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Bioidentical Hormone Therapy

Bioidentical hormone therapy (BHT) uses bioidentical hormones, derived from plant extracts which have been chemically modified to be structurally identical to endogenous human hormones (1). This is in contrast with conventional hormone replacement therapy (HRT) which uses conventional hormones, such as Premarin (conjugated estrogen) and Provera (medroxyprogesterone acetate; a progestin), which are not identical to endogenous human hormones (1,2). Bioidentical hormones include estriol, estradiol, estrone, progesterone, and testosterone (1). Bioidentical estrogens may originally be derived from soy, whereas bioidentical progesterone may be derived from diosgenin extracted from wild Mexican yam (3).

Compounded Bioidentical Hormone Therapy (BHT)

In addition to the commercially available bioidentical hormone therapy (BHT), compounded BHT is also available; the benefit of these compounded products is that they can be individualized to the patient’s needs; however, they are more expensive (3).

A Note on the Women’s Health Initiative (WHI)

The WHI trial examined the risks and benefits of combined estrogen plus progesterone therapy, estrogen only therapy, and placebo in postmenopausal women (4). Both the combined therapy and estrogen only therapy showed an increased risk of stroke (1,2,4,5). The combined therapy also shows an increased of risk of coronary heart disease (4). The HERS and HERS II trials support this link between combined HRT and heart disease (4). The hormones used in this trial were conjugated equine estrogens and medroxyprogesterone acetate, i.e. they were not bioidentical hormones (1,2,4,5). This study has led many patients and physicians to turn to BHT as an alternative to HRT, due to the belief that BHT may be more natural and safe; however, evidence is still lacking (1,2,4,5). Below is a discussion of progesterone and estrogen BHT.

Progesterone

Background, Indications, and Mechanism of Action

Progesterone, whose chemical name is pregn-4-ene-3,20-dione, is a steroid hormone produced by the ovaries and adrenal glands, as well as the placenta during pregnancy (5). The roles of progesterone include regulating the female menstrual cycle, embryogenesis, maintenance of pregnancy (5). Progesterone has been used for a great variety of indications, include the treatment of menopausal symptoms, improvement of bone density, improvement of cognitive performance, Alzheimer’s disease, birth control, fertility, endometriosis, pre-eclampsia, and hormone-related psychosis (5). However, the evidence for these conditions is unclear or conflicting (Grade C) (5). Prometrium, in the form of micronized bioidentical progesterone, is indicated for women with an intact uterus as an adjunct to postmenopausal estrogen replacement therapy to reduce the risk of endometrial hyperplasia and carcinoma (4). It is inferred that Prometrium, as an exogenous progesterone, will act in the same way as endogenous progesterone; they bind to the progesterone receptors on target tissues and lead to modulation of gene transcription, thus causing the same effects as endogenous progesterone (4). The findings of a cross-sectional study in menopausal women found that a polymorphism in CYP1B1 was associated with lower dehydroepiandrosterone-sulfate (DHEA-S) and progesterone levels, which has been associated with the experience of hot flashes (4). Lower progesterone and sex hormone-binding globulin levels, a lower free estradiol index, and a higher ratio of total androgens to total estrogens were also associated with the experiencing of hot flashes (4).

As menopause nears, the ovaries reduce most of their production of estrogen and progesterone (2). Lowered or fluctuating hormone levels may cause menopause symptoms such as hot flashes dryness, atrophy, fine wrinkling, poor healing, and medical conditions such as osteoporosis (2). BHT helps to replenish the progesterone, relieving some of the symptoms of menopause (2).

