FEMALE HORMONE MEDICATIONS

• ACRONYMS AND DEFINITIONS

• DVT - Deep vein thrombosis
• EE - Ethinyl estradiol
• HRT - Hormone replacement therapy
• PE - Pulmonary embolism
• PI - Prescribing information
• RCT - Randomized controlled trial
• SERM - Selective estrogen receptor modulator
• SPAQI - Society for Perioperative Assessment and Quality Improvement
• VTE - Venous Thromboembolism (DVT and PE)

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• ESTROGEN GELS

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• ESTROGEN INJECTIONS

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• ESTROGEN PATCHES

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• ESTROGEN PILLS

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• ESTROGEN SPRAYS

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• ESTROGEN CREAMS

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• ESTROGEN VAGINAL INSERTS

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• INTRAROSA VAGINAL INSERT

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• PROGESTIN GEL

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• PROGESTIN TABLETS

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• ESTROGEN + PROGESTIN PILLS

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• ESTROGEN + PROGESTIN PATCHES

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• Information is from the Premarin PI
• Information is for the 0.625 mg/day dose in women who had a uterus
• Only side effects that occurred at an incidence ≥ 2% more than placebo are listed

Estrogen side effects
Side effect	Premarin 0.625 mg/day	Placebo
Vaginal hemorrhage	13%	0%
Abdominal pain	11%	6%
Breast pain	11%	8%
Flatulence	6%	2%
Endometrial hyperplasia	5%	0%
Vaginitis	5%	0%
Weakness	5%	1%
Back pain	5%	1%
White or yellow vaginal discharge	5%	2%
Yeast infection	4%	2%
Metrorrhagia (menstrual bleeding at irregular intervals)	3%	0%
Uterine spasm	3%	1%
Pelvic pain	3%	1%
Leg cramps	3%	1%
Itching	3%	1%
Dysmenorrhea (painful menses)	3%	1%
Cervix disorder	2%	0%

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• Estrogens are contraindicated in the following conditions:
• Undiagnosed abnormal genital bleeding
• Known, suspected, or history of breast cancer
• Known or suspected estrogen-dependent neoplasia
• Active deep vein thrombosis (DVT), pulmonary embolism (PE), or a history of these conditions (See hormone therapy during anticoagulation for VTE for more on this topic)
• Active or recent arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
• Know hypersensitivity
• Known liver impairment or disease
• Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
• Known or suspected pregnancy

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• ESTROGEN PRECAUTIONS

• Women's Health Initiative (WHI) study
• The WHI study was a large (over 27,000 subjects), randomized controlled trial that evaluated the long-term risks of hormone replacement therapy in postmenopausal women. The study had two arms. In one arm, women with a uterus were randomized to Prempro® or placebo. In the other arm, women who had no uterus were randomized to Premarin® or placebo.
• The study measured a number of outcomes, and they are presented in our WHI study results tables


