogn with the typical estradiol levels of 30 to 200pg/ml at various times in the menstrual cycle.The combination of estradiol and estriol is called "Biest". It typically contains estradiol and estriol in a 20:80 ratio. When estrone is added it is called “Triest”. Women on these preparations often receive too little estradiol, and thus have persisting symptoms of estradiol deficiency. Practitioners who attend weekend BHRT are often taught to prescribe Biest and to adjust the estradiol dose using saliva testing. This leads to gross underdosing (See Appendix 3). Estriol levels are rarely measured either before starting therapy or during therapy. How much of it is absorbed transdermally is unknown, likely it is less well-absorbed than estradiol due to its three hydroxyl groups. Many practitioners still routinely prescribe estriol along with estradiol. He performed study showing that In fact estriol exists in very low concentrations. It is just a weak metabolite of estradiol. Its levels are very high only in pregnancy when the placenta produces it from DHEA sulfate. Estriol binds preferentially to the second estrogen (ERbeta). ERbeta may function as a tumor suppressor. Estriol’s estrogenic activity at estradiol receptors is a small fraction of that of estradiol, possibly due to its more rapid dissociation from receptors. Therefore, in a state of complete estradiol deficiency, estriol supplementation will produce estrogenic effects. However, when estradiol is supplemented to sufficient levels, estriol may act more like and estradiol-blocker—inhabiting estradiol receptors but stimulating them much less than estradiol would. Vaginal estriol, for instance, is very effective at reversing the urogenital atrophy caused by estradiol deficiency. Oral estriol, 2mg/day, given to elderly women, increased their estradiol levels and improved endothelial function and bone density.The evidence we have currently suggests that estradiol replacement is all that is needed. Transdermal estradiol is naturally metabolized into estriol and estrone and restores them to normal follicular levels. For me to be convinced that every woman should pay the additional cost of adding estriol to estradiol, I would need to see evidence showing that 1. That the metabolism of estradiol on estradiol-only replacement therapy does not produce normal follicular phase estriol levels. 2. That transdermal estriol does restore follicular phase estriol levels, and 3. That estriol supplementations improves symptoms or long-term health outcomes. Over-the-counter (OTC) non-prescription 2% progesterone cream is bioidentical and is beneficial to women in perimenopause and menopause. Percutaneous progesterone has a much greater effect upon the endometrial lining than indicated by serum progesterone levels. I recommend OTC progesterone cream for every woman in perimenopause and for every woman in menopause who is not taking estradiol. OTC creams at the typical doses of 20 to 40mg applied daily, do not provide sufficient progesterone for women who are replacing estradiol to optimal levels., An adequate dose should be 80 to 100mg or more applied daily. A cream with a higher progesterone concentration requires a prescription. Saliva tests may be accurate for assessing sex hormone levels before supplementation, although some researchers found little correlation between saliva and serum estradiol and progesterone levels. However, saliva tests grossly overreact to even minimal amounts of hormones applied to the skin. , In general, hormone test results require careful interpretation when the hormone is being restored. The delivery methodand the time from the last dose greatly effect the result. but with the application of any steroid hormone to the skin, including sublingual and vaginal application, saliva levels rise excessively—many times higher than levels seen on a blood test and as indicated by symptoms. This is due to the unusual soaking of red-blood cell membranes with the fat-soluble steroid hormone. Red blood cells must deform to pass through the smallest capillaries. In areas where the hormone is applied, these capillary walls are soaked with hormone, and so it is taken up into the red-blood cells walls. Steroid hormones in the red blood cell membrane can be delivered to the tissues., For some reason, this causes much more hormone to get into the saliva. Blood tests almost always measure the hormone in the watery serum and not what is incorporated into blood cells. So blood tests can underestimate delivery of transdermal steroids to the tissues, while saliva tests grossly overestimate it. This discrepancy is greatest with progesterone because it is the most fat-soluble of the steroid hormones. For instance, practitioners who dosetransdermal hormones to produce normal saliva levels are underdosing their patients. On theother hand, serum blood tests (with the red cells removed) can underestimate the actual blooddelivery of transdermal progesterone and estradiol, causing the practitioner to overdose thepatient. Studies have shown that 80mg/day of progesterone in a cream produces significantwhole-blood progesterone levels, equal to 200mg of Prometrium, but dose not produce muchincrease in serum progesterone levels (Hermann, 2005). Most labs test only serumprogesterone and this has caused doctors to erroneously conclude that progesterone creamshave no effect. The Wiley Protocol is a type of compounded BHRT endorsed by T. S. Wiley. It uses transdermal estradiol and progesterone, in varying amounts throughout the cycle, to produce both serum levels of estradiol and progesterone levels that are identical do those of a menstruating young woman. As mentioned above, normal menstrual cycle hormone levels are for producing pregnancy, not for optimizing a woman’s health. So the primary motivation for this protocal is flawed. However there is a bigger problem. Serum hormone levels can underestimate the total hormone delivery of transdermal steroid hormones. This is especially for true for progesterone. Women on the Wiley Protocol are thus grossly overdosed, both with estradiol and progesterone, producing a state resembling pregnancy. ................
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