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This report is about the worldwide market for human prescription drugs as it transitions through 2003. The study provides readers with recent information and analysis about key developments driving the industry. The research reviews the broad areas of major company activities ranging from planning new drugs with disease demographics, through to strategic alliances, and market forecasts. The report reviews the challenges of patent expirations, developing new drug pipelines and what companies must do to get their drugs approved around the world. A review of price/cost aspects and drug distribution approaches uncovers the kinds of business activities that the pharma companies must do the market their products through to the end patients in different countries.

The worldwide pharmaceutical industry is complex to all the business participants as well to the end patients. The report works from the standpoint of disease categories and unravels what the key health issues are through disease demographic data from around the globe. The study looks at what disease categories of the top 276 drug products that the drug companies are selling and ranks the best selling areas and products.

This study has found that the market size for worldwide human drugs at yearend 2002 was about $430 billion. Despite the current weak global economy, the market is projected to grow to about $543 billion in 2005 with a CAGR of about 8.1%. The pharmaceutical industry faces numerous challenges that could be helped with newer business approaches. The report discusses these important items with interesting and useful findings. This study uses more than 48 figures and tables to illustrate the findings. Detailed information about the activities of the top companies important to this market is listed in numerous areas of this report.

Major Disease and the Disease Breakdown

Cancer

Colorectal cancer, Breast cancer, Lung/airway cancers, Prostate cancer, Bladder cancer, Lymphomas, Multiple myeloma, Stomach cancer, Melanoma and other skin cancers, Uterine cancer, Pancreas cancer, Leukemia, Liver cancer, Ovarian cancer, Mouth and throat cancers, Esophagus cancer, Cervical cancer

Cardiovascular

Ischemic heart disease (angina heart attack), Cerebrovascular disease (stroke), Other cardiovascular diseases, Hypertensive heart disease (angina, CHD), Inflammatory heart disease (from Infection)

Central Nervous System (CNS)

Migraine, Depressive disorders, Alcohol use disorders, Alzheimer and other dementias, Insomnia (primary), Drug use disorders, Epilepsy, Bipolar disorder, Schizophrenia, Panic disorder, Obsessive-compulsive disorder, Post-traumatic stress disorder, Parkinson disease, Multiple sclerosis

Gastro-Intestinal

Misc. digestive diseases, GERD, etc, Peptic ulcer disease, Cirrhosis of the liver, Appendicitis

Infections

Tuberculosis, STDs excluding HIV, Chlamydia, Gonorrhea, Syphilis, HIV/AIDS, Diarrheal diseases, Childhood diseases, Pertussis, Measles, Tetanus, Poliomyelitis, Diphtheria, Meningitis, Streptococcus pneumoniae, Meningococcemia without, Hemophilus influenzae, Hepatitis B, Hepatitis C, Malaria, Lower respiratory infections including Influenza, pneumonia, or others

Metabolic

Diabetes

Musculo-skeletal

Osteoarthritis, Rheumatoid arthritis

Respiratory

Asthma, Chronic obstructive pulmonary disease

Skin

Skin diseases

Urogenital

Benign prostatic hypertrophy, Renal failure

Report Contents:

1. Major Disease Populations in the Developed World

2. Regulatory Issues By Disease: Drug Development & Sales

3. Current Drug Patent Expiration Date and New Drug Pipeline in Development By

4. Price, Cost & Distribution Structure

5. Strategic Alliances and M&As By Disease

6. WW Rx Drug Market Size and Forecast by Disease

7. Top Selling Rx Drugs by Revenue and Pharmaceutical Companies

8. Conclusions and Thoughts

9. Appendix

What’s old? What’s new?

Get the pros and cons on the birth control options soon available to youGet the puGet the preuGet the preuGet the prere

BY DR. GRACE MORRISON

In our society, the desire to control reproduction has resulted in many contraceptive options, with many more on the horizon arriving at a dizzying rate. The numbers of options can be daunting and overwhelming.

Behavioral methods

Continuous abstinence from intercourse guarantees protection from pregnancy but is not often practical.

Another approach is “natural family planning,” based on prediction of fertility, both by the calendar and by the quality of cervical mucus and abstinence from intercourse during fertile days.

Generally, the success is greater if menstrual periods are regular. This method requires specific education, diligence and persistence on the part of the couple. Some people use the method of “withdrawal,” which relies on removal of the penis from the vagina prior to ejaculation. The failure rate for this method can be high because of leakage of semen and sperm prior to actual ejaculation.

Barrier methods

Condoms represent the most common barrier method, and although they provide some protection against sexually transmitted diseases, they can fail on the contraceptive front. Health care providers usually recommend use of a spermicide, such as foam, suppositories or gel, along with the condom, to maximize their contraceptive effectiveness.

