madman
Super Moderator
Postmenopausal Hormone Therapy—Local and Systemic: A Pharmacologic Perspective
Taryn Smith, MD, NCMP, Sabrina Sahni, MD, NCMP, and Holly L. Thacker, MD, FACP, CCD, NCMP
Abstract
Every woman, if she lives long enough, will transition into menopause, and as the US population ages, women will be spending more time in a postmenopausal state than before. For postmenopausal women, the decision to initiate menopausal hormone therapy should be individualized. A thorough evaluation of the patient’s cardiovascular, venous thromboembolic, cancer, and fracture risk should be considered along with the woman’s quality of life. Hormone therapy exerts its therapeutic effects on vasomotor symptoms, the skeleton, and the genitourinary system independent of age since menopause, and these benefits are lost once hormone therapy is stopped. Here we review the pharmacologic properties of dose, formulation, mode of administration, the timing of initiation, and duration of hormonal therapies in regard to optimizing benefit and minimizing risk to the patient. This discussion will focus on the effects of common hormonal therapies including estrogen (local and systemic), progesterone, estrogen receptor agonist/antagonist, and local dehydroepiandrosterone, and include a brief review of compounded bioidentical hormone therapy.
Every woman, if she lives long enough, will transition into menopause. According to the North American Menopause Society (NAMS), roughly 6000 US women transition to menopause each day. It has been estimated that >50 million women will be postmenopausal in 2020,1 and as the US population ages, women will be spending more time in a postmenopausal state than before. In addition to bothersome vasomotor symptoms, postmenopausal women are at greater risk for genitourinary and sexual dysfunction, cognitive decline, cardiovascular disease, and significant bone loss.2 Hormone therapy has repeatedly been shown to be the most effective treatment for problematic vasomotor symptoms of menopause while significantly decreasing the risk of postmenopausal bone loss.3 However, following the Women’s Health Initiative (WHI) trials, many questions regarding the safety of hormone therapy have arisen. The WHI trials were conducted to evaluate the risks and benefits of hormone therapy taken for primary prevention of chronic diseases among postmenopausal women, whose average age was 63 years.4 Women were stratified to either combined conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg if they had a uterus and conjugated equine estrogen alone if they had had a hysterectomy. The conjugated equine estrogen plus MPA arm was terminated after 5.6 years because of increased risk of breast cancer, whereas the conjugated equine estrogen-only arm was terminated after 7.2 years because of increased stroke risk.4 The results of the WHI trials cannot be applied to other hormone regimens, as each arm of the trials evaluated a single dose and formulation of orally administered hormone therapy. Since the publication of the WHI trials, experts have investigated how hormone therapy formulation, the timing of administration, mode of hormone therapy delivery, and combination of hormones used to impact a woman’s risk. New data have improved expert understanding, allowing for individualized hormone therapy regimens that optimally balance risk and benefit. This article reviews the available data regarding conventional and newer options for systemic and local hormone therapies.
Systemic Hormone Therapy
Estrogen
Metabolism and Pharmacokinetics
In circulation, roughly 37% of estrogen is bound to sex hormone-binding globulin with high affinity, 61% is bound to albumin with low affinity, and 2% is free.9 Both free estrogen and albumin-bound estrogen are biologically active. Oral estradiol, when used in a microcrystalline form, has rapid absorption and increased bioavailability. After administration of oral estradiol, serum estradiol peaks within 6 hours and is maintained for up 12 hours before starting to slowly decline.9 With 2 mg of oral micronized estradiol, serum estradiol peaks around 40 pg/mL within 24 hours of administration. Over time a steady state is reached, and by day 21 serum estradiol reaches 80 pg/mL.
Oral estrogens undergo first-pass liver metabolism, with conjugated equine estrogen having greater effects on liver protein production compared with estradiol. In the liver, estradiol is converted to estrone and estriol, the major urinary metabolite. Following administration of oral conjugated equine estrogen, conjugated estrogens are hydrolyzed in the gut and small intestine and then converted to active estrogens in the liver and other tissues.9 Because of liver metabolism, higher doses of oral estrogen are needed to achieve therapeutic effects compared with transdermal routes. With aging, women may experience changes in body composition and increased volume of distribution for lipophilic drugs with a reduced volume of distribution for water-soluble drugs. Reduced renal clearance and polypharmacy may also impact drug therapy.10 Therefore, the dosing of hormone therapy may need to be adjusted over time.
