Methods of treatment for endometriosis - Continuing Education, includes test questions - Inside Pharmacy

Janet McCombs

Methods of treatment for endometriosis

Goal:

The goal of this lesson is to make the pharmacist more familiar with endometriosis and the various treatments available to today's practitioners.

Objectives:

Upon completion of this lesson, the pharmacist should be able to: 1. Define endometriosis and explain the theories regarding the etiology of the disease. 2. Discuss the incidence of endometriosis and methods of diagnosis. 3. Compare the medications commonly used to treat endometriosis including factors influencing the choice for individual patients based on her needs, economic factors and side effects.

Endometriosis, a common disorder among American women, is responsible for many lost working days each year and is a major cause of infertility. With current procedures such as laparoscopy, the disease is easily diagnosed but therapy is less straightforward. Fortunately, in 1990, we have several different types of treatment available, both medical and surgical, to offer the patient with endometriosis. Unfortunately, the medical treatments are not curative and the disease tends to recur following theraphy. In this lesson we will discuss the pathophysiology, diagnosis and treatment of endometriosis.

Incidence

Endometriosis may be defined as the presence of functioning endometrial tissue outside the uterus. This extra-uterine-endometrium proliferates under the normal hormonal stimuli and sloughs during menstruation just as the normal endometrium does. The disease was first described in 1860 by von Rokitansky, but did not receive significant clinical attention until Sampson published his theories in the early 1920s.

The incidence of endometriosis has seemed to dramatically increase in recent years and has, on occasion, been referred to as a twentieth century or professional woman's disease. Several factors have probably contributed to such terminology. Endometriosis may indeed be more prevalent today, because more women are delaying pregnancy to complete their education and establish careers. This delay leads to longer intervals of uninterrupted menstruation and a greater chance of developing endometriosis. The incidence may also be greater because physicians are more willing to pursue the cause of severe or chronic pelvic pain and infertility.

Though many of the women who are diagnosed with endometriosis are professional women in the 30 to 40 age group, women of all ages and socioeconomic levels have the disease. The average age at diagnosis is 30, but many teenagers are also found to have the disease if laparoscopy is used liberally. It is estimated that four of every 1,000 women aged 14 to 64 are hospitalized annually for endometriosis or associated problems. The overall incidence is estimated to be 10 percent to 25 percent of all premenopausal women.

The woman most likely to have endometriosis is in her third or fourth decade of life, had an early menarche, has a short menstrual cycle with long, heavy periods and delayed childbearing. She is also more likely to have the disease if she has a first degree female relative with endometriosis.

Etiology

The etiology of endometriosis continues to be one of the great mysteries in gynecology. There are three primary theories about the origin of the abnormal tissue. Sampson proposed the idea that retrograde menstruation or menstrual flow which flows backwards through the fallopian tubes rather than out the vagina implants on pelvic structures and grows in response to hormonal stimulation. Most women have some degree of retrograde menstruation as noted during abdominal surgery at the time of menstruation. Why this tissue implants in some women but not in others remains unknown. Another theory which may explain this proposes that immunologic factors may be involved which might explain why this tissue grows in some women but not in others. The metastatic theory suggests that undifferentiated coelemic epithelial cells are transported throughout the body via the lymph system. This tissue lies dormant until growth is triggered by ovarian hormones. This theory is supported by patients who have endometriosis outside the pelvis in such areas as the lungs or diaphragm.

Diagnosis

The diagnosis of endometriosis may be suggested by the patient's history and suspected following the pelvic examination, but can only be diagnosed with certainty by laparoscopic or laparotic visualization. Patients should not be labeled with the disease or treated with specific agents until the endometriosis is confirmed. Currently, there are no non-invasive tests for this disease. Confirmation of treatment efficacy also requires a surgical procedure, but a repeat laparoscopy is not usually done unless there is reason to believe that the treatment was not effective.

The lesions of endometriosis may appear as small, punctuated hemorrhages which are cherryred to blue-black in color and resemble powder burns or a sprinkling of black pepper. Larger implants may appear as dark, blood-filled cysts surrounded by scar tissue which may cause puckering. If these larger cysts rupture and the liquid portion of the blood is reabsorbed leaving only the pigmented portion; puncture of the cysts releases a thick dark liquid - thus the term "chocolate" cysts.