• Estrogen therapy
• Women with a uterus - estrogen therapy increases the risk of endometrial hyperplasia. Progestins reduce the risk. In general, women with a uterus who are taking estrogens should receive a progestin either daily in a continuous regimen or for 10 days out of the cycle in cyclical regimens. Women without a uterus (s/p hysterectomy) do not need a progestin.
• Endometrial cancer - unopposed estrogen therapy increases the risk of endometrial cancer. Adding a progestin may help reduce the risk.
• Stroke - in the WHI study, estrogen therapy increased the risk of stroke
• Deep vein thrombosis (DVT) - in the WHI study, estrogen therapy increased the risk of deep vein thrombosis (DVT)
• Gallbladder disease - estrogen therapy may increase the risk of gallbladder disease
• Surgery and immobilization - the prescribing information for estrogen products states that they should be discontinued at least 4 - 6 weeks before surgery that is associated with an increased risk of thromboembolism or during periods of prolonged immobilization. Guidelines from SPAQI state that it is okay to continue them before surgery (see preoperative medication management).
• Hypothyroidism - estrogens increase levels of thyroid-binding globulin. Women with normal thyroid function can compensate by making more thyroid hormone. Women with hypothyroidism may require an increase in levothyroxine dosage.
• Retinal vascular thrombosis - has been reported in women taking estrogens. Discontinue medication if sudden visual changes occur.
• Plasma lipids - estrogens may raise triglyceride and HDL levels while decreasing LDL levels
• Hypertriglyceridemia - estrogens may raise triglyceride levels. Use caution in patients with elevated triglycerides, particularly those with severe elevations as they can lead to pancreatitis.
• Liver disease - estrogen levels may be increased. Estrogens may exacerbate cholestatic jaundice in susceptible women.
• Fluid retention - estrogens may cause fluid retention. Use caution in susceptible patients (e.g. kidney failure, heart failure).
• Hypocalcemia - estrogens may worsen hypocalcemia in women with hypoparathyroidism
• Hypercalcemia - estrogens may cause severe hypercalcemia in women with breast cancer and bone metastases
• Elevated blood pressure - estrogens may raise blood pressure in some patients
• Endometriosis - estrogens may exacerbate endometriosis. For women with residual endometriosis s/p hysterectomy, consider addition of a progestin.
• Hereditary angioedema - estrogens may exacerbate hereditary angioedema
• Exacerbation of other conditions - estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas
• Dementia - in an ancillary study of the Women's Health Initiative Study, estrogen-treated women had a higher risk of dementia than placebo-treated women, but the risk was not statistically significant. The absolute risk of probable dementia for estrogen versus placebo was 37 versus 25 cases per 10,000 women-years.
• Platelets and clotting factors - estrogens may increase levels and activity of platelets and clotting factors
• Binding proteins - estrogens may increase levels of binding proteins (e.g. corticosteroid binding globulin, sex hormone-binding globulin). Other plasma proteins may also be increased (e.g. angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin)
• Photosensitivity - estrogens may cause photosensitivity. Limit sun exposure and/or wear sunscreen to help prevent reactions.

• Estrogen + progestin therapy
• Pulmonary embolism (PE) - in the WHI study, estrogen + progestin therapy increased the risk of pulmonary embolism
• Myocardial infarction - in the WHI study, women taking estrogen + progestin therapy had a borderline nonsignificant increase in risk of myocardial infarction
• Dementia - in an ancillary study of the Women's Health Initiative Study, estrogen+progestin-treated women had a significantly higher risk of dementia than placebo-treated women. The absolute risk of probable dementia for estrogen+progestin versus placebo was 45 versus 22 cases per 10,000 women-years.
• Invasive breast cancer - in the WHI study, estrogen + progestin therapy increased the risk of developing invasive breast cancer
• Ovarian cancer - observational studies have found an increased risk of ovarian cancer in women using HRT. In the WHI study, women in the estrogen/progestin arm had a higher incidence of ovarian cancer when compared to placebo (4.2 versus 2.7 cases per 10,000 women-years). The difference was not statistically significant.

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• ESTROGEN DRUG INTERACTIONS

• CYP3A4 inducers and inhibitors - estrogens are partially metabolized by CYP3A4. CYP3A4 inducers may decrease estrogen levels and CYP3A4 inhibitors may increase estrogen levels.
• Technivie® (ombitasvir, paritaprevir, and ritonavir)
• Drugs with ethinyl estradiol (e.g. Femhrt, Jevantique, Fyavolv, Jinteli) should not be taken with the hepatitis C drug Technivie
• ALT elevations > 5 - 20 ULN have been seen in some patients
• Viekira-Pak™ (ombitasvir, paritaprevir, ritonavir, and dasabuvir)
• Drugs with ethinyl estradiol (e.g. Femhrt, Jevantique, Fyavolv, Jinteli) should not be taken with the hepatitis C drug Viekira Pak
• ALT elevations > 5 - 20 ULN have been seen in some patients

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• PROGESTIN SIDE EFFECTS

• NOTE: the incidence of side effects from progesterone and progestins is not well-defined. Information below is from the Provera PI.