Transdermal administration of estradiol circumvents the first-pass metabolism in the liver, providing higher and more stable systemic levels of estradiol (3.5 to 7 days) compared with oral estrogen.11 Sufficient skin permeability is necessary for the delivery and efficacy of transdermal formulations. Transdermal preparations are typically applied to the groin, lower abdomen, buttock, or lower back. After diffusing through the layers of skin, transdermal estradiol permeates capillaries over time based on the concentration gradient between the application site and capillaries.9 The rate of hormone delivery varies by transdermal formulation. Matrix patches contain estradiol dispersed throughout a polymeric acrylate or vinyl acetate adhesive and penetration enhancers.9 Delivery of estradiol is based on the area of the patch, peaks at 12 hours, and steadily decline over 7 days. The average maximal serum estradiol concentration with a 100-μg patch is around 90- 140 pg/mL, with a 50-μg patch is 40-80 pg/mL, and with a 25-μg patch 30-45 pg/mL.9 Reservoir patches deliver hormone through an alcohol gel, with estradiol levels peaking after approximately 30 hours and slowly declining over the course of 3.5 days.9 The average maximal serum estradiol concentration with a 100-μg patch is around 60-110 pg/mL, with a 50-μg patch is 40-60 pg/mL, and with a 25-μg patch is 30-40 pg/mL.9
Estradiol gel is also alcohol-based and leads to the rapid diffusion of estradiol into the stratum corneum until the gel has completely dried. The stored estradiol permeates the remaining skin layers and capillaries based on a concentration gradient over 2-14 hours.9 There are 2 preparations of estradiol gel. The 0.06% estradiol pump system delivers 0.75 mg of estradiol per pump and should be applied to the abdomen, thigh, or upper arm. Serum estradiol peaks around 60-90 pg/mL with a daily dose of 1.5 mg and 100-120 pg/mL with a daily dose of 3 mg.9 The 0.1% estradiol gel formulation delivers 0.25, 0.5, 0.75, 1, or 1.25 mg of estradiol per packet. Serum estradiol reaches a steady state of around 80 pg/mL with a daily dose of 1.5 mg estradiol in 1.5 g of gel.9
A vaginal delivery also bypasses the first-pass metabolism in the liver and allows for rapid absorption of estradiol through the vaginal mucosa. There are 2 doses of estradiol acetate in a silicone elastomer vaginal ring. The 12.4- and 24.8-mg estradiol acetate rings steadily release 0.05 and 0.10 mg of estradiol a day respectively. Serum estradiol rapidly increases, reaching maximal concentrations within 1 hour. Estradiol then decreases after 24-48 hours and remains relatively constant over 3 months. It is important for prescribers to distinguish between the estradiol vaginal ring that delivers systemic estradiol doses (and thus necessitates the use of progestogen in women with an intact uterus) and the low-dose estradiol vaginal ring intended for local treatment of vaginal atrophy (which does not require concurrent progestogen therapy)
Side Effects
Drug-Drug Interactions
Clinical Data
Mortality Data
Cardiometabolic Data
Breast Cancer Data
Mammography Effects
Other Cancers
Bone Health
Bioidentical and Compounded Data
Progestogens
Metabolism and Pharmacokinetics
Metabolism and Pharmacokinetics Like oral estrogens, oral progesterone undergoes hepatic first-pass metabolism and is subject to hydroxylation by cytochrome P450 enzymes.10 The metabolism of synthetic progestogens is not fully understood and may differ based on the class of progestogen. In circulation, progestogens are either free or bound to albumin and/or other transport proteins. Progestogens have a low affinity and high binding capacity for albumin; therefore, these progestogens are considered biologically active. Some progestogens structurally similar to testosterone also have a high affinity and low binding capacity for sex hormone-binding globulin or corticosteroid-binding globulin.10
Orally administered progesterone has 30 or more metabolites including 5α- and 5β-pregnanolone (which has sedating effects), 20-dihydroprogesterone (potent progestogen), 11-deoxycorticosterone (potent mineralocorticoid), and pregnanediol (inactive).9 Oral progesterone micronized in oil has high bioavailability. Oral progestogens reach maximal serum concentrations within 1-3 hours of administration; half-life varies based on progestogen type (shortest is 8 hours with norethindrone up to 32.5 hours with drospirenone).10 Like oral estrogens, the bioavailability of oral progestogens is dependent on cytochrome P450 activity.