The most common locations of endometrial implants are the ovaries, uterosacral ligaments and the cul-de-sac. Less common but also found are lesions on the cervix, vagina, bladder, appendix and uterus. Unusual but reported sites include the lung, kidney, diaphragm, episiotomy scars and umbilicus.

The most utilized classification system for staging endometriosis was developed by the American Fertility Society and was revised in 1985. Points are assigned based on the location and size of the lesions, the presence and extent of adhensions and the involvement of the cul-de-sac. Based on the total number of points, the disease is described as minimal (Stage I), mild (Stage II), moderate (Stage III), or severe (Stage IV).

Clinical Features

Patients with endometriosis may present with numerous symptoms, but those most consistently seen are complaints of pelvic pain and/or infertility. Other symptoms may include abnormal uterine bleeding, dyspareunia, back pain, dyschezia and rectal bleeding. On the other hand, many patients who have even severe disease are asymptomatic.

Pelvic pain is perhaps the most common symptom of endometriosis. Dysmenorrhea is present in many endometriosis patients but is not necessarily related to endometriosis. Primary dysmenorrhea is painful menstruation in the absence of underlying pelvic pathology. It usually begins soon after menarche and the pain is usually described as cramp-like beginning at the onset of flow and decreasing during the period. Secondary dysmenorrhea is painful menstruation caused by underlying pelvic pathology which is frequently endometriosis. Patients with dysmenorrhea related to endometriosis often describe the pain as constant and deep and which may radiate to the lower back and thighs. Pain may begin during mid-cycle but is usually worse just prior to and during menstruation. The pain is consistent throughout the menstrual period, but subsides with the cessation of flow. It is not uncommon for a patient to have both primary dysmenorrhea and later develop secondary dysmenorrhea due to endometriosis. This should be investigated in a patient with a history of primary dysmenorrhea who reports that her pain has significantly increased or changed in character. She may also report that the prostaglandin synthetase drugs which worked well in the past are no longer satisfactory.

It is interesting to note that patients with minimal disease may have severe, chronic or incapacitating symptoms but women with extensive disease may have no symptoms at all.

The cause of the pain of endometriosis is unknown but it has been suggested that as the ectopic endometrium proliferates and bleeds, it swells and bleeds into the surrounding tissues causing distention and pain. Prostaglandins, well documented to cause the pain of primary dysmenorrhea, have also been found in women with endometriosis and it is suspected that the small, petechial lesions have the greatest potential for prostaglandin production. Unfortunately, the pain of endometriosis is usually only partially diminished by the antiprostaglandin drugs.

Infertility

Infertility is the other most frequent symptom of endometriosis. It is easy to understand how endometriosis can cause has significant when the patient has significant disease to the extent that pelvic structures are immobilized or ocluded by adhensions. But in the patient with minimal disease, the relationship is not as obvious.

Theories about the cause of infertility in the endometriosis patient that are not associated with mechanical disease are numerous. One theory suggests that this is an autoimmune response triggered by phagocytized endometrial tissue which results in rejection of the embryo. Another theory indicates that the ovary fails to release the ovum following normal ovulatory preparation due to biochemical changes caused by the disease. Others have postulated that the increased presence of prostaglandins in the peritoneal cavity may alter tubal transport or damage sperm.

Endometriosis has also been associated with other causes of infertility such as oligo-ovulation and hyperprolactinemia. Simultaneous treatment of all factors is recommended to achieve the optimal chance of pregnancy. Women who have endometriosis often have higher than average numbers of spontaneous abortions, but the incidence usually returns to control values following medical and/or surgical treatment. Thirty percent of all women with endometriosis are infertile, but many others with the disease seem to have no apparent decrease in fertility.

Treatment

Although there is no cure for endometriosis, there are several different types of treatment available to both relieve the symptoms and improve fertility. Endometriosis is a chronic disease and should be viewed as such by both patient and physician. The disease may be more troublesome at some times than at others and the patient should understand that this pattern is common in chronic diseases. By definition, a chronic disease requires an ongoing relationship between both the patient and physician and it is important to keep the lines of communication open to achieve the best results. The patient, especially with a chronic problem such as endometriosis which can potentially affect the patient not only physically but emotionally and financially, needs to have a good understanding of the disease. its pathophysiology, its prognosis and possible effects on other areas of her life. With this background, the patient can best assist the physician in choosing the best course of theraphy for her individually.