Efficacy in the treatment of menopausal symptoms and prevention of osteoporosis:

As mentioned above, the evidence for recommending progesterone for menopausal symptoms (including hot flashes, oral and sleep symptoms, and overall effect on quality of life) and prevention of osteoporosis is Grade C (5). A small study found that applying a quarter teaspoon of cream (20mg progesterone from diosgenin extracted from Mexican yams) to the skin daily showed improvements in vasomotor symptoms (most had maximum relief after 1 month) but not in the prevention of osteoporosis (after 1 year) (6,7). In contrast, in a more recent RCT where women used a 32mg/day progesterone cream, no benefit was found in regards to vasomotor symptoms, mood, sexual feelings, lipid levels, or bone metabolic markers, but women were only followed for 12 weeks (6,8). Despite these conflicting findings on the efficacy of progesterone, the Scientific Advisory Council of the Osteoporosis Society of Canada still recommends that progesterone or a progestin be used as first-line therapy in the prevention of postmenopausal osteoporosis and second-line in its treatment (5,9). This recommendation may be due to the role of progesterone in reducing the risk of endometrial hyperplasia (8). The usual dose of Prometrium (PO micronized progesterone capsules) that is used is 200mg/day at bedtime for the last 14 days of estrogen treatment per cycle OR 300mg/day divided BID for the last 12-14 days of estrogen treatment per cycle (4,5,10). Progesterone is also available as intravaginal gels, such as Crinone 8% (90mg; indicated for in vitro fertilization, not menopausal symptoms or osteoporosis) (2,11,12). Crinone was found to be more bioavailable, have less variable absorption, and provide more reliable delivery than Prometrium; although this was in comparison to 100mg Prometrium daily, which is less than the recommended dose (11).

Safety

Contraindications: hypersensitivity to any component of the formulation (e.g. peanut oil in Prometrium), active hepatic dysfunction or disease, personal history of estrogen/progestin-dependent malignancy, endometrial hyperplasia, undiagnosed abnormal genital bleeding, pregnancy, active or history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary artery disease), classical migraine, active or past venous thromboembolism (e.g. deep vein thrombosis, pulmonary thromboembolism) or active thrombophlebitis, and partial or complete loss of vision due to ophthalmic vascular disease (4,5).

Caution in: hypertensive patients (monitor for increase in blood pressure); diabetic patients (monitor glucose and lipid levels); patients with metabolic and malignant bone diseases associated with hypercalcemia and patients with renal insufficiency (due to the effect on the metabolism of calcium and phosphorus with prolonged use of estrogens with or without progestins); liver disease (monitor liver function tests periodically); renal dysfunction, epilepsy, and asthma (due to estrogens with or without progestins causing fluid retention) (4). Discontinue if any of the following occurs: visual disturbances, classical migraine, transient aphasia, paralysis, loss of consciousness (4,5).

Side effects: transient somnolence/dizziness; cramps, nausea; fatigue, headache; increased blood pressure; worsened glucose tolerance and lipid metabolism; abnormal vaginal bleeding/spotting; fluid retention; breast tenderness; musculoskeletal pain; see A Note on the Women’s Health Initiative (WHI) above for more on the risk associated with combined estrogen/progestin therapy (4).

Drug interactions: liver enzyme inducers (e.g. barbiturates, rifampin) increase the metabolism of progesterone; liver enzyme inhibitors (e.g. ketoconazole) slow the metabolism of progesterone; food increases the AUC (area under the curve) and Cmax (maximum concentration) while not effecting the Tmax (maximum time); St. John’s wort may also alter the metabolism of progesterone; progesterone decreases the reliability of lab tests including glucose tolerance tests, serum folate concentration, and plasma lipoprotein levels (4,5).

Counseling points

Counsel patient on the above safety points and the associated monitoring points (4,10). Take only as directed (2 capsules/day (usually at bedtime) for the last 14 days of estrogen treatment OR 3 capsules (one AM, two HS) for the last 12-14 days of estrogen treatment each cycle) (10). Expect vaginal bleeding a few days after completion of the 3 capsule/day course, but not the 2 capsule/day course (10). In case of overdose, contact doctor/pharmacist, emergency room, or a poison control center immediately (10). In case of missed dose: with the 2 capsule/day regimen, take one capsule the following morning and continue taking the rest of the capsules as prescribed; with the 3 capsule/day regimen, if you forget either morning or evening dose, you should not take the missed dose (10). Store at room temperature and use by the expiry date (10).

