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An In-Depth Look At Your Hormone Options


Hormones have been used for many different purposes for many years--prescribers may use them for various reasons, including weight loss, libido, birth control, menstrual regulation, fertility, mental health, sexual function, perimenopause & menopause, insomnia, growth, transgender care and more.


Menopausal hormone therapy is the term used to describe the two hormones, estrogen, testosterone and progestin, that are given to relieve bothersome symptoms of menopause. Estrogen is the primary hormone that relieves the symptoms. Those with a uterus must also take progestin (a progesterone-like hormone) to prevent uterine cancer. This is because estrogen alone can cause the lining of the uterus to overgrow (potentially leading to uterine cancer). Those who have had their uterus removed (hysterectomy) are not at risk for developing uterine cancer and can use estrogen alone.


Transgender hormone therapy is the term used to describe using estrogen, progesterone or testosterone to achieve feminizing or masculinizing characteristics. Feminizing hormone therapy is used to induce physical changes in your body caused by female hormones during puberty (secondary sex characteristics) to promote the matching of your gender identity and your body (gender congruence). If feminizing hormone therapy is started before the changes of male puberty begin, male secondary sex characteristics, such as increased body hair and changes in voice pitch, can be avoided. Feminizing hormone therapy is also known as gender-affirming hormone therapy.


Masculinizing hormone therapy is used to induce the physical changes in your body caused by male hormones during puberty (secondary sex characteristics) to promote the matching of your gender identity and body (gender congruence). If masculinizing hormone therapy is started before the changes of female puberty begins, female secondary sex characteristics, such as the development of breasts, can be avoided. Masculinizing hormone therapy is also known as gender-affirming hormone therapy.


Hormones are also used for birth control and/or menstrual regulation. Read our entire blog on your options for this purpose here ***


Regardless of your purpose for using hormones, it is helpful to understand the safest routes to take those hormones (patch, pill, injection, etc) and precautions to take as well as side effects and adverse (dangerous) effects that may occur.


What are my hormone options?


Your options will vary according to your medical health, your finances, and your goals. Hormone options usually include estrogen, testosterone, and progesterone, though some providers prescribe additional hormones. The categories of hormones gets broken down into bioidentical versus synthetic, and FDA-approved versus non-FDA-approved.


FDA-Approved Hormone therapy


Numerous FDA-approved hormone preparations are available for the treatment of menopausal symptoms, gender-affirming therapy, birth control, and menstrual regulation. These include those that fulfill the definition of bioidentical and those that are clearly not bioidentical. Products can contain only estrogen (synthetic conjugated estrogens; natural, nonhuman conjugated estrogens; or plant-derived bioidentical estrogens), only progestogens (synthetic progestin or bioidentical progesterone), or a combination of estrogen and progestin. Those that contain synthetic conjugated estrogens, conjugated estrogens (derived from the urine of pregnant mares), or progestins are not bioidentical to the endogenous human sex steroid hormones.


FDA-Approved Bioidentical therapy (BHT)


Currently, FDA-approved products containing bioidentical estrogen and progesterone are available. Bioidentical estrogen derived from plant sources (17β-estradiol) is available in pills, patches, sprays, creams, gels, and vaginal tablets. These preparations differ from custom compounded (CBHT) preparations in that they are carefully controlled and regulated formulations (eg, oral, transdermal, and vaginal preparations), they are manufactured under strict standards, and their effects are subjected to scientific scrutiny.


Numerous peer-reviewed publications have documented the beneficial effects of various doses of FDA-approved estrogen products on vasomotor symptoms, hot flashes, bone density, urogenital atrophy, and fracture prevention.


Both the FDA-approved and compounded hormones come in a variety of doses and routes of delivery (pills, creams, gels, sprays, and vaginal inserts).


In contrast, large-scale, randomized, controlled studies have not been conducted for custom bioidentical hormones (meaning, hormones from a compounding pharmacy). That being said, CBHT is very common method of delivery for hormones.


Compounded Custom Bioidentical Hormones


The term custom bioidentical hormones (CBHT) refers to hormone preparations that (1) have exactly the same chemical and molecular structure as the estrogens and progesterone produced within the human body, (2) are plant derived, and (3) are specifically compounded for an individual patient. Custom CBHT is not FDA-approved for treatment of menopausal symptoms which is why it is not covered by insurance.


