Aspectos éticos

Part of "Chapter 7 - Postanesthesia and Postoperative Care"

During the past decade, few subjects in medicine have engendered greater controversy than the use of estrogen by postmenopausal women. In the postoperative patient who has undergone bilateral

oophorectomy at the time of pelvic surgery, important metabolic changes occur as a result of estrogen deficiency. The most significant effects include vasomotor symptoms, genitourinary atrophy, osteoporosis, cardiovascular disease, and cognitive disturbances. In counseling the patient about the advisability or the necessity of oophorectomy and surgical castration at the time of surgery, it is important that the surgeon take the time to explain all the benefits and risks of postoophorectomy estrogen replacement.

In most cases, the uterus is removed with any gynecologic disease that requires bilateral oophorectomy.

This prophylactic oophorectomy is reasonable if the patient is approaching menopause, because ovarian cancer is the major cause of death from gynecologic malignancy, and its cure rate has remained

unchanged for the past three decades. These facts have encouraged many gynecologists to remove the ovaries at the time of hysterectomy in patients who are 45 years of age or older and approaching menopause. The ease of oral estrogen replacement has made this surgical approach quite acceptable.

Estrogen preparations may be administered in a variety of ways including orally, vaginally, and

transdermally. The equivalent and usual doses for daily replacement are listed in Table 7.23. All of these estrogen preparations have demonstrated effectiveness for alleviating most menopausal symptoms.

Conjugated equine estrogen at a dose of 0.625 mg/d for 25 days each month is one of the more common agents used. The prophylactic use of estrogen must be decided on an individual basis. Each patient must be counseled regarding the risk:benefit ratio and informed consent should be obtained and documented in the patient record. There are a select group of patients in which estrogen replacement has been

considered contraindicated. Those patients with a history of thromboembolic disease or significant liver function impairment should avoid estrogen use. Endometrial cancers have long been considered a contraindication to estrogen use, presumably because these neoplasms are considered

estrogen-dependent. However, three different studies involving early-stage endometrial cancer patients who received postoperative estrogen replacement therapy revealed no increased incidence of recurrent disease or decrease in overall survival when compared to controls.

TABLE 7.23. Daily Dosing Equivalents of Estrogen Replacement Therapy

Estrogen Type Daily Dose

Conjugated equine estrogen 0.625 mg

Ethinyl estradiol 5.0 µg

Micronized estradiol 1.0 mg

Transdermal estradiol 50 µg

Mestranol 30 µg

mg, milligram; µg, microgram.

One of the most important sequelae of castration or of natural menopause is bone demineralization or osteoporosis. With the sudden decrease in plasma estrogen after oophorectomy, there is bone

reabsorption without change in the chemical composition of the bone. This reabsorption involves the entire skeleton, although the soft cancellous bone undergoes the demineralization process before the hard cortical bone. For this reason, the earliest effects of advancing osteoporosis are seen in spontaneous fracture of the distal radius, the weight-bearing vertebral bodies, and the neck of the femur.

In 1979, more than 125,000 women in the United States suffered a fracture of the proximal femur, and 12% died as a direct result. Of white women older than 60 years of age, 25% have radiographic or clinical evidence of vertebral crush injuries. Although bone loss is a normal aging process for both men and women, the most significant physiologic event associated with skeletal fractures in women is the loss of ovarian function, whether owing to oophorectomy or spontaneous menopause. Although there are apparently no estrogen receptors in bone, estrogen plays an important role in calcium metabolism.

Osteoporosis is perhaps the most significant abnormality resulting from estrogen deficiency and is a major cause of morbidity and mortality.