Diaphragms are flexible rings with a soft latex cup, inserted along with a spermicidal gel, just prior to intercourse. They must be fitted and therefore are available only through a medical care provider. The cost is relatively low, but for success, the couple must be motivated to use it regularly.

Diaphragm usage can result in increased vaginal infections or urinary tract infections. The cervical cap, similar to the diaphragm but smaller, also requires fitting, and can be more difficult to place and remove.

Hormonal contraception

These methods are among the most popular because of their ease of use, preservation of spontaneity during intercourse, and often regulation of menses.

Oral contraceptives, or the pill, enjoy marked popularity for these reasons and for their 97 percent effectiveness. Numerous brands exist, but nearly all contain the two hormones, estrogen and progesterone, in various combinations and subtle permutations of dosages and chemical formulation.

In reality, most women do well with most pills, and there is no clear formula for success. Although side effects are usually mild and short-lived, they can include breakthrough bleeding, nausea and headaches. Usually menstrual periods are lighter, shorter and less painful.

Other significant benefits can include reduction in long-term risk of ovarian cancer and uterine cancer. We now know that most women can safely continue birth control pill use through menopause, and providers often prescribe them for alleviation of peri-menopausal symptoms.

Birth control pills shouldn’t be used by women who smoke and are older than 35 or who have a history of blood clots, stroke, heart disease, estrogen-dependent tumors, high blood pressure and other circumstances.

Depo-Provera, or the shot, contains progesterone only and is injected every three months. It is highly effective (99.7 percent), but troublesome side effects can include weight gain, irregular bleeding, abnormal hair growth, mood changes and acne. Sometimes resumption of menstrual periods and fertility is delayed significantly.

Intrauterine devices (IUDs) are plastic devices with copper or progesterone, which are inserted into the uterine cavity, and which can remain for five to 10 years. Effectiveness approaches 99 percent, and with the newest one, Mirena, menses are actually lighter and shorter.

Caution should be used if the relationship isn’t monogamous, as the risk of sexually transmitted diseases can increase.

The newest available methods of hormonal contraception are the birth control shot (Lunelle), the vaginal ring (NuvaRing) and the patch (OrthoEvra). All three contain estrogen and progesterone, and have similar side effects as the birth control pill.

Lunelle is administered as a monthly injection. NuvaRing, a flexible ring with imbedded medication, is placed in the vagina and left in place for three weeks, then removed for one week. Usually, neither the woman nor her partner can detect it. Ortho Evra delivers the hormones in patch form and requires the patch to be changed weekly for three weeks, then removed for one week.

Emergency contraception

The “morning-after pill” is gaining wide acceptance and is highly effective but must be used within 72 hours of unprotected intercourse. Pharmaceutical companies have developed “Plan B” and “Preven” specifically for this purpose, but many other standard birth control pills, if used according to specific instructions, can be equally effective.

Many care providers recommend that such contraception be provided and kept on hand at all times upon request.

xThere has long been a big discrepancy between what doctors tell women about the aftereffects of a hysterectomy and what is reported in the medical journals. And nowhere is the information gap more apparent than in the area of sexuality. Female sexuality is entirely in the mind, according to the basic tenets of gynecologic medicine, and anyone who reports sexual dysfunction following hysterectomy is either an aberration or a neurotic complainer. The prevailing medical attitude is difficult to understand considering that the operation was originally promoted in the 19th century as the cure for “excessive sexual desire.” What’s more, it ignores the last 25 years’ worth of research on female physiology.

Once the techniques for delivering anesthesia were perfected in the late 19th century, it became “open season” on the female reproductive tract, as the authors so aptly put it in a new book called The NoHysterectomy Option by Herbert A. Goldfarb, M.D., and Judith Greif, M. S. Hysterectomy is the second most common major operation in the U.S. It is primarily performed on women in their 30s and 40s, and in about 40% of all who have the operation, the ovaries are removed along with the uterus (oophorectomy). About 660,000 hysterectomies are performed annually in the U.S. If the trend of the last 12 years continues, one out of every three American women will not make it to the age of 60 with an intact uterus, according to the most recent calculations of the Metropolitan Life Insurance Company.

There is no question that it can be a life-saving operation for women who have cervical or uterine cancer and those who, in the rare instance of an obstetrical complication, require an emergency hysterectomy. In such circumstances, the risks of surgery are outweighed by its obvious benefit. These examples, however, represent less than 10% of all the reasons the operation is performed. Concerns that the operation may often be unnecessary and that women may not be receiving in-depth information on after, effects have triggered informed consent legislation in California and New York requiring hospitals or doctors to provide women with details on risks and alternatives to hysterectomy.

