Two Cervical Cancer Vaccines

1. Two prophylactic HPV vaccines, Cervarix™ (GlaxoSmithKline) and Gardasil™ (Merck) have been licensed for use. Both have been tested in large randomised placebo-controlled trials involving thousands of women from different countries across the world.
2. Impressive protection against persistent vaccine-specific HPV infection has been demonstrated over short- to medium-term follow-up periods. Long-term follow-up data are still required to answer the question of longevity of immune protection and whether booster vaccination(s) will be necessary, and at what time interval.
3. Because of ethical and consent issues, efficacy cannot be determined among pre-adolescent girls, but is assumed by extrapolating data from the young women involved in the original vaccination trials. These suggest higher immune responses following vaccination among young adolescent girls (and boys) when compared with young adults, suggesting that vaccination at this younger age may result either in longer sustained immunity, improved long-term clinical efficacy, or both.
4. It is difficult to assess the impact of an immunisation strategy when many factors are still unknown. 
5. The coverage for the third dose is critical as the vaccine is locally painful and girls may be reluctant to complete the course.
6. The vaccines remain prohibitively expensive - universal HPV vaccination is unlikely in resource-poor countries lacking organised screening programmes, where cervical cancer remains a major cause of cancer-related death in women, and vaccination would be most beneficial. Those countries providing HPV vaccination at the moment have more efficient cervical screening programmes and lower cervical cancer rates than those yet to introduce it.
7. Merck was the first of two pharmaceutical companies to license its vaccine in October 2006, giving it a commercial head start. This quadrivalent vaccine confers immunity against the two oncogenic strains of HPV responsible for 70% of cervical cancers (HPV 16 and 18), as well as two strains that together cause 90% of genital warts (HPV 6 and 11). To many, a vaccine that protects against four strains has appeared to be inherently ‘better’ than one protecting against two strains.15 The bivalent vaccine Cervarix did not become available until almost a year later, in September 2007. Cervarix protects against HPV types 16 and 18, but does not prevent genital warts.
8. Insofar as Cervarix does not prevent genital warts, its use may amount to a ‘missed opportunity’. Genital warts are a very common sexually transmitted viral infection responsible for unsightly lesions that are both difficult and costly to treat. Women with genital warts also risk spread of the infection to the respiratory tract of their newborn infant during childbirth. Recurrent respiratory papillomatosis is a rare, but chronic, debilitating disease characterised by hoarseness, stridor and respiratory distress in the newborn, and requires lifelong repeated surgical intervention and prolonged hospital stays, even causing death in a minority of cases.
9. Published data do not distinguish either vaccine as superior in terms of clinical effectiveness or toxicity. However, recent data released by GlaxoSmithKline from their head-to-head comparison of the two vaccines reported that Cervarix induced significantly higher HPV 16 and 18 serum neutralising antibody titres, as well as higher levels of neutralising antibodies in cervicovaginal secretions and circulating HPV 16 and 18-specific memory B-cells. These results would suggest that a longer duration of protection against HPV infection may be conferred by Cervarix. Declining antibody levels post-vaccination may not, however, indicate a loss of protection, as immunological memory may persist at low levels, and is difficult to measure. Natural viral challenge may be sufficient to ‘boost’ declining serological responses, although booster vaccination is superior.
10. Future cervical screening. Cervical cancer develops after an infection period of a decade or more, and up to 30% of cervical cancers are caused by HPV types not included in either vaccine. Although some degree of cross-protection against similar high-risk HPV types has been presumed from trial data, vaccinated women are still clearly at risk of contracting other oncogenic HPV types that can cause cervical cancer, and cervical screening will still be necessary, even for vaccinated women.
11. Safety scares. In general, both Cervarix and Gardasil appear to be safe and well tolerated. Injection site adverse events, including pain, swelling and redness, have been reported more frequently by women receiving the vaccine, compared with those receiving placebo in clinical trials. Cervarix is recognised to be a more painful inoculation than Gardasil, but even so, most side effects disappear within the first day or two.
12. There have been no deaths attributable to either vaccine in any of the clinical trials to date. Pregnancy and congenital anomaly data have been reported for Gardasil, but not for Cervarix. Higher rates of congenital anomalies unrelated to type have been observed.
13. Maintaining high vaccine coverage. Interim results for the uptake of the third dose has shown a drop in coverage from 83% at the first dose to 74% for dose 3. Whether girls who receive only the first two doses of the vaccine will show sufficient immunity against HPV to prevent subsequent infection remains unclear.
14. The effect of mistimed doses is not fully understood. Data from hepatitis B vaccination studies suggest that longer intervals between second and third doses of the HPV vaccine may not be detrimental to the strength of the immunity generated, presumably as long as HPV exposure does not occur during the delay.

