What are the differences Between Bioidentical and Synthetic Hormones? 

Conventional (FDA-approved) products are available as both non-bioidentical (synthetic and nonhuman) hormones and bioidentical hormones.  Synthetic hormones are commercially manufactured in a lab and do not match what the woman’s own body makes; they are structurally different.  As a result, the side effect profiles can vary between bioidentical and synthetic hormones and some studies suggest the risks, too, may differ.  Premarin, which is derived from a pregnant mare’s urine, is the most common synthetic estrogen used in the United States.   Examples of FDA-approved bioidentical estrogen (estradiol) include Estrace, Vivelle-Dot, Climara, and estradiol gels, sprays and creams.  Synthetic progestogens include Provera (medroxyprogesterone acetate) and Micronor (norethindrone).  Prometrium (progesterone) is a bioidentical, FDA-approved progestogen. 

Progestogens (bioidentical progesterone and synthetic progestins like medroxyprogesterone acetate or norethindrone acetate) are used to balance the effects of unopposed estrogen on the endometrium and prevent uterine cancer.  Although progestogens have comparable effects on the endometrium, significant differences arise in their effects on lipids, sleep, mood, fluid-electrolyte balance, and breast tenderness.  The PEPI trial showed that progesterone does not negate the favorable effects of estrogen on lipids or increase glucose levels when combined with Premarin.  Smaller controlled studies have also shown that progesterone may have a positive effect on sleep, mood, and fluid retention.  Most large-scale trials on breast cancer risk have used synthetic hormones.  The largest trial, the WHI, studied Premarin (conjugated equine estrogen) and Prempro (conjugated equine estrogen + medroxyprogesterone acetate).  There was an increased risk of breast cancer in those who took Prempro for 5 years but the risk was not seen in those who took Premarin.  For FDA-approved bioidentical estradiol and progesterone, there is no WHI-equivalent study that has demonstrated breast cancer risk.  However, a large amount of observational data from the E3N cohort study in France showed the risk of breast cancer was lower in patients who took progesterone (and not increased compared to women who took no hormones) compared to synthetic progestogens.  The absorption of transdermal bioidentical progesterone cream is variable and unpredictable, so it is not recommended for opposing the effects of estrogen on the uterine lining.  Oral progesterone is the preferred choice for this situation. 

Many women seek testosterone therapy due to low sex drive.  Again, this comes in a synthetic form, methyltestosterone, and bioidentical forms.  Methyltestosterone is combined with conjugated equine estrogen (Estratest) in a tablet and can potentially cause liver damage and worsen a patient’s lipid profile.  Bioidentical testosterone has not been shown to have these negative systemic effects and can dramatically improve sexual function in some patients.  There is no form of bioidentical testosterone that is FDA-approved for women; however, there are gels and injections that are FDA-approved for men.  Some women choose to use these forms off-label under physician guidance.  Others choose to go with a compounded bioidentical testosterone in the form of a cream, injection, pellet, or capsule. 

What is Compounded Hormone Therapy? 

Compounded hormone therapy is not synonymous with bioidentical hormone therapy.  Bioidentical hormones can be obtained via custom-compounded formulations or standardized, commercially available, FDA-approved products.  Traditionally, compounding is used to provide treatment for patients when the exact products needed are not commercially available or different ingredients, preservatives, or routes of administration are required because of patient intolerances.  Other potential advantages of compounded compared to FDA-approved therapy include greater dosage flexibility, availability of low-dose preparations, and potential lower cost.  Compounded products are made by a pharmacist and custom-made for a patient according to a physician’s specifications.  They are available in numerous forms including gels, creams, lotions, suppositories, troches, rapid dissolve tablets, pellets, and capsules.  FDA-approved and compounded bioidentical hormones contain the same United States Pharmacopeia (USP) – grade hormones.  The USP standards help ensure quality, purity, strength, and consistency of active hormones.  FDA approval indicates that an agent has undergone extensive testing, scrutiny, and standardization.  Compounded hormones are regulated by state boards of pharmacy and there are specific guidelines for appropriate use, but they are not subject to the same federal laws.  The American College of Obstetricians and Gynecologists (ACOG) recommends that patients should be counseled that menopausal hormonal therapies proven to be safe and effective by the FDA are more appropriate for their use than individual pharmacy-compounded preparations.  Furthermore, ACOG claims that evidence is lacking to support the superiority of compounded bioidentical hormones over conventional menopausal hormone therapy.  It contends that customized compounded hormones pose additional risks and that they have variable purity and potency.  Lastly, ACOG states that because of the variable bioavailability and bioactivity, both underdosage and overdosage are possible.  The North American Menopause Society (NAMS) also voices concerns regarding the safety and efficacy of compounded bioidentical hormones; however, it acknowledges that compounded bioidentical hormone therapy may be appropriate in certain situations such as allergies to specific ingredients in FDA-approved products or dosages needed that are not available as an FDA-approved drug product. 

Is Measuring Hormone Levels in Postmenopausal Women Useful? 

Measuring hormone levels in postmenopausal women is an area of debate.  For some, testing may add little benefit.  However, some women do not get the expected or desired symptom relief and checking levels in this group may help determine adequate or inadequate hormonal absorption.  There are also no well-defined goal ranges for hormones in menopause, but the information regarding serum blood levels can be used by experienced physicians to guide treatment and evaluate side effects. 

Consistency is Key

Patients may choose to utilize a pill, cream, or patch to supplement the hormones their body is unable to produce naturally. You will discuss with your doctor the best option for you based on your personal needs, medical conditions, and ability to be consistent with therapy.