Progesterone administered vaginally leads to higher circulating progesterone than oral progesterone.9 Because of the bioadhesive properties of progesterone micronized in oil, vaginal administration leads to a sustained release of progesterone over 24-72 hours.9 Studies have shown that maximal serum concentration rises rapidly with intramuscular administration and is reached gradually via transdermal routes.
Side Effects
Drug-Drug Interactions
Clinical Data
Cardiometabolic Data
Bone
Estrogen Receptor Agonist-Antagonists
Testosterone
There may be a select role for testosterone therapy in postmenopausal women with sexual dysfunction. However, there are currently no FDA-approved testosterone formulations for women.51 Combination oral esterified estrogen (EE) with methyltestosterone (MT)—2 doses of EE 0.625 mg/MT 1.25 and EE 1.25 mg/MT 2.5 mg— was approved prior to the enactment of the FDA’s current safety and efficacy regulations. Oral EEMT is indicated in postmenopausal women with bothersome vasomotor symptoms despite adequate treatment with estrogen-containing hormone therapy. Postmarketing surveillance studies have revealed a few serious adverse events.52 Our discussion will focus on menopausal hormone therapies approved by the FDA.
*Vaginal Estrogen
*Vaginal Dehydroepiandrosterone
*ERAAs for the Treatment of Genitourinary Syndrome of Menopause
Conclusion
For postmenopausal women, the decision to initiate menopausal hormone therapy should be individualized. A thorough evaluation of the patient’s cardiovascular, VTE, cancer, and fracture risk should be considered along with the patient’s quality of life. Menopausal hormone therapy should not be used for the primary prevention of chronic disease. Hormone therapy exerts its therapeutic effects on vasomotor symptoms, the skeleton, and the genitourinary system independent of age because menopause and these benefits are lost once hormone therapy is stopped. The dose, formulation, mode of administration, timing of initiation, and duration of treatment should be optimized to provide the greatest benefit and minimize risk. Based on its potential vascular effects, it is optimal to start systemic hormone therapy within 10 years of menopause. After age 65, hormone therapy does not need to be stopped; rather, the dose may need to be lowered because of changes in metabolism, and consideration to use a transdermal may be given. Vaginal estrogen and vaginal DHEA have few systemic effects and can be safely administered to postmenopausal women with genitourinary syndrome of menopause despite age.
Taryn Smith, MD, NCMP, Sabrina Sahni, MD, NCMP, and Holly L. Thacker, MD, FACP, CCD, NCMP
Abstract
Every woman, if she lives long enough, will transition into menopause, and as the US population ages, women will be spending more time in a postmenopausal state than before. For postmenopausal women, the decision to initiate menopausal hormone therapy should be individualized. A thorough evaluation of the patient’s cardiovascular, venous thromboembolic, cancer, and fracture risk should be considered along with the woman’s quality of life. Hormone therapy exerts its therapeutic effects on vasomotor symptoms, the skeleton, and the genitourinary system independent of age since menopause, and these benefits are lost once hormone therapy is stopped. Here we review the pharmacologic properties of dose, formulation, mode of administration, the timing of initiation, and duration of hormonal therapies in regard to optimizing benefit and minimizing risk to the patient. This discussion will focus on the effects of common hormonal therapies including estrogen (local and systemic), progesterone, estrogen receptor agonist/antagonist, and local dehydroepiandrosterone, and include a brief review of compounded bioidentical hormone therapy.
Every woman, if she lives long enough, will transition into menopause. According to the North American Menopause Society (NAMS), roughly 6000 US women transition to menopause each day. It has been estimated that >50 million women will be postmenopausal in 2020,1 and as the US population ages, women will be spending more time in a postmenopausal state than before. In addition to bothersome vasomotor symptoms, postmenopausal women are at greater risk for genitourinary and sexual dysfunction, cognitive decline, cardiovascular disease, and significant bone loss.2 Hormone therapy has repeatedly been shown to be the most effective treatment for problematic vasomotor symptoms of menopause while significantly decreasing the risk of postmenopausal bone loss.3 However, following the Women’s Health Initiative (WHI) trials, many questions regarding the safety of hormone therapy have arisen. The WHI trials were conducted to evaluate the risks and benefits of hormone therapy taken for primary prevention of chronic diseases among postmenopausal women, whose average age was 63 years.4 Women were stratified to either combined conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg if they had a uterus and conjugated equine estrogen alone if they had had a hysterectomy. The conjugated equine estrogen plus MPA arm was terminated after 5.6 years because of increased risk of breast cancer, whereas the conjugated equine estrogen-only arm was terminated after 7.2 years because of increased stroke risk.4 The results of the WHI trials cannot be applied to other hormone regimens, as each arm of the trials evaluated a single dose and formulation of orally administered hormone therapy. Since the publication of the WHI trials, experts have investigated how hormone therapy formulation, the timing of administration, mode of hormone therapy delivery, and combination of hormones used to impact a woman’s risk. New data have improved expert understanding, allowing for individualized hormone therapy regimens that optimally balance risk and benefit. This article reviews the available data regarding conventional and newer options for systemic and local hormone therapies.