The question of how many hysterectomies, if any, are unnecessary is open to debate. In 1981, a study published by the U.S. Centers for Disease Control found 15% of hysterectomies were “questionable,” and this year, Blue Cross/Blue Shield of Illinois found one-third to be medically unnecessary. When the American College of Obstetricians and Gynecologists (ACOG) looked into the question recently, it found no evidence of unnecessary surgery, a spokesman told HEALTHFACTS. The well-documented regional variations in hysterectomy rates are difficult to explain. A woman under the age of 45 living in the South, for example, is more than twice as likely to have her uterus removed than her counterpart in the Northeast.

“Hysterectomy is associated with a substantial complication rate; one-fourth to one-half of women who undergo hysterectomy for all indications will sustain one or more complications,” wrote Charles L. Easterday, M.D., and colleagues at ACOG and the Centers for Disease Control (Obstetrics & Gynecology, August 1983). Fever is the most common complication, and as many as one in every ten women who undergoes hysterectomy will require a blood transfusion due to hemorrhage. Depression, sexual dysfunction, bladder lacerations, development of chronic pain in the intact ovaries, and adhesions (scar tissue from the surgery) were also found to be common.

Compared to other major operations, the mortality rate for hysterectomy is low-perhaps because the operation is primarily performed on younger women. But its death rate of one out of every 1,000 operations should be looked at in the context of overuse. If, for example, the Blue Cross/Blue Shield study is correct in its estimate of one-third unnecessary hysterectomies, this would mean that over 200 American women die each year because of an operation they didn’t need.

The debate over its usefulness is likely to continue for some time because of the lack of well-designed studies to identify the appropriate indications for hysterectomy. Incredibly enough-considering the prevalence of this operation-the first steps toward this end have been taken only recently. The results of these studies, now in progress, will not be ready for two years.

Until more research is published, we are left with agreement among physicians on only two indications: cancer is a good reason for having hysterectomy and sterilization is not (there are safer alternatives). In between these two extremes lies a large grey area that encompasses the majority of the reasons why this operation is performed. They include excessive bleeding (menorrhagia), fibroid tumors of the uterus (myomas), sagging of the uterus into the vagina (prolapse), pelvic pain, and a disease called endometriosis in which tissue fragments of the uterine lining migrate outside the uterus causing pain and discomfort. More than half of the healthy adult female population has one or more of these conditions at any given moment. Many find the symptoms painful or distressing enough to seek treatment. In short, hysterectomy is performed primarily to improve the quality of life in women with conditions that are not life-threatening.

“On the whole, the contraceptive choices that Americans have are very safe and effective,” says Dennis Barbour, president of the Association of Reproductive Health Professionals, “but a method that is very good for one woman may be lousy for another.”

The choice of birth control depends on factors such as a person’s health, frequency of sexual activity, number of partners, and desire to have children in the future. Effectiveness rates, based on statistical estimates, are another key consideration (see “Birth Control Guide”). FDA is developing a more consumer-friendly table to be added to the labeling of all contraceptive drugs and devices.

Barrier Methods

* Male condom. The male condom is a sheath placed over the erect penis before penetration, preventing pregnancy by blocking the passage of sperm.

A condom can be used only once. Some have spermicide added, usually nonoxynol-9 in the United States, to kill sperm. Spermicide has not been scientifically shown to provide additional contraceptive protection over the condom alone. Because they act as a mechanical barrier, condoms prevent direct vaginal contact with semen, infectious genital secretions, and genital lesions and discharges.

Most condoms are made from latex rubber, while a small percentage are made from lamb intestines (sometimes called “lambskin” condoms). Condoms made from polyurethane have been marketed in the United States since 1994.

Except for abstinence, latex condoms are the most effective method for reducing the risk of infection from the viruses that cause AIDS, other HIV-related illnesses, and other STDs.

Some condoms are prelubricated. These lubricants don’t provide more birth control or STD protection. Non-oil-based lubricants, such as water or KY jelly, can be used with latex or lambskin condoms, but oil-based lubricants, such as petroleum jelly (Vaseline), lotions, or massage or baby oil, should not be used because they can weaken the material.

* Female condom. The Reality Female Condom, approved by FDA in April 1993, consists of a lubricated polyurethane sheath shaped similarly to the male condom. The closed end, which has a flexible ring, is inserted into the vagina, while the open end remains outside, partially covering the labia.

The female condom, like the male condom, is available without a prescription and is intended for one-time use. It should not be used together with a male condom because they may not both stay in place.

* Diaphragm. Available by prescription only and sized by a health professional to achieve a proper fit, the diaphragm has a dual mechanism to prevent pregnancy. A dome-shaped rubber disk with a flexible rim covers the cervix so sperm can’t reach the uterus, while a spermicide applied to the diaphragm before insertion kills sperm.