• Genitourinary system
• Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions
• Breasts
• Breast tenderness, mastodynia or galactorrhea has been reported
• Cardiovascular
• Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported
• Gastrointestinal
• Nausea, cholestatic jaundice
• Skin
• Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported.
• Eyes
• Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis
• Central nervous system
• Mental depression, insomnia, somnolence, dizziness, headache, nervousness
• Miscellaneous
• Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance.

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• Progestins are contraindicated in the following conditions:
• PEANUT ALLERGY (Prometrium®) - Prometrium capsules contain peanut oil
• Undiagnosed abnormal genital bleeding
• Known, suspected, or history of breast cancer
• Known or suspected estrogen- or progesterone-dependent neoplasia
• Active deep vein thrombosis (DVT), pulmonary embolism (PE), or a history of these conditions (See hormone therapy during anticoagulation for VTE for more on this topic)
• Active or recent arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
• Know hypersensitivity
• Known liver impairment or disease
• Known or suspected pregnancy

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• PROGESTIN PRECAUTIONS

• Women's Health Initiative (WHI) study
• The WHI study was a large (over 27,000 subjects), randomized controlled trial that evaluated the long-term risks of hormone replacement therapy in postmenopausal women. The study had two arms. In one arm, women with a uterus were randomized to Prempro® or placebo. In the other arm, women who had no uterus were randomized to Premarin® or placebo.
• The study measured a number of outcomes, and they are presented in our WHI study results tables

• Progestin therapy
• Women with a uterus - estrogen therapy increases the risk of endometrial hyperplasia. Progestins reduce the risk. In general, women with a uterus who are taking estrogens should receive a progestin either daily in a continuous regimen or for 10 days out of the cycle in cyclical regimens. Women without a uterus (s/p hysterectomy) do not need a progestin.
• Endometrial cancer - unopposed estrogen therapy increases the risk of endometrial cancer. Adding a progestin may help reduce the risk.
• Stroke - in the WHI study, women taking Prempro (conjugated estrogens + medroxyprogesterone) had an increased risk of stroke when compared to placebo. The risk of stroke was also increased in women who took conjugated estrogens only. The strength of association between stroke and progesterone is unknown.
• Deep vein thrombosis (DVT) - in the WHI study, women taking Prempro (conjugated estrogens + medroxyprogesterone) had an increased risk of DVT when compared to placebo. The risk of DVT was also increased in women who took conjugated estrogens only. The strength of association between DVT and progesterone is unknown.
• Pulmonary embolism (PE) - in the WHI study, women taking Prempro (conjugated estrogens + medroxyprogesterone) had an increased risk of PE when compared to placebo. The strength of association between PE and progesterone is unknown.
• Dementia - in the WHI study, women ≥ 65 years old taking Prempro (conjugated estrogens + medroxyprogesterone) had an increased risk of probable dementia when compared to placebo. The strength of association between dementia and progesterone is unknown.
• Invasive breast cancer - in the WHI study, women taking Prempro (conjugated estrogens + medroxyprogesterone) had an increased risk of invasive breast cancer when compared to placebo. The risk of invasive breast cancer was not increased in women who took conjugated estrogens only. The strength of association between invasive breast cancer and progesterone is unknown.
• Heart attack - in the WHI study, women taking Prempro (conjugated estrogens + medroxyprogesterone) had a borderline nonsignificant increased risk of heart attack when compared to placebo. The strength of association between heart attack risk and progesterone is unknown.
• Endometriosis - estrogens may exacerbate endometriosis. For women with residual endometriosis s/p hysterectomy, consider addition of a progestin.
• Hypothyroidism - estrogen + progestin therapy may increase levels of thyroid-binding globulin. Women with normal thyroid function can compensate by making more thyroid hormone. Women with hypothyroidism may require an increase in levothyroxine dosage.
• Elevated blood pressure - progestins may raise blood pressure in some patients
• Plasma lipids - progestins may raise triglyceride and HDL levels while decreasing LDL levels
• Liver disease - progestin levels may be increased
• Fluid retention - progestins may cause fluid retention. Use caution in susceptible patients (e.g. kidney failure, heart failure).
• Exacerbation of other conditions - estrogen + progestin therapy may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas
• Platelets and clotting factors - estrogen + progestin therapy may increase levels and activity of platelets and clotting factors
• Binding proteins - estrogen + progestin therapy may increase levels of binding proteins (e.g. corticosteroid binding globulin, sex hormone-binding globulin). Other plasma proteins may be increased (e.g. angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin)

