Michael J. Koronkowski, Pharm.D.
Spring 1998
Michael J. Koronkowski, Pharm.D.
Spring 1998
Menopause, Osteoporosis, and Hormone Replacement Therapy
Assigned Readings:
Recommended Reading:
Learning Objectives: Upon completion of the required readings the student should be able to:
World Wide Web Resources:
1. National Osteoporosis Foundation
I. The Female Reproductive System and Aging
A. Definitions (WHO, 1981)
1. Menopause - the permanent cessation of menstruation resulting from a loss ovarian follicular activity.
2. Perimenpause - the period immediately prior to and at least 1 year after the menopause, characterized by physiologic and clinical features of ovarian involution.
3. Postmenopause - the period of life remaining after the menopause.
4. Premenopause - an ambiguous term used to describe the 1 to 2 years prior to the menopause.
B. Estrogen Formation
1. Premenopausal, ovulatory women
a. 17-beta estradiol - primary estrogen
- 90% produced by the ovaries
- 10% peripheral conversion of estrone and testosterone
b. Estrone - less potent
- 75-90% from the peripheral conversion of androstenedione and estradiol
- 10-25% from the adrenal gland
- small amount form the ovaries
c. Estriol - weak
- primarily from the metabolism of estradiol
2. Menopausal/postmenopausal women
a. 17-beta estradiol production decreases to >90% of premenopausal rate
b. Estrone - predominant hormone
- production decreases to 33% of the pre-menopausal rate
- principal source is the conversion of
- androstenedione the adrenals
c. overall effect
- negligible estradiol production
- estrone is the dominant estrogen
- increased ovarian testosterone secretion
- a relative greater decrease in estrogen than androgen concentrations
- a positive shift in the ratio of androgens to estrogens
C. Epidemiology
1. In 1975, the median age of women in the U.S. was 30 years and there were 36 million women >45.
2. In the year 2000, the median age of women is projected to 36 years, totaling 49 million >45.
3. The mean age for menopause in modern western civilization is 50 ± 4 years (42-58)
4. Only since 1900 has the average female life expectancy exceeded the age of menopause, hence the complications associated with the postmenopausal period are new to medicine.
II. Clinical Symptomatology of the Postmenopausal Period
A. Vasomotor Symptoms ("hot flushes")
1. Prevalence - up to 75% of all postmenopausal women, only 45% seek medical treatment. The FDA estimates that of the 4 million women without ovarian function only 10% receive treatment.
2. Occurs early in the menopause/post-menopause period and can occur in the peri-menopausal period.
3. Strong sensation of warmth, skin irritation, and perspiration beginning in the upper thorax and neck, spreading to the face and arms which last a few seconds to minutes
4. Self-limited, with spontaneous resolution in 1-5 years
5. Associated with decreased estrogen levels. It is postulated that the hypothalamic temperature set point is decreased resulting in heat loss and a drop in body core temperature. This may be the result of pulsatile luteinizing hormone release.
6. Treatment
Low dose oral or transdermal estrogen therapy decreases the number of episodes per week.(see attached table)
Clonidine 0.1 to 2mg bid has been shown to decrease the number, severity, and duration of flashes compared to placebo. Its mechanism may involve a decrease in norepinephrine stimulation at the thermoregulatory center and a decrease in norepinephrine stimulation of gonadotropin releasing hormone in the anterior hypothalamus and a subsequent decrease in luteinizin hormone release.
B. Atrophic vaginitis
1. The vaginal epithelium relies on estrogen to maintain its thickness and adequate glycogen production to maintain vaginal acidity.
2. With a decrease in estrogen, over several years the vaginal wall thins and the vagina atrophies
3. Symptoms - vaginal irritation, itching, discharge
4. Treatment - low dose estrogen (see attached table)
a. oral or transdermal estrogen therapy is preferred because insertion of an applicator into the vagina may be painful and the cream can melt and soil undergarments. Because these tissues are so estrogen sensitive, the duration of treatment can be as short as 3 months. Repeated treatments may be necessary as needed.
C. Trigonitis (Atrophic Cystoureteritis, Stress Incontinence)
1. The base of the bladder and the proximal urethra are estrogen-dependent tissues and with a loss of estrogen the tissues atrophy
2. Symptoms include: urgency, frequency, incontinence
3. Treatment low dose estrogens (see attached table )
Oral or transdermal estrogen therapy is preferred because insertion of the applicator into the vagina may be painful and the cream can melt and soil undergarments. Because these tissues are so estrogen sensitive, the duration of treatment can be as short as 3 months. Repeated treatments may be necessary as needed.