The FDA defines compounding as: “the combining or altering of ingredients by a pharmacist, in response to a licensed practitioner's prescription, to produce a drug tailored to an individual patient's special medical needs”.


The most common compounded hormones include combinations of the endogenous estrogens (17β-estradiol, estrone, estriol) and progesterone.


Custom CBHT is available only at select pharmacies. Proponents of custom CBHT preparations believe they offer improved safety, efficacy, and tolerability because of the individualization of the formulas, the source of the hormones, and the routes of delivery.


Bioidentical testosterone is currently not FDA approved or commercially available for cis women. Through compounding pharmacy technology, the product can be formulated for off-label use, but again, will not be covered by insurance. Two gels are approved in the U.S. for cis men only: AndroGel and Testim (1%). There are no FDA approved products for cis women. However, many prescribers will prescribe testosterone to cis women. Since the commercially available dosages are too strong for cis women, testosterone compounded at a dosage of 0.5 to 2 mg per day is typically used for cis women wanting to slightly increase their levels (or a very small amount of Androgel can also be used). The dose is much higher for transgender purposes.


Transdermal testosterone appears to be the safest route. When taken orally, there is extensive first-pass metabolism in the liver that increases risks, including increases in cholesterol and risk for blood clots. Other risks include acne, male pattern hair loss and growth, along a long list of potential side effects.


Bioidentical progesterone is FDA approved, available commercially as a capsule of micronized progesterone in peanut oil. The micronization process allows the hormone to be better absorbed, but does not change the basic molecular structure of the hormone. For those allergic to peanut oil, it is possible to formulate progesterone in olive oil through compounding pharmacy technology. Bioidentical progesterone is also available as vaginal progesterone gel. If one has a uterus and are taking estrogen, they must take progesterone to protect themselves against endometrial cancer, which can happen when the uterus is exposed to estrogen without progesterone (we call this "unopposed estrogen").


Estrogen patch: Minivelle and Vivelle Dot are two brand name bioidentical estradiol patches, available in a range of dosages.


**The dose of estrogen in a patch is not equivalent to the dose in a pill, so if you changing from pill to patch or vice versa, know that your dose may look very different. The dose for menopausal therapy vs birth control vs transgender therapy will be very different.


Patches should be placed on the lower abdomen and changed once or twice weekly, per prescription order, providing steady levels of estrogen throughout the day and night.


The patch sticks to the skin, even with showering, swimming, or sweating. The adhesive may cause skin irritation for some. The adhesive can be removed with rubbing alcohol or sometimes oil.


Estrogen Gel:


Estrogel, Elestrin, and Divigel are brand names of bioidentical estradiol gels to be used topically. The gel is supplied in a pump dispenser or in foil packets, and should be rubbed into the skin of the inner arm daily. Your dose may be one, two, or three pumps gel per day (or the contents of one foil packet per day). Your dose will of course depend on the purpose for which it is being prescribed.


Estrogen Spray:


Evamist is the brand name of a bioidentical estradiol spray. It is sprayed onto the soft skin of the inner forearm and dries quickly – no rubbing-in is required. Your dose may be one, two, or three sprays daily, sometimes more, depending on the purpose prescribed.


Estrogen Cream:


This can be produced in a compounding pharmacy in any dose needed. The bioidentical estradiol cream is supplied in a specialized dispenser, called a topiclick. The dispenser has a dial on the bottom and a hole in the top, through which a measured dose is delivered when the bottom is twisted. The cream is low volume, non-greasy or smelly, and easy to rub into the arms or legs for daily use.


Troches:


A troche is a type of oral lozenge absorbed directly through the soft tissues of the mouth. Rather than swallowing the dissolving troche, place it between cheek and gum and allow to dissolve slowly into the oral mucosa; this allows it to be delivered directly into the bloodstream from the oral tissues and thus avoid first-pass with the liver. Some of the hormone may be swallowed and absorbed via the gut route, but this is likely negligible if troches are used correctly. This route does carry the disadvantage of short half-life (hormone levels fade before the day is done), so multiple doses per day may be required.


Troches must be compounded by a compounding pharmacist and are generally not covered by insurance. A benefit of a troche is that we as prescribers can have it compounded to contain estrogen and testosterone—two-in-one—to make taking daily hormones easier. Sometimes, we add progesterone as well, but this may cause sleepiness, so you may opt for bio-identical progesterone by pill before bed.