Systemic Hormone Therapy
Estrogen
Metabolism and Pharmacokinetics
In circulation, roughly 37% of estrogen is bound to sex hormone-binding globulin with high affinity, 61% is bound to albumin with low affinity, and 2% is free.9 Both free estrogen and albumin-bound estrogen are biologically active. Oral estradiol, when used in a microcrystalline form, has rapid absorption and increased bioavailability. After administration of oral estradiol, serum estradiol peaks within 6 hours and is maintained for up 12 hours before starting to slowly decline.9 With 2 mg of oral micronized estradiol, serum estradiol peaks around 40 pg/mL within 24 hours of administration. Over time a steady state is reached, and by day 21 serum estradiol reaches 80 pg/mL.
Oral estrogens undergo first-pass liver metabolism, with conjugated equine estrogen having greater effects on liver protein production compared with estradiol. In the liver, estradiol is converted to estrone and estriol, the major urinary metabolite. Following administration of oral conjugated equine estrogen, conjugated estrogens are hydrolyzed in the gut and small intestine and then converted to active estrogens in the liver and other tissues.9 Because of liver metabolism, higher doses of oral estrogen are needed to achieve therapeutic effects compared with transdermal routes. With aging, women may experience changes in body composition and increased volume of distribution for lipophilic drugs with a reduced volume of distribution for water-soluble drugs. Reduced renal clearance and polypharmacy may also impact drug therapy.10 Therefore, the dosing of hormone therapy may need to be adjusted over time.
Transdermal administration of estradiol circumvents the first-pass metabolism in the liver, providing higher and more stable systemic levels of estradiol (3.5 to 7 days) compared with oral estrogen.11 Sufficient skin permeability is necessary for the delivery and efficacy of transdermal formulations. Transdermal preparations are typically applied to the groin, lower abdomen, buttock, or lower back. After diffusing through the layers of skin, transdermal estradiol permeates capillaries over time based on the concentration gradient between the application site and capillaries.9 The rate of hormone delivery varies by transdermal formulation. Matrix patches contain estradiol dispersed throughout a polymeric acrylate or vinyl acetate adhesive and penetration enhancers.9 Delivery of estradiol is based on the area of the patch, peaks at 12 hours, and steadily decline over 7 days. The average maximal serum estradiol concentration with a 100-μg patch is around 90- 140 pg/mL, with a 50-μg patch is 40-80 pg/mL, and with a 25-μg patch 30-45 pg/mL.9 Reservoir patches deliver hormone through an alcohol gel, with estradiol levels peaking after approximately 30 hours and slowly declining over the course of 3.5 days.9 The average maximal serum estradiol concentration with a 100-μg patch is around 60-110 pg/mL, with a 50-μg patch is 40-60 pg/mL, and with a 25-μg patch is 30-40 pg/mL.9
Estradiol gel is also alcohol-based and leads to the rapid diffusion of estradiol into the stratum corneum until the gel has completely dried. The stored estradiol permeates the remaining skin layers and capillaries based on a concentration gradient over 2-14 hours.9 There are 2 preparations of estradiol gel. The 0.06% estradiol pump system delivers 0.75 mg of estradiol per pump and should be applied to the abdomen, thigh, or upper arm. Serum estradiol peaks around 60-90 pg/mL with a daily dose of 1.5 mg and 100-120 pg/mL with a daily dose of 3 mg.9 The 0.1% estradiol gel formulation delivers 0.25, 0.5, 0.75, 1, or 1.25 mg of estradiol per packet. Serum estradiol reaches a steady state of around 80 pg/mL with a daily dose of 1.5 mg estradiol in 1.5 g of gel.9
A vaginal delivery also bypasses the first-pass metabolism in the liver and allows for rapid absorption of estradiol through the vaginal mucosa. There are 2 doses of estradiol acetate in a silicone elastomer vaginal ring. The 12.4- and 24.8-mg estradiol acetate rings steadily release 0.05 and 0.10 mg of estradiol a day respectively. Serum estradiol rapidly increases, reaching maximal concentrations within 1 hour. Estradiol then decreases after 24-48 hours and remains relatively constant over 3 months. It is important for prescribers to distinguish between the estradiol vaginal ring that delivers systemic estradiol doses (and thus necessitates the use of progestogen in women with an intact uterus) and the low-dose estradiol vaginal ring intended for local treatment of vaginal atrophy (which does not require concurrent progestogen therapy)