III. Osteoporosis (see assigned reading)
A. Introduction
1. Definition - an absolute decrease in the amount of bone leading to fractures after minimal trauma. [Bone resorption > Bone formation]
- Affects 15 million men and women
- 1.2 fractures in the U.S. per year
- Cost - 6.1 billion in U.S. per year
B. Clinical Features
1. Patients present with bone pain, fractures, loss of height
| FRACTURE SITE ..................................FRACTURE #/YEAR | |
| Vertebrae | 538,000 |
| Hip | 227,000 |
| Colle’s (lower radius) | 172,000 |
| Other | 283,000 |
C. Risk Factors for Osteoporosis
- Age
- Female Gender
- Amenorrhea (premature menopause, oophorectomy, secondary amenorrhea)
- Family History
- Race (white or Oriental)
- Low lifelong calcium intake (including lactosse intolerence)
- Thin body habitus
- Sedentary life-style or immobilization
- Smoking
- Alcoholism
- Protein calorie malnutrition
- Gastrectomy
- Drugs (glucocorticoids, aluminum antacids, heparin, phenytion, isoniazid)
D. Age-Related Bone Loss - (see assigned reading)
1. Types of bone
a. Cortical - shafts of the long bone
slow loss begins at 40 for both men and women
b. Trabecular - vertebrae, pelvis, flat bones and the end of long bones
loss begins at age 30 for both men and women
E. Management of Osteoporosis
1. Estrogens (see table for doses)
a. Summary of the effects of estrogens
- decreases bone resorption
- alters sensitivity of bone to PTH
- administration will improve calcium balance
- is associated with slowing cortical bone loss
- long term use may increase bone mass
Risks versus benefits associated with estrogen therapy
(1) Endometrial cancer - unopposed estrogen therapy has been shown to increase the risk of endometrial cancer 2-10 fold. The amount of risk is dependent on dose and duration or therapy and does not decrease after exposure-free periods of up to 4 years. Cycling with a progesterone reduces the risk of endometrial cancer below that of postmenopausal women never exposed to estrogen therapy. Women should be warned of withdrawal bleeding.
(2) Breast cancer - a history of breast cancer is a definite contraindication to estrogen therapy. A controversial topic that fluctuates between pro and con. A recent meta-analysis of 16 studies found that the use estrogens by postmenopausal women did not increase the risk of breast cancer until after at least 5 years of exposure. After 15 years of exposure the risk increased 30% and was largely due to studies that used women who took estradiol or who were perimenopausal
(3) Fibrocyctic breast disease - has been increase in postmenopausal women exposed to estrogens
(4) Cardiovascular disease - Perhaps the greatest benefit and potential use of postmenopausal estrogen therapy will be the prevention in the advancement of coronary artery disease. Ten year survival in postmenopausal women with existing coronary artery disease on coronary angiography has been reported to be significantly greater in women who had ever used estrogen therapy. Five year survival was only significantly longer in women with 70% coronary stenosis who had ever used estrogen after menopause. Several studies have found about a 50% reduction in the risk of major coronary artery disease in current estrogen users and this effect appears to be independent of duration of use.
(5) Hypertension should not be considered contraindication to estrogen therapy. Estrogen use does not increase an individuals risk for hypertension. Estrogens can increase renin substrate resulting in sodium and water retention in some women. Since there is no way to predict which individuals will increase their renin substrate, blood pressure should be monitored. Women who develop hypertension believed to be secondary to oral estrogen therapy can be tried on transdermal estrogen since one study did not demonstrate an increase in blood pressure with this dose deliver system.
(6) The risk of stroke is known to be increased in women who take oral contraceptives, especially in smokers. The Framingham Study found that nonsmoking estrogen users were at decreased risk for cardiovascular disease, but increased risk for stroke. Conversely, estrogen users who smoked were at an increased risk for cardiovascular disease, but decreased risk for stroke. An explanation of this finding is that estrogen stimulates thrombus formation and smoking accelerates the hepatic metabolism of estrogen resulting in lower estrogen concentrations. A recent 10 year follow-up study of postmenopausal nurses reported that estrogen use did not affect the risk for stroke; risks for smokers and nonsmokers were not reported.
(7) Gallbladder disease was reported to be increased 2.5 fold in estrogen users compared to nonusers in the Boston Collaborative Drug Surveillance Program. These findings have been refuted by another study. In theory, estrogens could increase the risk for gallstone formation since they decrease the solubility of cholesterol. To date, the association between estrogen use and gallbladder disease is unclear and it should not stand as a contradiction to their use.
(8) Effect on lipids. Oral doses of 0.625mg and 1.25mg of conjugated estrogen and 2mg of estradiol have been shown to decrease serum cholesterol and LDL, and increase HDL and TG (see table below). These changes may protect postmenopausal women from arteriosclerosis an coronary artery disease. The decrease in LDL levels are a result of accelerated LDL catabolism while the increase in TG is secondary to the increased production of VLDL
Drug Cholesterol HDL LDL VLDL TG Estrogens: Conjugated Estrogen (po) ¯ ¯ Ethinyl Estradiol (po) ¯ ¯ Ethinyl Estradiol (patch) has not been shown to significantly affect lipids Progesterones@ 1 / 1 / ¯ 1 / 1 1 / ¯
@ - information of progesterones extrapolated from combination studies, the effects may vary dependent on the type of progesterone used.