A troche causes the hormone to bypass the liver’s metabolism so it is not like taking a pill-- it sometimes absorbs more reliably than topical estrogen, but it does not give the steady levels of a topical methods, so often twice daily dosing is required for optimal symptom relief.

This method does not give the steady and consistent hormone delivery of the patch or subcutaneous pellet; hormone levels will vary significantly from the time the troche dissolves and the time the next one is due.


Vaginal Estrogen:


Vagifem is a very low dose bioidentical estradiol tablet that is supplied in a prefilled applicator for intra-vaginal use. It should be used twice weekly. Estrace cream is a brand name bioidentical estradiol cream for vaginal use.


Vaginal application of estradiol can be extremely beneficial for vaginal dryness and painful intercourse, as it replenishes blood supply, moisture, tissue integrity, and elasticity. It is also beneficial for bladder health, often improving symptoms of urinary urgency or frequency. Vaginal estradiol can be supplied as a cream, a vaginal tablet, or a flexible plastic ring inserted into the vagina.


Another option for vaginal health that provides equal benefit is DHEA supplied as a vaginal cream or suppository. As previously stated, there are no tissue receptors for DHEA, but it is converted to estradiol (or testosterone) within the cells of certain tissues, the vagina being one example, and the benefits are essentially the same as vaginal application of estradiol, providing improvement of vaginal and bladder health without increase in circulating estradiol.



Estrogen Pill (not preferred):


Oral estradiol can sometimes be less costly than brand-name products, but it is not ideal for a number of reasons. Use of oral estrogen slightly increases the risk of blood clots, because metabolism of estrogen stimulates liver production of clotting factors. Smokers, diabetics, and those with certain blood disorders are at very high risk of having clots (strokes, heart attacks) and thus should be discouraged from using pills unless no other alternative can be found.


Liver metabolism of oral estrogens also can cause elevated triglycerides (fat in the blood such as cholesterol), elevation of a protein called sex-hormone binding globulin (which can bind to testosterone, thereby contributing to decreased libido), and elevation of C-Reactive Protein (a marker for inflammation in the body).


Oral estrogen can also increase the risk of gallbladder disease.


These risks are drastically lowered when estradiol is absorbed through the skin.


However, sometimes the pill is the best option for a specific individual and the goals trying to be achieved.


**The dose of estrogen in a patch is not equivalent to the dose in a pill, so if you changing from pill to patch or vice versa, know that your dose may look very different. The dose for menopausal therapy vs birth control vs transgender therapy will be very different.


Intramuscular Estrogen (injection):


Intramuscular (IM) Hormone Injection is not preferred over other methods. Some data shows less consistent symptom relief, and more side effects with IM hormone delivery. A significant drawback, besides the inconvenience of receiving a shot every 1-2 weeks, is the highly variable level of serum hormones with this method, resulting in a roller coaster pattern of hormone excess and deficiency---levels are very high just after the injection, then drop quite low before the next is due.


For relief of symptoms to last the duration of the injection, it requires a high dose be given, and still, often symptoms return before the next injection.


This results in side effects of too much and/or too little hormone at different times in the two-week time frame between injections. Serum hormone tests show peak levels that can be frighteningly elevated - up to 10 or 15 times normal for a pre-menopause person.


Overall, this method results in much more than physiologic doses of estrogen being administered. For typical patients, this is not the best choice.


Estrogen Pellets:


Estrogen and other hormones can be administered via small pellets injected beneath the skin at intervals of 3 to 6 months. The concerns are the same as the above description on intramuscular injection. According to some studies, hormone levels can be extreme and inconsistent with pellet therapy. However, other studies show the release of hormone into the body is most continuous.


Subcutaneous hormone pellet therapy avoids the liver first-pass effect. This method involves a minor office procedure with insertion of 2 to 3 tiny pellets consisting of bioidentical estradiol and/or testosterone into the fatty tissue of the upper hip just beneath the skin. The pellets release hormones into the circulation gradually and consistently, and over 3-5 months are completely absorbed.