Bioidentical hormone pellets release a steady supply of needed hormones, and are much easier for individuals to maintain without worry of remembering to take a pill or position a new patch each day. The process of implanting these pellets takes only a few minutes, which last for several months at a time.

What are the Benefits of Bioidentical Hormone Replacement Therapy? 

Estradiol has numerous benefits for postmenopausal women.  It protects against heart disease, stroke, Alzheimer’s disease, memory disorders, vaginal atrophy, vaginal dryness, painful sex, urinary incontinence, urinary tract infections, macular degeneration, colon cancer, and cataracts.  Estradiol also prevents hot flashes, temperature dysregulation, and mood disorders.  Some patients may develop breast tenderness, bleeding, or fluid retention.  These issues can typically be resolved by adjusting the dosage or changing the route of estradiol administration.  The key is for the patient to communicate with the physician to trouble-shoot the side effects and avoid stopping the treatment without discussing with the doctor.   

Progesterone can be helpful in many patient populations, not just menopause.  It can be used to treat PMS/PMDD as well as cyclic migraines and bloating associated with menstruation.  In perimenopause and menopause, it can help with bleeding issues, hot flashes/night sweats, sleep, mood, joint pain, breast tenderness, and fluid retention.  It works with estradiol to keep the bones strong and lipids in check.  It is also protective against uterine cancer, osteoporosis, fibrocystic breast disease, ovarian cysts, and coronary artery disease.  Drowsiness is usually the only side effect associated with progesterone.  This can be managed by changing the dose or route of hormone administration.  In contrast, synthetic progestins (medroxyprogesterone acetate and norethindrone) have many side effects including depression, breast swelling and tenderness, weight gain, and fluid retention.  Synthetic progestins are also associated with an increased risk of breast cancer, cardiovascular disease, and diabetes mellitus. 

Testosterone has multiple benefits for perimenopausal and postmenopausal women.  There are no FDA-approved forms of bioidentical testosterone for use in women; however, it is commonly prescribed off-label to help a multitude of symptoms.  Testosterone therapy can improve energy, sex drive, orgasm, and well-being.  It also improves body composition by increasing muscle mass and lowering visceral fat mass.  Testosterone improves strength and bone density, which are especially important in postmenopausal women who are at risk for osteoporosis due to declining hormones.  Regarding skin, it increases collagen and thickness while decreasing wrinkles and cellulite.  Possible side effects include excess facial hair, acne, thinning of hair on the scalp, clitoral enlargement, and voice change.  These side effects can often be managed by adjusting the dose or form of the medication. 

DHEA is made in the adrenal gland and naturally decreases as we age.  It is often not optimal in patients with fatigue and has been shown in clinical studies to improve joint pain in patients with autoimmune disease, in particular Systemic Lupus Erythematosus (SLE).  DHEA aids in reducing cardiovascular risk by increasing the breakdown of fat around the organs, decreases cholesterol, and lowers overall body fat.  It also boosts the immune system, restores vitality, improves quality of life, mood, memory, and energy, and may have anti-cancer properties by enhancing the immune system.  Furthermore, it aids in preventing osteoporosis, which is particularly important for postmenopausal women.  Side effects of treatment include acne or excess hair growth on the face.  These can be managed by adjusting the dosage of DHEA. 

Melatonin is produced in the pineal gland in the brain.  Melatonin has been shown to improve sleep, enhance mood, boost the immune system, lower blood pressure, prevent some cancers, and decrease migraines and cluster headaches.   Side effects include mild grogginess in the morning, hair color change, vivid dreams, and in rare circumstances, stimulation instead of drowsiness.   

Thyroid hormone is produced by the thyroid gland in the neck.  The two main thyroid hormones affecting humans are T4 and T3, the latter being the more potent, active form.  Some patients may have normal laboratory values, but still have numerous symptoms associated with thyroid disease.  This can be due to a decreased production of T4 by the thyroid gland, decreased conversion of T 4 to T3 in the body, or a resistance in the receptors in the body to respond normally to thyroid hormone.  Symptoms of thyroid dysfunction include fatigue, weakness, feeling cold, thinning of hair, skin, and nails, weight gain, increased body fat, impairment in cognition or memory, loss of well-being, and depression.  Adequate thyroid hormone protects against cardiovascular disease, diabetes, cognitive impairment, fatigue, weight gain, cholesterol problems, and memory loss.  It regulates temperature, metabolism, cerebral function, energy, and fat mass.  Side effects of thyroid hormone treatment can include sweating, palpitations, fast heart rate, tremor, and nervousness.  These can typically be addressed by adjusting the dosage of the medication. 

Overall, bioidentical hormone therapy improves cardiovascular markers such as hemoglobin A1C, insulin resistance, blood pressure, lipids, and glucose.  A 2022 meta-analysis of 29 randomized, controlled trials involving almost 2000 perimenopausal and postmenopausal women, concluded that compounded hormones were not associated with negative impacts on lipid profiles or glucose metabolism, which are both risk factors for cardiovascular disease.  The study also stated, “Despite the variations in absorption from different types of compounded hormones, routes, and strengths, the trends were consistent with published data from FDA-approved products.” 

How Safe Is HRT?

Many patients are hesitant to begin hormone replacement therapy because they are wary of its safety, and for good reason. There are several types of unregulated bioidentical hormones available in today’s market, and so individuals should be encouraged to ask their physician about the proven science behind the specific product being recommended for use.