C. Monitoring Estrogen Safety
(1) Self-breast exams
(2) Clinical breast exams
(3) Mammogram - baseline, then every 18 - 24 months
(4) Endometrial surveillance (PAP smear)
Unopposed estrogen in a women with a uterus.Baseline, then every 2 years indefinitely, even if therapy is discontinued.
Combination: estrogen-progesterone. Baseline, then repeat only in the absence of scheduled bleeding.
2. Calcium loss - prevention
a. Primary target population is women, especially young women
b. RDA = 800mg /day
* for adolescents 1500mg/day of elemental calcium
* for adults 800mg/day
* for postmenopausal women 1000 - 1500mg/day
c. Replacement is associated with improved calcium balance
d. Replacement has been shown to reduce fracture rates in some studies
e. Replacement has not been shown to increase bone mass
3. Sodium fluoride - 40 to 80 mg/day in divided doses
a. has been shown to increase trabecular-bone density in the axial skeleton
b. direct stimulation of osteoblasts to from fluorapatite which is not as strong as hydroxyapatite.
c. 50% of Fl-treated patients respond by increasing bone mass, 25% have an incomplete response, and 25% no response.
d. adverse effects limit its use
g.i. irritation in 30%
lower-extremity pain syndrome in 10%
e. Current status - Despite showing an increase in bone mass in the lumbar spine, femoral neck and trochanter, the number of vertebral fractures were similar compared to controls and the number of nonvertebra fractures in the sodium fluoride treated patients were 3 times more commo compared to controls. In addition, the gi irritation and pain syndrome liimits its use. Sodium fluoride to date, has been a disappointment. However, experimentation with alternative salt formulations (i.e. sodium monoflourophospahate) in combination with calcium supplementation may show promise.
4. Biphosphonates
Etidronate, a diphosphonate, reduces bone reabsorption by inhibiting osteoclast activity. Intermittent cyclic therapy for 150 weeks has been shown to significantly increase vertebral bone mineral content compared to placebo. A significant lower fracture rate from weeks 60 to 150 was found. However, data from another study by Watts et al., found an initial decrease in fractures and an increase in bone mass over the first 2 years. However, the 3rd year of study found a 50% increase in new vertebral fractures.
Several questions must be answered before etidronate can be recommends for treatment of osteoporosis
1) Is the new bone weaker or more brittle than normal bone?
2) Does the long-term cyclic therapy have a deleterious effects on bone architecture?
3 ) How long must cyclic therapy be continued? A lifetime?
Note: 9/95 the FDA approved alendronate sodium (Fosamax) for the treatment of osteoporosis in postmenopausal women
- alendronate sodium (Fosamax)
- dosing - 10mg po qd (one a day, every day)
- must be taken on an empty stomach - poor bioavailability
- avoid lying down for at least 30 minutes following administration - esophageal irritation
- to be used in combination with calcium supplementation
5. Calcitonin - FDA approval 10/95 refer to reading for background and clinical effectiveness.
Indications for Use and Dosing of Postmenopausal Hormonal Replacement Therapy
Estrogens:
Moderate to Severe Vasomotor Symptoms Associated with Menopause: Administration: Continuous estrogen dosing with or without progesterone with the lowest estrogen dose for 5 years.
Oral Agents:
- Conjugated Estrogens 0.3-1.25mg/day
- Estradiol valerate 1-2mg/day
- Ethinyl Estradiol 0.02-1.5mg/day
- Estropipate 0.625mg - 5mg/day
- Esterified Estrogens 0.3-1.25mg/day
- Chlortrianisene 12-25mg/day
Transdermal Estrogens:
- Estradiol 0.05-0.1mg patch twice weekly
Atrophic Vaginitis, Kraurosis Vulvae:
Administration: as above, but duration may be as short as 6 months.