The diaphragm protects for six hours. For intercourse after the six-hour period, or for repeated intercourse within this period, fresh spermicide should be placed in the vagina with the diaphragm still in place. The diaphragm should be left in place for at least six hours after the last intercourse but not for longer than a total of 24 hours because of the risk of toxic shock syndrome (TSS), a rare but potentially fatal infection. Symptoms of TSS include sudden fever, stomach upset, sunburn-like rash, and a drop in blood pressure.

* Cervical cap. The cap is a soft rubber cup with a round rim, sized by a health professional to fit snugly around the cervix. It is available by prescription only and, like the diaphragm, is used with spermicide.

Benefits of Oral Contraceptives The substantial and widespread benefits of oral contraceptives are often taken for granted or forgotten amid the controversies and concerns about the pill that range from legitimate scientific questions to unfounded neighborhood rumors. The chief benefit of OCs, of course, is their effectiveness in preventing pregnancy. OCs protect millions of women from the burden of unwanted pregnancies and childbearing and prevent thousands of women’s deaths in childbearing. Other important benefits of OCs are reductions in the risks of iron-deficiency anemia and of endometrial and ovarian cancer.

The fertility-related benefits of oral contraceptives include not only:

* Effectively preventing unwanted pregnancy, but also

* Better maternal and child survival,

* Prevention of ectopic pregnancy, and

* Reduced risk of pelvic inflammatory disease.

Preventing pregnancy. The most important benefit of the pill is its convenient, highly effective, and reversible protection against unwanted pregnancy. All widely available types of pills–combined estrogen-progestin, progestin-only, and multiphasics–are highly effective. Among women using combined estrogen-progestin OCs correctly, in the first year of use pregnancy occurs in fewer than one in every 100.

Most authorities consider combined pills containing less than 50 [mu]g of estrogen to be as effective as those containing 50 [mu]g or more. The few comparative studies have reported no significant difference (48, 259, 313).

Few studies have been conducted in which women were randomly assigned to use one type of pill or the other. A multicenter World Health Organization (WHO) study compared six combined OCs containing 20 to 50 [mu]g estrogen. No significant differences in effectiveness appeared. Even the highest pregnancy rate observed was less than 1.5 pregnancies per 100 woman-years of use (545).

Progestin-only pills may be slightly less effective than any combined pills. In clinical trials failure rates range from about 1 to 3 per 100 woman-years of use. While minipills fail to prevent ovulation in about 40 percent of users, other effects contribute to contraceptive protection. In particular, progestins change cervical mucus so that sperm find it more difficult to penetrate (153, 194, 398, 511).

Because all pills are so effective, identifying any small differences in effectiveness among specific formulations would require very large studies. In clinical trials other factors may be more important than formulation. Such factors include differences among pill groups in age and other characteristics of women recruited, the number lost to follow-up, and compliance with the pill-taking regimen (487).

Because women sometimes forget to take their pills, switch to another method, or discontinue contraceptive use altogether, actual effectiveness in day-to-day use is often less than reported in clinical trials. Surveys of married women in the US have found that 2 to 3 percent of women have unplanned pregnancies in the first year of pill use (170, 171, 432, 499). Actual failure rates are probably somewhat higher, however, since abortions are seriously underreported in most surveys (143, 205).

In some developing countries OC failure rates have been much higher. For example, according to World Fertility Survey data from five Latin American countries in the 1970s, the pregnancy rate among OC users was 8 per 100 per year. By comparison, the pregnancy rate among IUD users was 5 ler 100 (165). In the Philippines a 1980 national survey reported 19 pregnancies per 100 woman-years of pill use compared with 4 per 100 among IUD users (273). Other population-based surveys report pregnancy rates among OC users of 15 per 100 woman-years in Bangladesh (85) and 13 per 100 woman-years in Sri Lanka (480). Irregular pill-taking may explain these relatively high pregnancy rates.

Multiphasic pills have only recently been widely used, but some evidence suggests that one triphasic formulation may be slightly less effective than combined pills. During their first year on the market in Britain, several pregnancies were reported among users of a triphasic pill consisting of .05/.075/.125 mg levonorgestrel and 30/40/30 [mu]g ethinyl estradiol (133, 173). Subsequently, a study in the Netherlands found that, from 1982 to 1984–when this triphasic formulation was the only one marketed–women using triphasics were about twice as likely to request abortions as were users of combined pills (259). Finally, a 6-month clinical trial conducted in 11 centers in Denmark, Norway, and Sweden reported three pregnancies in 1,063 cycles among women using the formulation, two of the pregnancies attributed to pill failure (101).