Side Effects
Drug-Drug Interactions
Clinical Data
Mortality Data
Cardiometabolic Data
Breast Cancer Data
Mammography Effects
Other Cancers
Bone Health
Bioidentical and Compounded Data
Progestogens
Metabolism and Pharmacokinetics
Metabolism and Pharmacokinetics Like oral estrogens, oral progesterone undergoes hepatic first-pass metabolism and is subject to hydroxylation by cytochrome P450 enzymes.10 The metabolism of synthetic progestogens is not fully understood and may differ based on the class of progestogen. In circulation, progestogens are either free or bound to albumin and/or other transport proteins. Progestogens have a low affinity and high binding capacity for albumin; therefore, these progestogens are considered biologically active. Some progestogens structurally similar to testosterone also have a high affinity and low binding capacity for sex hormone-binding globulin or corticosteroid-binding globulin.10
Orally administered progesterone has 30 or more metabolites including 5α- and 5β-pregnanolone (which has sedating effects), 20-dihydroprogesterone (potent progestogen), 11-deoxycorticosterone (potent mineralocorticoid), and pregnanediol (inactive).9 Oral progesterone micronized in oil has high bioavailability. Oral progestogens reach maximal serum concentrations within 1-3 hours of administration; half-life varies based on progestogen type (shortest is 8 hours with norethindrone up to 32.5 hours with drospirenone).10 Like oral estrogens, the bioavailability of oral progestogens is dependent on cytochrome P450 activity.
Progesterone administered vaginally leads to higher circulating progesterone than oral progesterone.9 Because of the bioadhesive properties of progesterone micronized in oil, vaginal administration leads to a sustained release of progesterone over 24-72 hours.9 Studies have shown that maximal serum concentration rises rapidly with intramuscular administration and is reached gradually via transdermal routes.
Side Effects
Drug-Drug Interactions
Clinical Data
Cardiometabolic Data
Bone
Estrogen Receptor Agonist-Antagonists
Testosterone
There may be a select role for testosterone therapy in postmenopausal women with sexual dysfunction. However, there are currently no FDA-approved testosterone formulations for women.51 Combination oral esterified estrogen (EE) with methyltestosterone (MT)—2 doses of EE 0.625 mg/MT 1.25 and EE 1.25 mg/MT 2.5 mg— was approved prior to the enactment of the FDA’s current safety and efficacy regulations. Oral EEMT is indicated in postmenopausal women with bothersome vasomotor symptoms despite adequate treatment with estrogen-containing hormone therapy. Postmarketing surveillance studies have revealed a few serious adverse events.52 Our discussion will focus on menopausal hormone therapies approved by the FDA.
*Vaginal Estrogen
*Vaginal Dehydroepiandrosterone
*ERAAs for the Treatment of Genitourinary Syndrome of Menopause
Conclusion
For postmenopausal women, the decision to initiate menopausal hormone therapy should be individualized. A thorough evaluation of the patient’s cardiovascular, VTE, cancer, and fracture risk should be considered along with the patient’s quality of life. Menopausal hormone therapy should not be used for the primary prevention of chronic disease. Hormone therapy exerts its therapeutic effects on vasomotor symptoms, the skeleton, and the genitourinary system independent of age because menopause and these benefits are lost once hormone therapy is stopped. The dose, formulation, mode of administration, timing of initiation, and duration of treatment should be optimized to provide the greatest benefit and minimize risk. Based on its potential vascular effects, it is optimal to start systemic hormone therapy within 10 years of menopause. After age 65, hormone therapy does not need to be stopped; rather, the dose may need to be lowered because of changes in metabolism, and consideration to use a transdermal may be given. Vaginal estrogen and vaginal DHEA have few systemic effects and can be safely administered to postmenopausal women with genitourinary syndrome of menopause despite age.