The following examples of bioidentical estrogen are available (this is not an all-inclusive list):


Bioidentical estradiol is FDA approved and commercially available under several different brand names: Vivelle Dot (patch), Estrogel, Elestrin, Evamist, Vagifem, Estring, FemRing, and others.


Estrogen patch: Minivelle and Vivelle Dot are two brand name bioidentical estradiol patches, available in a range of dosages.


Estradiol:


Trade names: Estrace , Gynodiol, Innofem

Form: Pill

Trade name: *Estrace

Form: Vaginal cream

+Yes


Trade Names: Alora, Climara, Esclim, Estraderm, FemPatch, Menostar, Vivelle, generic

Form: Transdermal patch

Yes


Trade names: Estrogel, Elestrin, Divigel

Form: Topical gel

Yes

Trade name: Evamist

Form: Topical spray

Yes


Trade name: Estring

Form: Vaginal ring

+Yes


Estradiol acetate

Trade Name: Femring

Form: Vaginal ring

Yes++


Estradiol hemihydrate

Trade Name: Vagifem

Form: Vaginal tablet

+Yes


Trade name: Estrasorb

Form: Topical lotion

Yes


Progesterone

Trade name: (Prometrium) or (Crinone 4%Vaginal gel)

Form: Pill or gel


Combined hormones

Estradiol and norethindrone acetate

Trade Name: (Combipatch)

Form: Patch

Note: The estradiol is bioidentical but not the progestin.

Estradiol and norgestimate

Trade Name: (Prefest)

Form: Pill

Note: The estradiol is bioidentical but not the progestin.

Estradiol and levonorgestrel

Trade Name: Climara Pro

Form: Patch

Note: The estradiol is bioidentical but not the progestin.


Symbols Key:

* Bioidentical estradiol until ingested and converted in the liver to estrone.

+ For vaginal symptoms only.

++ Converts to bioidentical estradiol in the bloodstream.


**For more information on birth control names/options/routes, please see our blog here****_______


Are all routes and forms of hormones equally safe?


There are some advantages of certain forms over others.


Estradiol and testosterone are best delivered by a non-oral route, one of which is the transdermal method (Patch, Cream, Gel).


This is preferable over pills to avoid the first-pass liver effect discussed above.


Transdermal hormone delivery also results in steadier hormone levels throughout the day compared to pills.


Preferred route in terms of safety and consistency of levels is transdermal—meaning, absorbed through the skin via gel, cream, patch or spray.


With transdermal delivery, the hormone is absorbed directly into the bloodstream, avoiding first-pass through the liver, thus avoiding increase in blood clot risk and higher triglycerides associated with oral estrogen. Also, blood levels are steady throughout the day and night, avoiding peaks and valleys associated with oral dosing.


Types & Routes of Estrogen


Estrogen is available in many different forms. All types of estrogen are effective for relieving hot flashes. Estrogen can be taken as a transdermal patch (worn on the skin), an oral pill, or a "ring" or tablet that is inserted into the vagina. There are also creams and sprays that can be put on the skin.


In a meta-analysis of 24 trials of menopausal estrogen in 3329 postmenopausal women, the frequency of hot flashes decreased by 75% in those using estrogen. Estradiol [oral 1 mg/day or transdermal 0.05 mg/day] and conjugated estrogen (0.625 mg/day), appeared to be equally effective for the treatment of hot flashes. These doses eliminate hot flashes completely in approximately 80 percent of women.


The preferred estrogen is estradiol. Estradiol is the estrogen that is identical to the one the ovary makes throughout reproductive life (meaning, bioidentical).Estradiol can be given by mouth, skin patch, or vaginal ring. The other form of estrogen that we do not typically use in our practice is conjugated estrogen (known as Premarin)--it is synthetic.


Estrogen patch — Many experts now prefer treating women with the estradiol patch rather than estrogen pills (because it is associated with a lower risk of blood clots than estrogen pills). A combination estrogen and progestin patch is also available. Some patches need to be replaced every few days, while others are only replaced once a week. At Hearthside Medicine, we tend to offer non-oral estrogen (such as patch, cream, or troche that dissolves in cheek).


Estrogen patches work as well as estrogen pills to increase bone density and treat menopausal symptoms. Women with a uterus who use an estrogen patch must also take a progestin to decrease the risk of uterine cancer. The patch should be placed on the lower abdomen and changed 1-2 twice weekly (depending on type and dose of patch), providing steady levels of estrogen throughout the day and night.