Maternal and child health. By preventing unwanted pregnancies and enabling women to time births, OCs–like other reliable methods of contraception–contribute to both maternal and child health. Worldwide, an estimated half a million women die in pregnancy and childbirth every year. About 99 percent of these deaths occur in developing countries, where, excepting China, on average 550 women die per 100,000 live births, or one for every 180 live births (422). Among children, as many as 20 percent of infants die in parts of Africa and Asia. Worldwide each year an estimated 14 million children die before age five (174).

* Objective.-Peritoneal washings are routinely performed during gynecologic surgery. The presence or absence of malignant cells in washings helps determine the stage of the malignancy. However, the efficacy of this procedure has not been studied recently.

Design.-All intraoperative washings for gynecologic disease at our hospital from 1992 through 1994 (901 cases) were reviewed. Of these, 380 were gynecologic malignancies that were reviewed for changes in staging based on the presence of malignant cells.

Results.-Histologically, 380 cases were gynecologic

malignancies, 521 benign, 79 nongynecologic, and 25 had no accompanying surgical pathology. Of the malignancies, 125 had a diagnosis of cancer on washings. In 12 cases (3.1 %), a change in stage resulted.

Conclusions.-In a small but significant number of cases, malignant cells in the washings changed postoperative staging, impacting therapeutic measures and prognosis for these patients greatly. Peritoneal washings remain a simple yet effective tool in the evaluation and management of gynecologic malignancies.

(Arch Pathol Lab Med. 1997;121:604-606)

Cytologic sampling of peritoneal fluid from the pouch of Douglas at the time of surgery, as a concept, was introduced in 1958. Peritoneal washings are now commonly performed during any exploratory laparotomy for gynecologic disease because peritoneal involvement can be undetectable by visual inspection alone. The application of peritoneal lavage in laparotomies serves three purposes: detection of occult tumor, determination of recurrent or persistent tumor, and staging. The presence of peritoneal tumor indicates a worse prognosis, and thus the results of peritoneal washing cytology are incorporated in staging and treatment decisions. In this era of managed care and cost containment, the significance of this procedure is being tested anew.

Cytologic preparations of all intraoperative washings from 1992 through 1994 at The Johns Hopkins Hospital, Baltimore, Md, were studied retrospectively. A total of 901 peritoneal washings from women undergoing laparotomy for gynecologic disease were reviewed, and 380 of these cases were reviewed for changes in staging.

All cytologic specimens were obtained intraoperatively; some had washings separately collected from multiple intra-abdominal sites, and these fluids were interpreted as all positive or all negative in all patients. All cytologic preparations (cytospin, Millipore filter preparations; Millipore Corp, Bedford, Mass) were subsequently stained with modified Papanicolaou and/or DiffQuik stains. All cell blocks were stained with hematoxylin-eosin.

In cases with documented malignancy, the results of peritoneal cytology and corresponding malignant histology, as well as pertinent clinical data, were reviewed for each patient to determine whether the cytopathologic diagnosis changed the FIGO (International Federation of Gynecology and Obstetrics,1988) stage of disease.

RESULTS

Histologically, 380 of the 901 cases were gynecologic malignancies, and 521 were benign. Of the 521 washings from patients with histologically benign genital disease, no false positives were found. This excellent concordance may be a result of good cytohistologic correlation, which enhanced the accuracy of interpretation. Of the gynecologic malignancies reviewed, a diagnosis of cancer was made in 125 cases, and in 12 cases (3.1%), a change in stage resulted (Table). Four of the 12 cases were endometrioid carcinomas of the uterus (one clear cell carcinoma [Fig 1], three endometrial cancers), two were clear cell carcinomas of the ovary, two were serous carcinomas, and one was a serous tumor of low malignant potential. The remaining cases involved three rare tumors, namely, a small cell carcinoma of the uterus (Fig 2), a mixed mullerian tumor, and a fallopian tube carcinoma. All but one of these 12 cases (the fallopian tube carcinoma) were primary neoplasms and not recurrences. Over the short follow-up period (at time of submission, 1992-1996), none of these cases had, nor subsequently developed, a second primary tumor, confirming that the malignant cells seen were not from an occult tumor. Four of the patients are dead of disease, six are disease-free, and one has evidence of disease. One patient was lost to follow-up. It is interesting to note that two of the patients with apparently limited disease (cases 2 and 4 in the Table) are dead of disease. The other two deceased patients (cases 10 and 11 in the Table) had minimal disease, but aggressive tumors with poor prognoses. On review of all the gynecologic malignancies, 25 were recurrences or second-look operations.