No benefit from GnRH analogue pretreatment for hysteroscopic submucous fibroid resection

Uterine fibroids are the most common benign tumours of the female reproductive tract. On the basis of their location, they can be divided into submucous, intramural or subserosal. Fibroids tend to grow in an estrogenic environment as evidenced by the reduction in size during menopause or in a medically induced hypoestrogenic state, such as with Gonadotrophin Releasing Hormone (GnRH) analogue therapy. Hysterectomy remains the only method of definitive treatment for symptomatic fibroids. However, conservative treatment may be desirable in many instances, chief among which would be the maintenance of child-bearing capability. Other reasons for keeping one’s uterus include better sexual functioning and avoidance of surgery, whether by choice or clinical reasoning.

This conservatism has lead to a proliferation of less invasive methods pursuing management of fibroids without recourse to surgery. Medical therapy provides only temporary relief of variable duration with repeat treatments a nuisance. Amongst the various radiological interventions, uterine artery embolization is an effective procedure, though not an ideal solution if future fertility is desired.(1) Hysteroscopic resection is quite feasible for treatment of submucosal fibroids, and the subject of our current attention.

Whether surgical or otherwise, all these methods can be hampered by complications such as bleeding, obstructed views and inadequate resection during the procedure. In order to minimize these risks, shrinking the fibroids to a more manageable size prior to the procedure offers a logical and practical proposition. GnRH analogue therapy has been advocated as a means to this end for some time now. Advantages of such pretreatment include reduction of fibroid size, bleeding and operating time and visual improvement during the procedure. Disadvantages, it has been said, include non-identification of tumour and tumour recurrence post-procedure. Many investigations in the past have set out to settle this issue once and for all but no definitive data has yet emerged.

The latest study to address this issue involved 47 reproductive-aged women with symptomatic submucosal fibroids randomly assigned to receive 3 months of depot goserelin or placebo injections prior to hysteroscopic resection (2). Sample size was calculated on the basis of an expected complete resection rate of about 50% without pretreatment and an improvement in resection rate to 92% with use of GnRH analogue. The primary outcome measure was the rate of complete resection of the fibroids.

Baseline characteristics and the number and size of submucous fibroids were well balanced in the study groups. Overall, 75% of the women had complete fibroid resection; this frequency was similar in both groups. Fibroid size and degree of intramural involvement were negatively associated with the frequency of successful complete resection. The duration of the procedure, the amount of distention fluid used, and the complication rates (excessive fluid deficit, bleeding, and perforation) were similar in the 2 groups. A similar proportion of women reported symptom improvement, and the need for second surgeries was not different between the 2 groups. On the basis of their findings, Mavrelos and colleagues concluded that preoperative use of GnRH analogues does not improve the outcome of hysteroscopic resection of submucous fibroids.

Evaluation of the outcomes of such trials requires the consideration of many factors. Although the study design seems sturdy, the number of patients involved in this case is not life-defining. A much larger number is required to provide significance. Surgical expertise plays an important part and a fairly high complete resection rate in the placebo arm might reflect the presumed above-average experience of the single surgeon involved. Results might differ with less experienced surgeons or in patients who truly benefit from GnRH analogue pretreatment. Since this study only evaluated women with submucous fibroids, the results obviously cannot be applied to fibroids of other persuasions. Thus, although this study did not find a benefit with GnRH therapy prior to hysteroscopic fibroid resection, use of this therapy should still be considered on an individual basis.

References

1. Freed MM, Spies JB. Uterine artery embolization for fibroids: a review of current outcomes. Semin Reprod Med. 2010;28:235-241. 