In discussing the various treatment options, the patient and physician should consider the patient's age, the severity and type of symptoms she is experiencing, her desire for current or future fertility and other reproductive system problems. In most cases, the goal(s) of treatment are relief of symptoms and restoration or maintenance of fertility.

It has been noted that during pregnancy and following menopause, endometriosis becomes quiescent. Thus, if pregnancy and menopause could be synthetically induced with medication, endometriosis could be treated. Therefore, most of the current medical therapies for treatment either produce a pseudopregnancy or pseudomenopause.

Treatment choices for endometriosis include no treatment, prophylaxis, observation and analgesia, ovarian suppression and/or surgical treatment. Drugs which have been used include estrogens and progestogens alone or in combination, androgens, gonadotropin releasing hormone agonists and analgesics.

Estrogens and progestogens

Estrogens alone (i.e., diethylstilbestrol, DES) were used primarily in the 1950s and 1960s to inhibit ovulation and suppress menstruation. However, it was noted that unopposed estrogen causes decidual rather than atrophic changes and initially causes stimulation which may last several months. This stimulation had the potential to increase the size of the lesions and increase resulting problems such as pain and infetility. Side effects associated with estrogen therapy included nausea, dysfunctional uterine bleeding, phlebitis, glucose intolerance, and fluid retention. Estrogens alone are no longer considered appropriate treatment for endometriosis.

Progestogens alone were most frequently used if estrogens were contraindicated. Depo medroxyprogesterone acetate is still used in the occasional patient following surgical castration for endometriosis to suppress any remaining lesions. Break-through is a frequent side effect and fertility may be delayed up to a year in some patients.

Currently, estrogens and progestogens are most often used in a combination product when treating endometriosis. The use of combination oral contraceptives causes a pseudopregnancy. This use was recognized as early as 1958 and the combination oral contraceptives were used extensively for this use until 1975 when danazol was introduced. Oral contraceptives are not FDA approved for the treatment of endometriosis.

Initially, the patient may experience exacerbation of symptoms due to stimulation but with continuous use, the patient usually reports improvement of symptoms. In proven endometriosis, the combination oral contraceptive is given continuously, one tablet daily with no interruption for nine to twelve months. When break-through-bleeding occurs, the dose is increased by one tablet a day until it is controlled. The maximum dose is four tablets per day. Of course, the lowest number of tablets which maintain amenorrhea should be used. Pregnancy rates following oral contraceptive treatment are not significantly increased but symptomatic relief is good. Combination oral contraceptives are often used in patients with mild disease who want to delay childbearing or in patients who have been treated aggressively with surgery, danazol or GnRH agonists to maintain suppression of the disease. The products most commonly used in endometriosis patients include Ovral [R], LoOvral [R], and Enovid [R]. Multiphasic products are not a good choice for continuous administration due to the variation in hormone dosage during the cycle. Continuous treatment is contraindicated in patients with unproven disease, a history of uterine fibroids, hepatic disease or thromboembolic disorders. All cautions and contraindications for oral contraceptive use should be strictly adhered to especially in these patients who may receive four times the usual daily dose for up to 12 months. The side effects are those seen with any use of combination oral contraceptives including nausea, fluid retention and breast tenderness. Periods usually resume in four to six weeks after theraphy is discontinued.

Androgens

Androgens such as testosterone and methyltestosterone cause atrophy of the endometrium and symptomatic relief of endometriosis. These drugs were unacceptable to most patients because of such side effects as acne, hirsuitism, deepening of the voice, loss of libido and clitoral hypertrophy. Never used extensively for endometriosis, androgens are rarely used today for this purpose.

Danazol, a synthetic 17 alpha ethinyltestosterone derivative, which is structurally related to the androgens, was introduced in the late 1960s. Researchers noted that danazol had antigonadotropic and androgenic properties. Danazol inhibits FSH and LH at the level of the hypothalamus and pituitary. Ovarian steriod production is suppressed due to lack of stimulation by FSH and LH. This ovarian suppression results in a hypoestrogenic state which leads to an ovulation and endometrial atrophy. Pseudomenopause is the term coined in 1975 to describe the physiologic activity of danazol. The androgenic effects are probably primarily related to interaction of danazol with androgenic receptors in peripheral tissues, but may also be due to increased availability of free testosterone. There is also some evidence that danazol has an effect on the immune system and this activity could aid in the resolution of the endometriosis.