COMMENT

Pelvic malignancies with accompanying exudates have been evaluated since as early as 1867. Peritoneal washing cytology as a diagnostic tool was proposed in 1958. The prognostic value for pelvic tumors was shown by Morton et al in 19611 and 10 years later by Creasman and Rutledge in 1971.23

Today, peritoneal washings have become an accepted adjunct to the pathologic evaluation of gynecologic malignancies.3 This was considered necessary because the rationale for peritoneal washing cytology since its inception has included the concept that some cases will be cytologically diagnostic before a clinically suspicious focus is found.2,5 The information obtained by this procedure is used to plan adjuvant therapy and management for patients with cytopathologic evidence of malignancy established by positive peritoneal washings.

Ever since oral contraceptives came on the market 35 years ago, questions have lingered over their safety: Do they increase the risk of stroke and breast cancer? Do they decrease libido? Two new studies and a survey have provided some answers–most of it encouraging.

Stroke is rare among reproductive-age women, and today’s oral contraceptives which contain a low dose of estrogen do not appear to increase the risk. The finding comes from a study by Diana B. Petitti, M.D., and colleagues at the Kaiser Permanente Medical Care Program (The New England Journal of Medicine, 4 July 1996). The researchers compared the 295 women who suffered strokes with the 1.1 million young women enrolled in their health maintenance program.

When the birth control pill first went on the market, it was associated with the risk of stroke because it contained very high doses of estrogen. Women today can choose among more than 50 brands of the birth control pill, which contain about one-fifth the estrogen of the earlier versions.

A slightly increased risk of breast cancer was found among women currently using combined oral contraceptives and those who had used them in the past ten years (The Lancet, 22 June 1996). This is the conclusion of a British team of researchers who analyzed 54 studies conducted in 25 countries. The combined number of participants included over 53,000 women with breast cancer and over 100,000 without the disease.

The researchers found no evidence of an increased risk of breast cancer diagnosed ten or more years after stopping the use oral contraceptives. Age appears to be a factor. The older a woman is at last use of oral contraceptives, the higher her odds of developing breast cancer. However, the cancers diagnosed among pill users tended to be less advanced than the cancers diagnosed among women who never used birth control pills.

When the birth control pill first came on the market, some researchers thought it might decrease sexual desire, but a new survey found that libido and sexual satisfaction are enhanced by one type of oral contraceptive known as the triphasic pills. Questionnaires were filled out by 364 women, aged 18 to 26 years, all sexually active and users of oral contraceptives.

Drs. Norma L. McCoy and Joseph R. Matyas reported that they had not expected to find sexual desire and satisfaction increased by any version of oral contraceptives. They theorized that the reason the triphasic pills had this effect was its varying levels of one hormone, progestin. Monophasic pills, on the other hand, provide the same level of estrogen and progestin per dose for 21 days of each menstrual cycle.

Hysterectomy, the most common major nonobstetric operation, is performed in more than 570,000 women in the United States each year. Although the number of hysterectomies has decreased In recent years, many authorities believe that hysterectomy is often unnecessary and unjustified. There is no universally accepted set of criteria regarding the appropriate indications for hysterectomy. The main indications for hysterectomy include the following conditions: uterine leiomyomas, dysfunctional uterine bleeding, endometriosis/adenomyosis, chronic pelvic pain and genital prolapse. Current literature, however, routinely recommends conservative management of most nonmalignant gynecologic conditions, with hysterectomy reserved for refractory cases. Several nonmedical factors, such as patient race, age, geographic location, medical history and background, as well as health care provider characteristics, such as time since completion of training, gender, and affiliation with teaching hospitals, are also associated with hysterectomy rates.

Annual hospital costs associated with hysterectomy, the second most common major surgery performed in the United States, surpass $5 billion.[1] After peaking in 1975 at 725,000 per year, the number of hysterectomies performed each year has declined and is currently estimated to be 576,000 per year.[2]

The majority of hysterectomies are elective, and more than 90 percent of all procedures are performed in women with nonmalignant conditions.[3] Currently, appropriate indications for hysterectomy remain controversial among health care professionals. Besides the medical indications for hysterectomy, both patient and health care provider characteristics may influence hysterectomy rates.

This article reviews the current recommendations concerning common nonmalignant indications for hysterectomy, suggests alternative treatments and discusses nonmedical predictors of hysterectomy.

Medical Indications for Hysterectomy

UTERINE LEIOMYOMAS

Uterine leiomyomas are the most common indication for hysterectomy and are the reason given for 25 to 30 percent of hysterectomies.[3,4] Leiomyomas, or benign tumors composed of smooth muscle cells and fibrous connective tissue, arise most often in women 30 to 49 years of age and are typically slow-growing, multiple and variable in size. Although the precise etiology of leiomyomas is unknown, sex steroid hormones, specific enzymes and epidermal growth factor are believed to play a role in their development.[5]

Women with leiomyomas are usually asymptomatic. They may, however, have abnormal uterine bleeding, pelvic pain and pressure, lower urinary tract symptoms, infertility, spontaneous abortion and preterm labor.