Recommended product line(s)/Manufacturer

Prometrium 100mg PO capsules (micronized progesterone; Merck) Based on the above evidence, it is unclear whether progesterone helps with menopausal symptoms and prevention of osteoporosis; however, it should still be recommended in women with an intact uterus who receive estrogen HRT or BHT to prevent endometrial hyperplasia. Prometrium is less expensive than the compounded products, requires no preparation, and has a good reputation, so we will be stocking it in our pharmacy (3).


Estrogen (Estrone, Estriol, and Estradiol)

Background, Indications, and Mechanism of Action

Biologically, there are 3 active forms of estrogen: estrone, estriol, and estradiol. Estradiol is the most active estrogen and estriol is the weakest estrogen and main urinary metabolite (2). Estriol and estrone are only available as compounded products called bi-estrogens (Biest) and tri-estrogens (Triest) (3). Biestrogen formulations are made up of 80% estriol and 20% estradiol only (3,13). Biestrogen is available as capsules, sublingual compounds, and transdermal creams or gels, and is the most commonly used preparation (13). Triestrogen formulations are made up of 80% estriol, 10% estradiol, and 10% estrone, and can be administered as a 1mg:0.125mg:0.125mg bid dose (3,13). 17β-estradiol is available as commercially available products such as patches, capsules, vaginal rings, creams, and suppositories (2). The roles of estrogens are numerous (including development and maintenance of the female urogenital system and sexual characteristics) due to the distribution of the estrogen receptor in a variety of organs including the hypothalamus, pituitary, vagina, urethra, uterus, breast and liver, and in osteoblasts (14–16). In addition to its individual mechanism of action, by binding to its receptor, estrogen up-regulates the expression of progesterone receptors, causing an increased influence by progesterone on the body (5). Bioidentical estrogen is indicated for numerous medical conditions including the treatment of menopausal symptoms, surgically induced estrogen deficiencies, and osteoporosis prevention (14–16). Exogenous bioidentical estrogen acts in the same way as endogenous estrogen; it binds to the estrogen receptors on target tissues and leads to modulation of gene transcription, thus causing the same effects as endogenous estrogen (2). As menopause nears, the ovaries reduce most of their production of estrogen and progesterone (2). Lowered or fluctuating hormone levels may cause menopause symptoms such as hot flashes dryness, atrophy, fine wrinkling, and poor healing (2). BHT helps to replenish the estrogen, relieving some of the symptoms of menopause (2).

Efficacy in the treatment of menopausal symptoms and prevention of osteoporosis:

Estriol’s potency is 1/10th to 1/100th that of estradiol, but most sources cite it as 1/80th; therefore, it is believed that the benefits for compounded products, such as Biest, in the treatment of menopausal symptoms is due to the estradiol component (3,13). Oral estrogen preparations are taken on the first 21-25 days of each month (14). Estrace (17β-estradiol) is usually started with a 1 mg tablet per day for menopausal symptoms, but may be adjusted to the individual’s needs (14). As per the WHI, estrogens should be used for the shortest time necessary; therefore, attempts to taper or discontinue should be made at 3-6 month intervals (14). For prevention of osteoporosis, Estrace is started at 0.5mg tablet per day, and may be titrated up to achieve a plasma [estradiol] of 50pg/mL (14). Estraderm (17β-estradiol) provides continuous, controlled transdermal release of 17β-estradiol to restore levels in those seen in the earlier follicular phase of the premenopausal range (15). It is believed that in so doing, it alleviates the symptoms of menopause (13,15). Estraderm 50µg or 100µg per day have been found to prevent bone loss in placebo-controlled clinical studies (15). Treatment with Estraderm 100µg for 2 years was shown to significantly increase vertebral bone density (3.7% above baseline) in premenopausal women (15). Treatment with Estraderm 50µg was shown to maintain bone density (15). Thus, the suggested duration would be 2 years as evident in the previously mentioned trial (15). Estrogel (17β-estradiol hemihydrate) is a gel which is absorbed transdermally (2,13,16). The advantage of this product over patches is that it does not require an adhesive, thus reducing skin sensitivity side effects (13). There is interindividual absorption variability with this product due to differences in site application; as such, doses should be adjusted based on serum estradiol levels after the patient has developed their technique as well as based on their symptoms (16). The treatment is started with 2.5g (2 metered-actuations) Estrogel daily, administered either on days 1-25 of a month or 1-21 of a 28-day cycle (16). After three days of once-daily administration to the upper arm, the release of estradiol from the skin will have reached steady state (13). There is significant relief of hot flashes by 4-12 weeks, reducing both frequency and severity (13). Estrogel 0.87g/day significantly reduces vulvovaginal atrophy symptoms by 12 weeks (13,17).