Following diagnosis of endometriosis by visualization, the patient is started on 200 to 800 mg of danazol daily, usually in four divided doses. The dose chosen by the physician usually depends on the extent of the disease and the severity of the symptoms. The medication should be started on the first day of menstrual bleeding to minimize the possibility of teratogenic effects in early pregnancy and to decrease the likelihood of escaped ovulation. Inhibition of ovulation may not be complete and it is necessary to use a barrier method of contraception during treatment, because virilization of the female fetus exposed to danazol has been reported.

Side effects of danazol are frequent and primarily androgenic and hypoestrogenic in nature. Androgenic effects include acne, hirsuitism and weight gain. Hot flashes, night sweats and vaginal dryness are hypoestrogenic effects. Muscle cramps are also common but the cause remains unknown. It would seem that these side effects would be dose-related and a lower dose would produce less problems. This in fact is quite the opposite. It has been suggested that because the androgenic side effects appear to be worse at lower doses, perhaps it is because at lower dosages the endogenous androgen inhibition may be incomplete thus causing a synergistic effect between endogenous and exogenous androgens. At higher doses, endogenous androgen production is most likely completely inhibited. Thus, the androgenic effects would be only those produced by the medication. There is some evidence that danazol decreases HDL and increases LDL levels. While this does seem to occur, it is probably of little significance in a six or nine month course of therapy because the values return to pretreatment levels after cessation of treatment. Liver function tests are also recommended periodically during therapy because hepatic dysfunction has been reported. Vaginal bleeding which may occur during danazol treatment is usually due to either inadequate ovarian suppression or bleeding from the atrophic endometrium. The estradiol level should indicate whether adequate suppression has been achieved.

Clinical improvement has been reported in 80 percent of patients treated with danazol. Symptomatic improvement usually accompanies the onset of amenorrhea which if often achieved in the first month of treatment. Pregnancy rates also improve greatly following danazol therapy. Periods usually resume 30 to 45 days following the end of treatment.

Danazol is used by some physicians prior to conservative surgery to decrease pelvic vasocongestion and edema to decrease blood loss and to soften the endometrial implants. Others believe this is not desirable because it can make smaller implants more difficult to see and therefore left behind after surgery.

With careful clinical monitoring, including cholesterol, triglycerides and liver function, there is not contraindication to repeated courses of danazol when indicated.

GnRH Agonists

The gonadotropin releasing hormone (GnRH) agonists are the newest class of drugs approved for the treatment of endometriosis. GnRH agonists currently marketed are synthetic analogs of the natural hormone. Most of these analogs have a substitution at the 6-glycine position which makes both the potency and halflife significantly greater than the natural hormone.

GnRH is produced by the hypothalamus and causes stimulation of FSH and LH production. FSH and LH stimulate production of ovarian hormones; thus, if GnRH could be inhibited, ovarian suppression (pseudomenopause) could be achieved. When GnRh agonists are initially administered, stimulation is observed. With continuous administration, the pituitary becomes desensitized and ovarian suppression occurs. This initial stimulation usually lasts only a few weeks.

There are only a few conditions such as ovulation induction which could benefit from treatment with GnRH stimulation, but many others such as prostatic hypertrophy and cancer, endometriosis and precocious puberty which could be treated with suppression of gonadal function. Several GnRH agonists are currently studied in the United States. These include buserelin, histrelin, leuprorelin and nafarelin. Two of these, leuprorelin and nafarelin, have already been approved for use. Leuprorelin is approved as both subcutaneous and intramuscular depo injections for the treatment of prostatic cancer. Nafarelin was recently approved as a nasal spray for the treatment of endometriosis. Because of their peptide structure, these drugs are inactivated by gastrointestinal administration.

To be effectivtment of endometriosis. Because of their peptide structure, these drugs are inactivated by gastrointestinal administration.

To be effectivnd cause adequate ovarian aspersion while avoiding stimulation as much as possible. Amenorrhea usually occurs within 60 days and decreased estradiol levels are noted after 1 month of treatment with GnRH agonists. Improvement in clinical symptoms was seen in 85 to 90 percent of patients with laparoscopically proven disease. Symptomatic relief usually begins during the first four weeks. Direct visualization also showed improvement of lesions in 80 percent of patients using GnRH agonists.

The major side effects of GnRH agonists are hypoestrogenic. Most women report the occurrence of hot flashes; vaginal dryness, insomia and mood swings are also common. While these effects occur frequently, they are not severe enough to cause many women to discontinue therapy. A major concern relates to possible adverse metabolic effects including skeletal calcium turnover and the effect of hypoestrogenism on blood lipids.