The patch sticks to the skin, even with showering, swimming, or sweating. You can use rubbing alcohol to remove the adhesive, or try olive oil. For some, the patch causes too much skin irritation and they need another method.


Estrogen pill


Oral estradiol can sometimes be less costly than brand-name products, but it is not ideal for a number of reasons. Use of oral estrogen slightly increases the risk of blood clots, because metabolism of estrogen stimulates liver production of clotting factors.


Liver metabolism of oral estrogens also can cause elevated triglycerides (fat in the blood), elevation of a protein called sex-hormone binding globulin (which can bind to testosterone, thereby contributing to decreased libido), and elevation of C-Reactive Protein (a marker for inflammation in the body).


Oral estrogen can also increase the risk of gallbladder disease.


None of these risks are incurred when estradiol is absorbed through the skin.


There are many types of estrogen pills. Estradiol is derived from plant sources and is the same estrogen that the ovary makes before menopause and is called bioidentical. The standard dose of oral estradiol is 0.5 or 1 mg daily by mouth. Lower doses seem to have fewer side effects.


Combination pills that include both estrogen and progestin are also available.

Low-dose birth control pill — Very low-dose birth control pills are a good option for those in their 40s who have bothersome hot flashes, irregular bleeding, and who still need a reliable form of birth control.

Caution should be used for those over 40 years who are also obese because of the higher risk of blood clots. Birth control pills are generally not recommended for postmenopausal women, because the dose of estrogen is higher than needed to relieve hot flashes.


Vaginal estrogen — Women with vaginal dryness can also be treated with very low doses of estrogen that treat the dryness but not hot flashes (because the dose is too low to get into the bloodstream). Vaginal estrogen comes in a cream, vaginal ring, or vaginal estrogen tablets. The low-dose vaginal estrogens do not usually require the use of a progestin pill.

Vagifem is a very low dose bioidentical estradiol tablet that is supplied in a prefilled applicator for intra-vaginal use. It should be used twice weekly. Estrace cream is a brand name bioidentical estradiol cream for vaginal use.


Vaginal application of estradiol can be extremely beneficial for vaginal dryness and painful intercourse, as it replenishes blood supply, moisture, tissue integrity, and elasticity. It is also beneficial for bladder health, often improving symptoms of urinary urgency or frequency. Vaginal estradiol can be supplied as a cream, a vaginal tablet, or a flexible plastic ring inserted into the vagina.


Another option for vaginal health that provides equal benefit is DHEA supplied as a vaginal cream or suppository. As previously stated, there are no tissue receptors for DHEA, but it is converted to estradiol (or testosterone) within the cells of certain tissues, the vagina being one example, and the benefits are essentially the same as vaginal application of estradiol, providing improvement of vaginal and bladder health without increase in circulating estradiol.


Estrogen Cream:


This can be produced in a compounding pharmacy in any dose needed. The bioidentical estradiol cream is supplied in a specialized dispenser, called a topiclick. The dispenser has a dial on the bottom and a hole in the top, through which a measured dose is delivered when the bottom is twisted. The cream is low volume, non-greasy or smelly, and easy to rub into the arms or legs for daily use.


Estrogen Gel:


Estrogel, Elestrin, and Divigel are brand names of bioidentical estradiol gels to be used topically. The gel is supplied in a pump dispenser or in foil packets, and should be rubbed into the skin of the inner arm daily. Your dose may be one, two, or three pumps gel per day (or the contents of one foil packet per day).


Estrogen Spray:


Evamist is the brand name of a bioidentical estradiol spray. It is sprayed onto the soft skin of the inner forearm and dries quickly – no rubbing-in is required. Your dose may be one, two, or three sprays daily.


Estradiol Troches:


A troche is a type of oral lozenge absorbed directly through the soft tissues of the mouth. Rather than swallowing the dissolving troche, place it between cheek and gum and allow to dissolve slowly into the oral mucosa; this allows it to be delivered directly into the bloodstream from the oral tissues and thus avoid first-pass with the liver. Some of the hormone may be swallowed and absorbed via the gut route, but this is likely negligible if troches are used correctly. This route does carry the disadvantage of short half-life (hormone levels fade before the day is done), so multiple doses per day may be required.