Safety

Contraindications: hypersensitivity to ingredients of drug formulation; liver dysfunction/disease with abnormal liver function tests (LFT’s); endometrial hyperplasia, history of breast cancer; undiagnosed abnormal genital bleeding; pregnancy; history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease); history of venous thromboembolism; vision loss due to ophthalmic vascular disease; thrombophilic disorders; porphyria; classical migraine; breast feeding (14–16).

Caution in: hypertension (monitor for elevated blood pressure); otosclerosis (monitor for hearing loss); diabetes (monitor for worsened glucose tolerance and lipid metabolism), metabolic and malignant bone diseases associated with hypercalcemia and patients with renal insufficiency, patients on thyroid HRT (monitor thyroid hormones); uterine leiomyomata (monitor for growth, pain and tenderness), endometriosis (monitor for recurrence/worsening of symptoms); hepatic hemangiomas (monitor for exacerbation), history of liver and/or biliary disorders (monitor LFT’s); systemic lupus erythematosus; age >65 years (monitor for development of dementia, based on the WHIMS trial); epilepsy (monitor for exacerbations); and cardiac/renal dysfunction or asthma (monitor for fluid retention) (14–16).

Side effects (general combination products): altered coagulation tests; palpitations, increased blood pressure; increased blood sugar levels; visual disturbances, dry eyes; nausea, vomiting, abdominal discomfort; fatigue, changes in appetite, weight and libido; gallbladder disorder, cholestatic jaundice; musculoskeletal pain; aggravated migraines, headaches, dizziness; depression, anxiety; sodium retention, edema; breakthrough bleeding, vaginal itching/discharge, breast swelling/tenderness; loss of scalp hair, hirsuitism, acne; thrombophlebitis; and endometrial hyperplasia (when used alone) (14–16).

Drug interactions: estrogens decrease the efficacy of anticoagulants, antidiabetics, and antihypertensives; altered estrogen levels (decreased [estradiol]) with enzyme inducers (barbiturates, phenytoin, carbamazepine, rifampin); atorvastatin, acetaminophen and ascorbic acid increases the plasma concentration of ethinyl estradiol and estrogen lowers plasma levels of acetaminophen; increases plasma concentrations of cyclosporine (CYP3A4 inhibition); St. John’s wort induces steroid metabolism via CYP3A4 induction, altering the efficacy and safety of estrogen/progestin products ; estrogen may affect endocrine and liver function tests; no lifestyle interactions have been tested with Estraderm, Estrogel and Estrace; no food interactions have been tested with Estraderm and Estrogel, however, grapefruit juice (CYP 3A4 inhibitor) may increase the plasma Estrace concentration (14–16).

Counseling points

General: Counsel patient on the above safety points and the associated monitoring points. Estrace (0.5mg, 1mg, 2mg tablets) Take Estrace as directed, i.e. for the first 21-25 days of each month (14). If you miss a dose, take Estrace as soon as possible; however, if it’s almost time for the next dose, skip the missed dose (14). Store at room temperature; keep container tightly closed and protected from light (14). Estraderm Patch (50µg and 100µg) Estraderm patch is to be placed on a clean, non-oily, dry area of intact skin which is not exposed to sun and have minimal wrinkling (e.g. buttocks (least irritation), lower abdomen, hip, side, lower back; but NOT the breasts or the waistline); press firmly with the palm of the hand (15). Do not apply patches to the same skin site twice in a row (15). If the patch falls off, it may be re-applied; if it does not adhere, a new patch may be used (15). If you miss applying a patch of Estraderm, apply a new patch as soon as possible and the subsequent patch according to the treatment schedule (15). Store Estraderm below 25°C, but do not freeze; keep out of reach of children (before use and when disposing of used patches (15). Estrogel (0.06% gel; pump) To prime the pump, 1-2 pumps may be required; the first dose released may be inaccurate and should be discarded (16). The pump contains enough gel for about 1 month (16). To measure a 2.5g dose, press firmly on the pump and apply with hands the gel to one arm over a large area of the skin in a thin, uniform layer; then repeat, applying to the other arm (16). Alternatively, Estrogel may be applied to the abdomen or inner thighs (16). Site rotation is not necessary (16). DO NOT apply to the breasts, face, or irritated/damaged skin (16). Allow the gel to dry (about 2 minutes) before covering with clothing (16). If you miss a dose, use Estrogel as soon as possible; however, if it’s almost time for the next dose, skip the missed dose (16). Store Estrogel at room temperature and keep out of reach of children (16).