There is evidence that some patients receiving GnRH agonists have a decreased bone mineral content in the trabecular bone of the spine. Other studies report that this does not occur. Studies which have reported decreased bone density also report that this effect is reversible within several months after the drug is discontinued. This controversy continues and due to the possible long-term effects such as osteoporosis, nafarelin is only approved for one 6 month course of therapy. With further study, the significance of this possible side effect should become more evident and further recommendations should be forthcoming.

Blood lipid level changes do not seem to be an especially significant problem with GnRH use. When an alteration is seen, it usually reverses soon after discontinuation of the medication.

The manufacturer recommends that patients using nafarelin nasal solution use a barrier method of contraception during therapy.

Summary

Danazol and nafarelin, currently the only two drugs specifically indicated and approved for the treatment of endometriosis, appear to have equivalent efficacy in the treatment of this chronic and possibly incapacitating disease. Symptomatic relief and post-treatment pregnancy rates are comparable. The major difference is the nature of the side effects. Some women may tolerate the side effects of one drug better than the other.

Surgical Treatment

Surgical treatment for endometriosis includes both conservative and definitive procedures. During conservative surgery, the physician usually attempts to remove as much disease as possible while retaining reproductive function. Lysis of adhesions is also performed especially since medical treatment such as danazol and GnRH agonists have no effect on this problem. Definitive surgery is reserved for the patient who no longer wishes to preserve fertility for in the patient with such severe disease that pregnancy is unlikely to occur and whose symptoms are intolerable. Definitive surgery includes removal of the uterus, ovaries and endometrial implants.

Patients may take any of the medications discussed previously prior to surgery if the physician feels that it would improve the surgical outcome. Other patients will receive the medications following surgery to suppress any remaining endometrial implants or to prevent recurrence of the disease.

Replacement estrogen for patients who have had their ovaries removed is indicated; however, in cases of severe disease or where it was not surgically possible to remove all lesions, this should be delayed. Hopefully, if the patient can tolerate the menopausal symptoms for six to twelve months, replacement therapy can proceed. Early administration of estrogens may once again cause some stimulation of the endometriosis. It is important for replacement to be given to prevent osteoporosis and cardiovascular disease just as in the menopausal patient.

Conclusions

Pharmacists can be of much assistance to their patients who have endometriosis if they will take time to understand the disease, the treatment and the many potential effects it may have on the patient's life. The patient with endometriosis will benefit from the same reassurance and caring service that all patients who have chronic illnesses find helpful.

Financially, the patient with endometriosis will often need assistance due to the cost of these medications. Patients who have insurance which requires filing of the claims before reimbursement rather than a copy will find it useful to find a pharmacy where the larger percentage can be charged until the patient is reimbursed by the insurance carrier. Unfortunately, this is the only way some patients can afford a medication which can potentially cost $400.00 per month. Should a patient present a medication and be unable to purchase it, it would be appropriate to contact the physician to explore other options. The physician may not realize that the patient is unable to afford the medication or may not realize just how costly these drugs are.

In this same area, most insurance companies will not pay for oral contraceptives when used for birth control, but will pay when they are required for medical treatment. The patient can often obtain a letter from her physician stating the diagnosis and medication prescribed to submit to her insurance carrier. You often help a patient taking up to 4 tablets or oral contraceptives a day to afford treatment (potentially costing $200.00 per month) by suggesting she try this justification.

Another helpful practice is to spend time with the patient initially describing exactly how she is to take the medication, when to expect relief of symptoms, when to expect to achieve amenorrhea, use of barrier methods of contraception and major side effects. It is also important for the endometriosis patient to understand the importance of compliance in the efficacy of these medications.

Endometriosis is indeed a common disorder that pharmacists will encounter often, particularly in the retail practice. This patient will appreciate compassion, intensive medication counseling and financial suggestions when possible.

QUESTIONS

Questions on "Methods of treatment for endometriosis", published Oct. 22, 1990 (lesson 679-401-90-10), are worth two hours of credit. Using blue of black ink, print the letter of the answer next to the corresponding number in the answer form at the bottom of this page. Fill out the information on the back of the answer form and send it to: Drug Store News/Inside Pharmacy Continuing Education Program, 305 Madison Ave., Suite 535, New York, N.Y. 10165. There is one correct answer for each question.