Medical management of symptomatic uterine leiomyomas may involve hormonal therapy or nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve menorrhagia, dysmenorrhea or pelvic discomfort. Gonadotropin-releasing hormone (GnRH) agonists may induce a state of hypoestrogenemia, causing a reduction in tumor size.[6] However, use of GnRH agonist therapy is limited by the rapid regrowth of tumors following cessation of therapy, decreases in bone density and vasomotor symptoms.[7,8]

Myomectomy is a conservative surgical management option for uterine leiomyoma, is often performed laparoscopically on an outpatient basis, and appears to have good long-term effectiveness.[7] The advantages of hysteroscopic resection of leiomyomas include preservation of fertility, reduced postoperative discomfort and a relatively short recovery period.[9] Unfortunately, leiomyomas recur in an estimated 15 to 30 percent of patients following myomectomy, and operative risks increase with multiple myomectomies.[10]

Hysterectomy is the appropriate and definitive treatment for a woman who has finished childbearing and who has large, symptomatic uterine leiomyomas.[7] Table 1 summarizes the recommendations of the American College of Obstetricians and Gynecologists (ACOG) regarding hysterectomy for leiomyoma.[11] Experts, however, disagree on whether hysterectomy is justified for a woman with asymptomatic or minimally symptomatic fibroids.[12] Traditionally, indications for hysterectomy in a woman with asymptomatic leiomyomas include the following: (1) nonpalpable adnexa that interferes with the diagnosis of ovarian cancer; (2) prophylaxis against future symptoms; (3) avoidance of increased surgical morbidity from continued uterine enlargement, and (4) avoidance of the rare disorder leiomyosarcoma.[12,13] Available evidence challenges these traditional arguments, and current guidelines do not recommend hysterectomy for an enlarged uterus caused by asymptomatic leiomyomas.[12,13]

TABLE 1

Criteria for Hysterectomy for Leiomyomas

Confirmation of leiomyomas (presence of 1 or 2 or 3)
1. Asymptomatic leiomyomas of such size that they are palpable
abdominally and are a concern to the patient
2. Excessive uterine bleeding evidenced by either of the following:
a. Profuse bleeding with flooding or clots or repetitive periods
lasting more than eight days
b. Anemia due to acute or chronic blood loss
3. Pelvic discomfort caused by myomas (presence of a or b or c)
a. Acute and severe
b. Chronic lower abdominal or low back pressure
c. bladder pressure with urinary frequency not due to urinary
tract infection

Actions prior to procedure
1. Confirm the absence of cervical malignancy
2. Eliminate anovulation and other causes of abnormal bleeding
3. When abnormal bleeding is present, confirm the absence of
endometrial malignancy
4. Assess surgical risk from anemia and need for treatment
5. Consider patient’s medical and psychologic risks concerning
hysterectomy

Contraindications
1. Desire to maintain fertility, in which case myomectomy should
be considered
2. Asymptomatic leiomyomas of size less than 12 weeks of gestation
determined by physical examination or ultrasound examination

From Quality assessment and improvement in obstetrics and
gynecology. Washington, D.C.: American College of Obstetricians
and Gynecologists, 1994. Used with permission.

Oral contraceptives, or birth control pills, have been used by more than 60 million women worldwide, and are considered by many to be the most socially significant medical advance of the twentieth century. The birth control pill is a tablet taken daily by a woman to prevent pregnancy. The birth control pill does this by inhibiting the development of the egg in the woman's ovary during her monthly menstrual cycle. During a woman's menstrual cycle, a low estrogen level normally triggers the pituitary gland to send out a hormone that initiates development of an egg. The birth control pill releases enough synthetic estrogen to keep that hormone from being released during the monthly cycle. The birth control pill also contains a second synthetic hormone, progestin, which increases the thickness of cervical mucus and impedes development of the uterine lining to further prevent pregnancy. Studies have shown that the birth control pill is 99% effective in preventing pregnancy. The results of studies on the safety of the birth control vary. Some studies show that its use increases the risk of certain types of cancer, while others show that risk to be minimal. There are also claims that the birth control pill increases risk of stroke and heart attacks.

The Planned Parenthood Federation of America commissioned Dr. Gregory Pincus and Dr. John Rock to develop a simple and reliable form of contraception in 1950. Over the next several years, the doctors worked on formulating a birth control pill at the Worcester Foundation for Experimental Biology in Massachusetts. They tested their invention on 6,000 women in Puerto Rico and Haiti. The invention was then marketed in the United States in 1960 as Enovid-10.