Several theories have been proposed to explain the mechanism of action of estrogen in retarding bone reabsorption. Estrogen is known to suppress the action of parathyroid hormone at the osteoclastic cellular level and thereby suppress the effect of parahormone on bone reabsorption. A diminished plasma level of estrogen results in an increased sensitivity in these cells to parathyroid hormone stimulation, which in turn results in an acceleration of bone reabsorption. As a result of the estrogen deficiency, bone

demineralization causes an increase in serum calcium. This, in turn, suppresses parathyroid hormone secretion. Consequently, the beneficial effect of parathyroid hormone on renal tubular reabsorption of calcium and the formation of the active, dihydroxy form of vitamin D is diminished. The low level of 1,25-dihydroxyvitamin D results in an increased renal excretion of calcium and a diminished calcium

absorption from the gastrointestinal tract. If low-dose estrogen is provided on a continued basis, the action of the parathyroid hormone on bone reabsorption is decreased. This, in turn, lowers the serum calcium level. The lowered serum calcium level enhances parathyroid hormone release, which has a positive effect on calcium metabolism by increasing renal tubular reabsorption of calcium. Calcium absorption from the gastrointestinal tract also is increased because activated vitamin D levels are higher.

Although the foregoing may be a plausible explanation of the role of estrogen in bone reabsorption, the exact mechanism is by no means fully understood. Many investigators believe that estrogen does not affect osteoclast activity directly, because estrogen receptors have not been shown to be present in bone.

There is some evidence that the effect of estrogen on bone metabolism is mediated by its control of calcitonin secretion. Calcitonin, a peptide hormone synthesized by the C cells of the thyroid gland, is decreased in the postmenopausal patient; calcitonin is known to reduce both the number of osteoclasts and their physiologic activity. The administration of estrogen not only prevents bone loss but also raises the plasma level of calcitonin to premenopausal levels. Therefore, another possible explanation of the pathogenesis of postmenopausal osteoporosis is the accelerated decline in calcitonin secretion that is associated with loss of ovarian function.

Photon absorptiometry studies have made it eminently clear that premature castration and the cessation of ovarian function at menopause are both associated with a dramatic and continued decline in bone density. Lindsay and colleagues (1978) showed that when oophorectomized perimenopausal patients were treated with estrogen for periods of up to 8 years, significant bone loss did not occur. When estrogen was withdrawn, bone mineral content fell at a normal postmenopausal rate, demonstrating the long-term prevention of bone loss by estrogen. This group also demonstrated a significant reduction in height loss among postoophorectomized women who were treated prophylactically with small doses of mestranol (mean dosage was 20 µg/d). It seems evident, therefore, that bone demineralization can be delayed with estrogen replacement therapy. Although no therapy now available can restore bone mass in a patient with osteoporosis, women who have premature ovarian failure or bilateral oophorectomy before 50 years of age would benefit if treated prophylactically with estrogen. At particular risk of osteoporosis are slender white or Asian women who smoke, have early menopause, have a low calcium intake, drink alcohol excessively, and are physically inactive. Kriska and associates identified an association between historical physical activity and bone density.

Patients receiving sequential or continuous therapy with estrogen and progesterone have demonstrated decreased vertebral bone loss. Savvas and colleagues used estradiol, 50 mg, and testosterone, 100 mg, in s.c. implants and were better able to prevent osteoporosis in these patients than in patients receiving sequential estrogen and progesterone therapy. Calcitonin and fluoride also have been shown to be efficacious in decreasing bone loss. Pak and associates demonstrated an increase in mineralized bone, an increase in vertebral bone mass, and a reduced frequency of vertebral fractures when using

intermittent sodium fluoride treatment without 1,25-dihydroxyvitamin D3. Future estrogen supplementation protocols to decrease osteoporosis may include agents such as calcitonin and fluoride.

The remaining major physiologic changes associated with loss of estrogen, namely, vasomotor symptoms and genitourinary atrophy, may or may not be clinically symptomatic. Although a hot flush appears to occur in synchrony with a pulsatile surge of luteinizing hormone, the change in hormone level is not the major causative factor. The major defect is in the heat regulatory mechanism in the intact hypothalamus. It has been postulated that gonadotropin-releasing hormone and the heat regulatory center are affected

concomitantly by adrenergic stimulation. This stimulation produces a secondary autonomic response that causes a hot flush. Although the precise stimulatory mechanism is as yet incompletely explained, estrogen replacement has a dampening effect on both the pulsatile gonadotropin release mechanism and the thermogenic center. The treatment for vasomotor symptoms and genitourinary atrophy, however, may be given on a very temporary basis until the patient has adjusted to the change in circulating estrogen level.