Troches must be compounded by a compounding pharmacist and are generally not covered by insurance. A benefit of a troche is that we as prescribers can have it compounded to contain estrogen and testosterone—two-in-one—to make taking daily hormones easier. Sometimes, we add progesterone as well, but this may cause sleepiness, so you may opt for bio-identical progesterone by pill before bed.


A troche causes the hormone to bypass the liver’s metabolism so it is not like taking a pill-- it sometimes absorbs more reliably than topical estrogen, but it does not give the steady levels of a topical methods, so often twice daily dosing is required for optimal symptom relief.


This method does not give the steady and consistent hormone delivery of the patch or subcutaneous pellet; hormone levels will vary significantly from the time the troche dissolves and the time the next one is due.


Intramuscular Estrogen (injection):


Intramuscular (IM) Hormone Injection is not preferred over other methods. Some data shows less consistent symptom relief, and more side effects with IM hormone delivery. A significant drawback, besides the inconvenience of receiving a shot every 1-2 weeks, is the highly variable level of serum hormones with this method, resulting in a roller coaster pattern of hormone excess and deficiency---levels are very high just after the injection, then drop quite low before the next is due.


For relief of symptoms to last the duration of the injection, it requires a high dose be given, and still, often symptoms return before the next injection.


This results in side effects of too much and/or too little hormone at different times in the two-week time frame between injections. Serum hormone tests show peak levels that can be frighteningly elevated - up to 10 or 15 times normal for a pre-menopause person.


Overall, this method results in much more than physiologic doses of estrogen being administered. For typical patients, this is not the best choice.


Estrogen Pellets:


Estrogen and other hormones can be administered via small pellets injected beneath the skin at intervals of 3 to 6 months. The concerns are the same as the above description on intramuscular injection. With these methods, hormone levels can be extreme and inconsistent.


Subcutaneous hormone pellet therapy avoids the liver first-pass effect. This method involves a minor office procedure with insertion of 2 to 3 tiny pellets consisting of bioidentical estradiol and/or testosterone into the fatty tissue of the upper hip just beneath the skin. The pellets release hormones into the circulation gradually and consistently, and over 3-5 months are completely absorbed.


Types of Progestin (Progesterone)


Postmenopausal people with a uterus who are treated with estrogen alone have an increased risk of developing uterine cancer and hyperplasia (a precursor to uterine cancer). Taking a second hormone, progestin, minimizes this risk


Bioidentical progesterone is FDA approved, available commercially as a capsule of micronized progesterone in peanut oil. The micronization process allows the hormone to be better absorbed, but does not change the basic molecular structure of the hormone. For those allergic to peanut oil, it is possible to formulate progesterone in olive oil through compounding pharmacy technology. Bioidentical progesterone is also available as vaginal progesterone gel.


Oral Progesterone:


Prometrium is the brand name of a bioidentical progesterone that is supplied in a small oil-filled capsule to be taken by mouth. Prometrium contains progesterone in peanut oil. If you are allergic to peanuts you should not use this product. In such cases a compounding pharmacy can prepare a progesterone pill that contains no peanut oil. Prometrium is best taken at night, since it can cause sleepiness, a side effect that can be quite beneficial for some.



Oral progestins – One commonly prescribed progestin pill is micronized natural progesterone (bioidentical). Other types of synthetic progestin pills (medroxyprogesterone acetate norethindrone, norgestrel) are also available, though we do not prefer these in our practice.



Natural progesterone has no negative effect on lipids and is a good choice for those with high cholesterol levels. In addition, natural progesterone might have other advantages when compared with medroxyprogesterone acetate.


Intrauterine progestin – An intrauterine device (IUD) is a form of birth control; one type, the levonorgestrel IUD (brand names: Mirena, Liletta, Kyleena, Skyla), releases progestin to prevent pregnancy. In some countries, these types of IUDs (using a lower dose of levonorgestrel) are used in menopausal folx taking estrogen to minimize the risk of developing uterine cancer. The IUD is not currently approved in the United States for use in menopausal women; however, if you already have one when you enter perimenopause, your provider may suggest that you keep it in until after menopause is complete.


Another choice for obtaining the progesterone without systemic side effects is the Mirena Intrauterine System. This is an intrauterine device (IUD) that contains a progestin called levonorgestrel. The pro