Recommended product line(s)/Manufacturer

Estrace 0.5mg, 1mg, 2mg tablets (17β-estradiol, Shire); Estraderm 50µg and 100µg patches (17β-estradiol, Novartis Pharmaceuticals); Estrogel 0.06% gel (17β-estradiol hemihydrate, Merck) As mentioned above, estradiol has been found to relieve menopause symptoms, as well as help prevent osteoporosis. The different preparations are equally effective, and the safety concerns are not unique to any one product (1–3,13–16). As such, our decision on which products to carry is based on the need to accommodate for patient preferences. As such, we are recommending reputable products from a number of different dosage forms: one oral, one patch, and one gel (14–16).

 

References

  1. Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Womens Health (Larchmt). 2007 Jun;16(5):600–31.
  2. Moskowitz D. A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks. Altern Med Rev. 2006 Sep;11(3):208–23.
  3. Gayle Nicholas Scott. Bioidentical Hormones. Pharmacist’s Letter. 2003 Oct;19(191011):3.
  4. Repchinsky, C. Prometrium. In: Compendium of Pharmaceuticals and Specialties (e-CPS). Ottawa: Canadian Pharmacists Association; 200 [Internet]. [cited 2012 Mar 26].
  5. Natural Standard - Progesterone [Internet]. [cited 2012 Mar 26].
  6. Haimov-Kochman R, Hochner-Celnikier D. Hot flashes revisited: pharmacological and herbal options for hot flashes management. What does the evidence tell us? Acta Obstet Gynecol Scand. 2005 Oct;84(10):972–9.
  7. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999 Aug;94(2):225–8.
  8. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause. 2003 Feb;10(1):13–8.
  9. Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002 Nov 12;167(10 Suppl):S1–34.
  10. Merck Canada Prescription Products [Internet]. [cited 2012 Mar 28]. Available from: http://www.merckfrosst.ca/merck-products/ca_en/merck-canada-prescription-products/home.html
  11. Levine H, Watson N. Comparison of the pharmacokinetics of crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women(3). Fertil. Steril. 2000 Mar;73(3):516–21.
  12. Repchinsky, C. Crinone. In: Compendium of Pharmaceuticals and Specialties (e-CPS). Ottawa: Canadian Pharmacists Association; 200 [Internet]. [cited 2012 Mar 28].
  13. Sites CK. Bioidentical hormones for menopausal therapy. Womens Health (Lond Engl). 2008 Mar;4(2):163–71.
  14. Repchinsky, C. Estrace. In: Compendium of Pharmaceuticals and Specialties (e-CPS). Ottawa: Canadian Pharmacists Association; 200 [Internet]. [cited 2012 Mar 26].
  15. Repchinsky, C. Estraderm. In: Compendium of Pharmaceuticals and Specialties (e-CPS). Ottawa: Canadian Pharmacists Association; 200 [Internet]. [cited 2012 Mar 26].
  16. Repchinsky, C. Estrogel. In: Compendium of Pharmaceuticals and Specialties (e-CPS). Ottawa: Canadian Pharmacists Association; 200 [Internet]. [cited 2012 Mar 29].
  17. Simon JA, Bouchard C, Waldbaum A, Utian W, Zborowski J, Snabes MC. Low dose of transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2007 Mar;109(3):588–96.

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