2. Marvelos D, Ben-Nagi J, Davies A et al. The Value of Pre-operative Treatment With GnRH Analogues in Women With Submucous Fibroids: A Double-Blind, Placebo-Controlled Randomized Trial. Hum Reprod. 2010;25:2264-2269

FDA approves novel folate OCP

The US Food and Drug Administration (FDA) on 25 September 2010 approved a novel oral contraceptive that is formulated to provide both contraception and reduce the risk for neural tube defects in their offspring if and when they give birth. The new contraceptive, Beyaz (Bayer HealthCare Pharmaceuticals), contains levomefolate calcium, a metabolite of folic acid. Prepregnancy folate supplementation has been associated with a decreased risk of fetal neural tube defects. Thus arises the recommendation that women of childbearing age supplement their diet with folate. This is a logical step since women may become pregnant during oral contraceptive use or shortly after discontinuation. The approval is based on the already-approved oral contraceptive drospirenone/ethinyl estradiol (Yaz, Bayer HealthCare Pharmaceuticals), which contains the same doses of estrogen and progestin.

Apart from the primary indication of contraception, Beyaz is also approved for the treatment of symptoms of premenstrual dysphoric disorder (PMDD), acne vulgaris and the prevention of fetal neural tube defects in women who choose an oral contraceptive as their method of contraception.

According to the FDA (www.fda.gov), the primary efficacy study for Beyaz was a multicenter, double-blind, randomized, controlled U.S. trial in 379 healthy women aged 18 to 40 who were treated with Beyaz or YAZ alone for up to 24 weeks. Beyaz was found to increase folate levels in women. In a German study of Beyaz, folate levels remained elevated for several weeks following discontinuation of Beyaz.  Safety and efficacy data for contraception, PMDD, and acne indications were obtained from previous YAZ clinical trials.

The clinical trials of Beyaz did not yield any findings that would suggest it differs from Yaz in terms of its overall safety profile. It is expected that the most common adverse events for Beyaz will be the same as those for Yaz. Adverse effects most frequently reported by users of combined oral contraceptives are irregular uterine bleeding, nausea, breast tenderness, and headaches.

New propylthiouracil warnings change face of hyperthyroid treatment in pregnancy

Untreated hyperthyroidism in pregnancy places the mother and child at an elevated risk for a number of adverse outcomes, including preeclampsia and congestive heart failure. Because radioactive iodine is not a viable option during pregnancy, and surgery is risky, health care professionals are limited to propylthiouracil and methimazole. 

Recent warnings from the FDA, however, have addressed serious adverse reactions to propylthiouracil, including severe liver injury and acute liver failure — some fatal — leading the agency to recommend reserving use for patients who cannot tolerate other available treatments. It has been known since the 1940s that PTU can cause severe, potentially life-threatening hepatotoxicity. While this risk is not necessarily new to endocrinologists, there has recently been a push to recognize it as a potential problem 

Physicians are faced with an additional challenge in treating pregnant women with hyperthyroidism because of risks for birth defects observed with the commonly used drug methimazole. Experts, professional guidelines and the FDA currently recommend PTU as the treatment of choice before and during the first trimester of pregnancy. 

A study published in the Journal of Clinical Endocrinology & Metabolism in June revealed that methimazole is now the most commonly prescribed antithyroid treatment. Prescriptions for methimazole increased ninefold between 1991 and 2008, from 158,000 to 1.36 million per year, and the number of prescriptions has surpassed PTU as the most frequently prescribed antithyroid drug. In the study, women of childbearing age were the only demographic for which methimazole prescriptions decreased. 

Risks of therapy 

Of the 4 million pregnancies in the United States each year, 4,000 women are treated with antithyroid drugs and, until recently, most were prescribed PTU. Although in-depth data on hyperthyroid pregnancies are generally unavailable, it is estimated that four pregnant women per year will develop severe hepatic issues linked to PTU use, according to information provided by the FDA. In June 2009, the FDA released a black box warning highlighting hepatic dangers associated with PTU treatment, including serious liver injury, liver failure and death in adults and children. The warning was based on 32 cases of serious liver injury — 10 in children — which resulted in 13 deaths and 11 liver transplants. According to the FDA alert, methimazole was also linked to serious liver injury but to a lesser extent: five adult cases resulting in three deaths. 