1. Endometriosis is almost exclusively found in professional women over age 30.

A. True

B. False

2. Definitive diagnosis of endometriosis is made by:

A. History

B. Pelvic exam

C. Laparoscopy

D. Laparotomy

E. C or D

3. Pregnancy rates following medical treatment for endometriosis are greater with:

A. Danazol

B. Combination oral contraceptives

C. GnRH agonists

D. All are equal

E. A and C are equal

4. The major side effects of the GnRH agonists are:

A. Estrogenic

B. Androgenic

C. Hypoestrogenic

D. Progestogenic

E. None of the above

5. Barrier methods of contraception are recommended with:

A. Continuous oral contraceptive treatment

B. Danazol

C. Nafarelin

D. All of the above

E. B and C only

6. Common sites for endometriosis include all of the following except:

A. Diaphragm

B. Ovaries

C. Cul-de-sac

D. Uterosacral ligaments

7. According to the classification system developed by the American Fertility Society, which of the following is most severe?

A. Stage I

B. Stage II

C. Stage III

D. Stage IV

E. Stage V

8. The two symptoms most often seen in endometriosis patients are:

A. Infertility

B. Pelvic pain

C. Rectal bleeding

D. A and C

E. B and C

9. It is impossible for a patient to have both primary and secondary dysmenorrhea.

A. True

B. False

10. Infertility in endoetriosis is most likely due to:

A. Mechanical obstruction

B. Prostaglandins

C. Biochemical changes

D. None of the above

E. A combination of the above factors

11. Which oral contraceptive would be most appropriate for treatment by continuous administration in a patient with laparoscopically proven endometriosis?

A. TriphasilR

B. Ortho Novum R 7/7/7

C. OvralR

D. Any of the above

E. None of the above

12. In definitive surgery for endometriosis, the ovaries are left to prevent osteoporosis.

A. True

B. False

13. Pseudopregnancy is produced by:

A. Androgens

B. Estrogens

C. Estrogen/Progestogen combination

D. Danazol

E. GnRH agonists

14. The pain associated with endometriosis is generally proportional to the extent of the disease, i.e. patient with severe disease always have the most symptoms.

A. True

B. False

15. In choosing the best treatment for an individual patient, which factors should be considered?

A. Frequency and severity of symptoms

B. Age

C. Desire for fertility

D. Economics

E. A, B and C

F. All of the above

16. The maximum number of tablets of combination oral contraceptives that a patient being treated for endometriosis should take daily is:

A. One

B. Two

C. Three

D. Four

E. Any number that is required to maintain amenorrhea

17. The least expensive treatment for endometriosis is:

A. Danazol (generic)

B. Combination oral contraceptives

C. DanocrineR

D. Nafarelin

18. Muscle cramps are a common side effect of:

A. Danazol

B. Nafarelin

C. Leuprorelin

D. Diethylstilbestrol

E. Testosterone

19. As long as the patient is monitored carefully, nafarelin treatment can be repeated as necessary.

A. True

B. False

20. Women most likely to develop endometriosis:

A. Had several children early in life

B. Have long menstrual cycles

C. Have delayed childbearing

D. Have light periods

E. Have taken oral contraceptives for many years

Bibliography

1. Rebar RW, editor. Endometriosis. Clin Obstet Gynecol 1988;31: 777-888. 2. Henzl MR, Corson SL, Moghissi K, et al. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med 1988; 318: 485-9. 3. Barbieri RL. New therapy for endometriosis. N Engl J Med 1988; 318: 512-513. 4. Johansen JS, Riis BJ, Hassager C, et al. The effect of a gonadotropin-releasing hormone agonist analog (nafarelin) on bone matabolism. J Clin Endocrinol Metab 1988; 67: 701-706. 5. Rumore MM, Rumore JS. Clinical Therapeutics of Endometriosis, Part 1. American Pharmacy 1989; 29: 49-52. 6. Rumore MM, Rumore JS. Clinical Therapeutics of Endometriosis, Part 2. American Pharmacy 1989; 29: 40-44. 7. Adamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol 1990; 162: 568-569. 8. Henzl MR, Kivei L. Efficacy and safety of Nafarelin in the treatment of endometriosis. Am J Obstet Gynecol 1990; 162: 570-574. 9. Product monograph. SynarelR. Syntex Laboratories.

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