Genitourinary symptoms are less common and have a delayed onset. A troublesome clinical problem of estrogen deprivation is the urethral syndrome. This is a recurrent sterile urethritis that causes dysuria, nocturia, and urinary frequency and urgency. The syndrome is usually well controlled with estrogen replacement therapy, with the most immediate response being produced by local vaginal estrogen.

The atrophic changes of the vagina are late sequelae of the diminished plasma estrogen level and do not occur for many months or years after removal of the ovaries. Such changes as vaginal dryness,

dyspareunia, irritation, and, occasionally, postcoital bleeding are associated with atrophy of the vaginal epithelium. Use of estrogen helps maintain the tissue integrity of the vaginal epithelium and may have a profound effect on improving these symptoms. Although vasomotor and genitourinary symptoms are troublesome, they produce no serious long-term health hazards to the patient.

Postmenopausal women receiving estrogen supplements have a marked reduction in cardiovascular

disease and mortality. Estrogen supplementation has been shown to exert this protective effect through a variety of mechanisms. These include increasing serum levels of high-density lipoproteins (HDL),

decreasing serum levels of low-density lipoproteins (LDL), decreasing fibrinogen levels, direct arterial vasodilation, and increased perfusion, and by way of its intrinsic antioxidant properties.

Some studies have suggested that norethindrone, megestrol acetate, medroxyprogesterone acetate, and levonorgestrel decrease HDL levels. Wren and Garrett demonstrated that low-dose levonorgestrel (30 mg) and low-dose estrogen therapy in postmenopausal women do not affect HDL levels. Additional studies by Ravnikar and colleagues evaluating medroxyprogesterone acetate sequentially administered with estrogen did not show a decrease in HDL serum levels. The Postmenopausal Estrogen/Progestin Intervention (PEPI) trial demonstrated a favorable affect on cardiovascular risk factors in women taking both estrogen and progestins. This multicenter controlled trial included 875 women over a 3-year period and randomized them to one of the following five groups: placebo, estrogen alone, sequential estrogen and micronized progesterone days 1 to 12, sequential estrogen and medroxyprogesterone days 1 to 12, or continuous combined estrogen and medroxyprogesterone daily. All patients receiving estrogen alone or estrogen plus a progestin were noted to have an increase in HDL and a decrease in LDL when compared to the placebo group. This favorable effect on the serum lipoprotein profile was greatest in the estrogen only and

estrogen plus micronized progesterone groups, but was also demonstrated to a lesser degree in the estrogen plus medroxyprogesterone group. Other prospective studies are in progress, but it appears that postmenopausal estrogen and progesterone supplementation diminishes the risk of cardiovascular disease and death and also prevents bone demineralization with resultant osteoporosis.

Alzheimer's disease or senile-associated dementia has become an increasingly recognized problem in society today. Improved memory and cognitive function have been demonstrated in patients taking estrogen. As this topic is more extensively studied, this may become an important benefit to consider in postoophorectomy patients.

Finally, another potential benefit of estrogen replacement therapy is a reduction in the risk of colon cancer.

Nanda and coworkers, in a metaanalysis of 42 studies, reported a 33% reduction in the risk of colon cancer in current and recent users of hormone replacement therapy. The authors found no association between hormone replacement therapy and rectal cancer.

The Women's Health Initiative (WHI) has discontinued the conjugated equine estrogen (CEE) 0.625 mg/day plus medroxyprogesterone acetate (MPA) 2.5 mg/day vs placebo arm. The study enrolled 16,608 women between the ages of 50 and 79 years. Each participant was randomized to the CEE/MPA or placebo arm. After an average 5.2 years of observation, the Data and Safety Monitoring Board halted participation in this arm of the WHI Study. Patients receiving CEE/MPA had a significantly increased risk of developing: breast cancer (26%), stroke (41%), coronary artery disease (29%), and thromboembolic events (110%). Advantages to patients in the ECC/MPA arm include a decrease in hip fractures (34%) and colon cancer (37%) when compared with placebo.

ACKNOWLEDGMENT

Part of "Chapter 7 - Postanesthesia and Postoperative Care"

Sections of this chapter were written by Doctors Richard Mattingly, Edward J. Quebbeman, and Donald P.

Schlueter, as in previous editions of this text.

Chapter 8