• Progestin + estrogen therapy
• Pulmonary embolism (PE) - in the WHI study, estrogen + progestin therapy increased the risk of pulmonary embolism
• Myocardial infarction - in the WHI study, women taking estrogen + progestin therapy had a borderline nonsignificant increase in risk of myocardial infarction
• Dementia - in the WHI study, estrogen + progestin therapy increased the risk of developing probable dementia in women ≥ 65 years old
• Invasive breast cancer - in the WHI study, estrogen + progestin therapy increased the risk of developing invasive breast cancer
• Ovarian cancer - observational studies have found an increased risk of ovarian cancer in women using HRT. In the WHI study, women in the estrogen/progestin arm had a higher incidence of ovarian cancer when compared to placebo (4.2 versus 2.7 cases per 10,000 women-years). The difference was not statistically significant.

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• PROGESTIN DRUG INTERACTIONS

• CYP3A4 inducers and inhibitors - progestins are metabolized by CYP3A4. CYP3A4 inducers may decrease progestin levels and CYP3A4 inhibitors may increase progestin levels.

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• DROSPIRENONE

• Overview
• Angeliq contains the progestin drospirenone. Drospirenone has antialdosterone properties which means it may contribute to hyperkalemia when taken by itself and/or when combined with other potassium-raising medications.


• Contraindications
• Angeliq is contraindicated in women with kidney or liver impairment. It is also contraindicated in women with adrenal insufficiency.


• Drug interactions
• CYP3A4 strong inhibitors - Use caution and consider monitoring potassium levels when taking Angeliq with strong CYP3A4 inhibitors
• Drugs that may raise potassium - Angeliq may raise potassium levels when taken with other drugs that raise potassium such as ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists, and NSAIDs. In studies involving postmenopausal women who were taking ACE inhibitors or ARBs, drospirenone 3 mg once daily for a month raised potassium levels an average of 0.11 mEq/L while placebo-treated patients saw an average increase of 0.08 mEq/L.

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• STUDIES

• STUDY
  Vaginal Estradiol vs Vaginal Moisturizer vs Placebo for Postmenopausal Vulvovaginal Symptoms, JAMA Intern Med (2018) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=302, length = 12 weeks) in postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration
• Treatment: Vaginal 10-μg estradiol tablet (Vagifem®) vs Vaginal Moisturizer vs Placebo gel/tablet
• Primary outcome: The main outcome was decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks
• Results:
• Primary outcome (decrease in MBS score): Vaginal tablet - 1.4, Moisturizer - 1.2, Placebo - 1.3 (1 vs 3 p=0.25 | 2 vs 3 p=0.31)
• Findings: Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms.

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• PRICE ($) INFO

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• BIBLIOGRAPHY

• 1 - Package insert for drug unless otherwise specified
• 2 - PMID 25423325 - SERM MOA
• 3 - PMID 26254516 - ACOG abnl bleeding GL
• 4 - PMID 28650869 - The 2017 hormone therapy position statement of The North American Menopause Society - Menopause (2017)