Many attribute the changing social land-scape in the United States during the 1960s to the widespread acceptance and use of the birth control pill. As sexual relations outside of marriage and for reasons other than childbearing became more socially acceptable and women seeking careers sought family planning methods, the environment was ripe for introduction of this discreet, easy-to-use form of contraception.

Despite its popularity, soon after the birth control pill was introduced, the public began to raise concerns about side effects and safety. As early as 1961, reports had begun to circulate that the birth control pill increased a woman's risk of suffering a stroke or a heart attack by causing blood clotting. In 1965, the federal Food and Drug Administration (FDA) provided a scientist at Johns Hopkins School of Hygiene and Public Health to study the side effects of the birth control pill. The agency also established an Advisory Committee on Obstetrics and Gynecology to study the relationship between oral contraceptives and blood clotting, as well as whether the birth control pill increased risk of breast, cervical, or endometrial cancer. The committee, the first-ever advisory committee established by the FDA, reported in 1966 that it had found no evidence to render the birth control pill unsafe for human use.

Unsatisfied, the FDA called for a larger study of the effects of the birth control pill on blood clotting. The agency also determined, Using a process known as the wet granulation method, the active ingredients are mixed together with a dilutant and a disintegrant in a large mixer. Once mixed, the powder mass is forced through a mesh screen. however, that the birth control pill had not been in use long enough for a study of its relationship to cancer to be observed. At the same time, the World Health Organization (WHO) also determined that the effects of the birth control pill on blood clotting warranted study. By 1968, a British study revealed an increase in blood clots among women taking oral contraceptives. The FDA required that packages of birth control pills contain warning labels. In 1969, the agency concluded that the amount of estrogen affected the level of blood clotting and that birth control pills containing lower dosages of estrogen were as effective as their high-estrogen counterparts. The agency began advising doctors to prescribe the lowest estrogen dosage possible to their patients.

An oral contraceptive containing only progestin was introduced in the early 1970s. Dubbed the mini-pill, this form of oral contraceptive prevented pregnancy solely by causing changes in the uterus and cervix. An egg was produced, but the changes caused by the mini-pill made it difficult for the egg to unite with sperm from the male. While the mini-pill eliminates the risks posed by estrogen, it has been found to be less effective in preventing pregnancy than pills containing estrogen. Throughout the 1970s, pills containing consistently lower doses of estrogen were introduced on the market.

In 1982 a biphasic birth control pill was introduced, followed by a triphasic pill in 1984. These low-dose pills contained varying ratios of progestin to estrogen. In 1988 all three drug companies still manufacturing high-dose birth control pills withdrew their high-dose products from the market, at the FDA's request. By 1990, the amount of estrogen in birth control pills had been reduced by at least two-thirds. Studies show that the risk of blood clotting in women taking the birth control pill has decreased accordingly. Further studies have shown that high-dose birth control pills actually reduced a woman's risk of ovarian and endometrial cancers, benign cysts of the ovaries and breasts, and pelvic inflammatory disease. The risk of breast or cervical cancer is still disputed.

In 1987, over 13 million women of reproductive age (15 to 44 years) reported using oral contraceptives. Despite widespread use, women are still concerned about adverse effects. A 1985 Gallup poll reported that three out of four women believe that the use of birth control pills causes serious health problems, including cancer, stroke and myocardial infarction.

Mishell points out that the current scientific literature does not support the belief that the use of oral contraceptives poses a significant health risk for most healthy women of reproductive age. For example, studies have shown that the use of oral contraceptives actually decreases the risk of ovarian and uterine cancer. There is no conclusive evidence that oral contraceptives increase cancer risk, with the exception of cervical cancer, which can be more easily diagnosed and treated than other types of cancer.

Previous studies suggesting an increased risk of cardiovascular disease in oral contraceptive users were conducted among women who received formulations that contained 50 lAg or greater of estrogen. This increased risk, however, was found only among older women with preexisting risk factors, such as smoking, hypercholesterolemia, diabetes and hypertension. Recent studies of healthy women taking primarily low-dose oral contraceptives (35 [mu]g or less of estrogen) indicate that there is no increased risk of myocardial infarction or stroke. In fact, studies suggest that estrogen may have a protective effect against atherosclerosis by increasing high-density lipoprotein levels and decreasing low-density lipoprotein levels. Estrogen use also causes a modest increase in triglyceride levels.

Consumers are generally unaware of other benefits of oral contraceptives. These include reduced risk of iron deficiency anemia, corpus luteal and follicular cysts, salpingitis, dysmenorrhea and premenstrual syndrome. Premenopausal use of oral contraceptives may also provide protection against the development of postmenopausal osteoporosis.