Oral Agents: as above
Transdermal Agents: as above
Vaginal Agents: Maintenance doses may be 1/2 to 1 applicatorful two or three times per week
Conjugated Estrogen (0.625mg/gm cream): 2-4gm cream/day
Estradiol (0.lmg/gm cream): 2-4gm cream/day
Estropipate (1.5mg/gm cream): 2-4gm cream/day
Osteoporosis: (see attached readings relative to biphosphonates, calcitonin, and calcium therapy)
Administration: continuous, as above
Oral Agents:
Conjugated Estrogens 0.625mg/day
Estradiol valerate 2 mg/day
Transdermal Agents:
Estradiol 0.1mg patch twice weekly
Vaginal Agents: not approved
Progesterones:
Prevention of Endometrial Hyperplasia and Carcinoma:
Administration:cyclically 10-13 days per month or continuous medroxyprogesterone 2.5 mg/day
Oral Agents:
Medroxyprogesterone acetate 2.5-10mg/day
SELECTED READINGS AND REFERENCES
Reviews
CASE STUDY #1
Mrs. A.L.V. is a 51 y.o. female who has been experiencing "hot flushes-for the past 2 months. They have become so debilitating that she has stopped going out in public to avoid embarrassment. How should Mrs. A.L.V. be treated for her "hot flushes"? (Be sure to state the dose, frequency and duration of therapy )
CASE STUDY #2
Mrs. T. Bone is a 55 y.o. white woman from Sweden who experienced her last menstrual period at age 50. Her present health is excellent BP 135/80, P 70, Wgt 45kg, and she does not smoke. Her only medication is a multiple vitamin and she hates milk. Dr. Marks consults you as to her risks for osteoporosis, and the risks versus the benefits of preventive and therapeutic measures (calcium, vit. D, estrogens and NaFl and biphosphonates). How would you respond to Dr. Marks? What are your recommendations regarding drug therapy for Mrs. Bone? Be sure and state doses and duration of treatment, and possible adverse effects. Justify your therapeutic selections.
CASE STUDY #3
Mrs. C.S. is a 60 yo female who presents to your pharmacy with two new prescriptions, one for Premarin 0.625mg (conjugated estrogens) tablets 1 tab every day on days 1-25 each month and one for Provera 10mg (medroxyprogesterone) tablets 1 tab every day on days 13-25 each month. Mrs. C.S. states that these pills are to prevent her from developing osteoporosis. You also learn from her that she had a natural menopause 10 years ago. She states that her physician didn't really tell her much about the medication, but that she has heard there are some potential serious adverse effects from this therapy and wants to know more about them. What side effects do you need to counsel Mrs. C.S. about? Are there any other positive effects that she may experience besides decreased bone loss?
Case 1.
Mrs. ALV should have a complete medical history and physical exam performed if her physician is unfamiliar with her history. If she has no contraindications to hormone replacement therapy (HRT) she should start on oral conjugated estrogens 0.3mg every day x 21 days with 7 days off or a transdermal estradiol patch 0.05mg applied twice a week and medroxyprogesterone 2.5 -10mg should be taken the last 10 - 13 days of estrogen administration. The dose can be increased if inadequate response is not achieved. HRT should be stopped after 3 months to see if the vasovagal symptoms haveresolved, if not therapy should be resumed for another 3 to 6 months and then stopped again. This pattern should be repeated for as long as symptoms continue.
If Mrs. ALV had a contraindication to HRT (a history of breast cancer) or was not interested because of withdrawal bleeding, clonidine O.lmg bid could be started. Her dose would need to be titrated until she responded or developed intolerable side effects (low blood pressure, dry mouth, etc.).
Case 2.
First address Mrs. Bone's risks for osteoporosis
Risks vs. benefits of preventive and therapeutic measures
1) Calcium supplementation will slow down the rate of bone loss, but will not increase bone mass. Calcium salts can be constipating, cause gi distress and renal stones in persons with poor renal function. She is in good health and would probably benefit.
2) Vitamin D will aid in the absorption of calcium. However, Mrs. Bone is in good heath, takes a multiple vitamin that may already contain vitamin D, and probably eats a sensible diet. In her case the risks of hypercalcemia probably out weigh the benefits.
3) Estrogen and progesterone (HRT). The decision to start an older women who has had a natural menopause on cyclical HRT should be made by the patient and her physician after she has been informed of the potential risks and benefits. Potential risks include breast cancer, fibrocystic breast disease, hypertension, gallbladder disease, and thromboembolism. At the present time the certainty of any of these risk is not clearly established since data is either limited or conflicting. The risk of endometrial cancer is increased only in the face of unopposed estrogen therapy; however, when cycled with progesterone, HRT is actually protective of endometrial cancer. A disadvantage of HRT is withdrawal bleeding which many women find undesirable. Potential benefits are a favorable lipid profile, decreased risk for cardiovascular events, and decreased bone loss and a decreased risk for fracture .
4) Sodium fluoride is an investigational agent that has fallen out of favor thus it is not indicated is this patient.
5) Biphosphonates and calcitonin possibly as adjunctive therapy (refer to reading for specifics)
Case #3
As stated above, the decision to begin preventive therapy and which ones should be made by the patient and her physician. If her diet is as low in calcium as is suspected, calcium supplementation equal to 1500mg of elemental calcium should be prescribed. Cyclical HRT consisting of 0.625 conjugated estrogen daily x 21 days per month and 2.5 to 10mg of medroxyprogesterone acetate for the last 10 to 13 days of estrogen therapy should be considered in this case.
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