The FDA updated its warning in April 2010 and recommended reserving use of PTU for those who cannot tolerate other treatments. The agency also required that a medication guide be distributed to each patient who fills a prescription for PTU. PTU had always been the preferred treatment in pregnancy over methimazole in the United States because it was thought from early studies that it did not cross the placenta to the same extent as methimazole. That has been proven wrong over the last 10 years. Recent studies, such as one published by Mortimer and colleagues in JCEM in 2007, have shown that PTU and methimazole have similar placental transfer kinetics. 

The original rationale for PTU no longer exists. However, PTU is still preferred, but not because of the reason initially thought; rather, it is now because of rare reports of birth defects associated with methimazole. Although the primary dangers of PTU treatment involve hepatic injury to the mother, the dangers of methimazole are concentrated on the developing fetus. The risks of methimazole include embryopathies such as aplasia cutis congenita, choanal atresia, esophageal atresia and tracheoesophageal fistula. According to the most recent FDA warning, congenital malformations were reported approximately three times more often with prenatal exposure to methimazole vs. PTU: 29 cases vs. nine cases. In addition, a distinct and consistent pattern of congenital malformations was observed with methimazole use. Developmental abnormalities such as cutis aplasia can occur with methimazole use early in the first trimester. However, these abnormalities are quite rare. It is not clear what the association is between methimazole and embryopathy due to lack of substantial data from large-scale studies. What is known is that based on several studies that looked at large cohorts of people, children exposed in utero to methimazole were at a greater risk for embryopathy compared with the general population. However, just how frequently it occurs remains unknown. 

It has been postulated that perhaps the embryopathy risk is not necessarily due to methimazole but rather the hyperthyroidism itself, according to a study cited by Mandel that was published in theAmerican Journal of Genetics in 2008. Barbero and colleagues conducted the multicenter, case-control study to compare the frequency of maternal hyperthyroidism treated with methimazole during pregnancy in children with choanal atresia. According to the results, prenatal exposure to methimazole was identified in 10 of 61 cases (16.4%) compared with two of 183 (1.1%) in a control group (OR=17.75; 95% CI, 3.49-121.40). The researchers concluded that prenatal exposure to maternal hyperthyroidism treated with methimazole appears to be associated with choanal atresia. Based on the cases and a critical literature review, they proposed that the mother’s disease might be the causal factor, and not the methimazole treatment. 

Combination treatment 

To avoid overt hyperthyroidism and adverse effects to the mother and baby, many experts and the FDA suggest a patchwork solution: treatment with PTU during the first trimester and, after organogenesis, a switch to methimazole. Guidelines from the American Thyroid Association and The Endocrine Society recommend: “Because available evidence suggests that methimazole may be associated with congenital anomalies, PTU should be used as a first-line drug, if available, especially during first-trimester organogenesis. Methimazole may be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse response to PTU.” There should not be any methimazole-related birth defects after the first trimester. 

But, the transition from PTU to methimazole presents a unique set of problems. One worry is that after managing the patient’s hyperthyroidism with PTU, control may be lost during the switch to methimazole. If control is lost, it should be regained as soon as quickly as possible. 

Goals of therapy 

Ultimately, the risks for hyperthyroidism in pregnancy outweigh the risks for rare hepatic injury and embryopathy associated with these antithyroid drugs.Management with antithyroid drugs should be approached not with the goal of attaining mid-range thyroid hormone levels, but those at the upper limits of normal. It is preferred for the patient to be mildly clinically hyperthyroid. Subclinical hyperthyroidism does not have any adverse effect of pregnancy or delivery or the baby, but it reduces the amount of drugs given to patients. Not overtreating a woman during pregnancy is integral. 

Prepregnancy planning 

A further consideration regarding hyperthyroid pregnant women is that of prevention. The first question to ask a hyperthyroid patient is: When do you plan on conceiving? The best approach for a woman with Graves’ disease may be to avoid the entire question of methimazole and PTU during pregnancy, and render her hypothyroid before she conceives. If antithyroid drugs are necessary during pregnancy, a positive trend is that the condition generally improves with treatment. Autoimmune diseases such as Graves’ disease do tend to improve during pregnancy, so it is often possible to stop the treatment late in pregnancy. But each patient is different, and the doses will need to be adjusted and monitored. Other times, the physician will be able to wean the woman off of treatment late in the second trimester. However, after giving birth, some women may become hyperthyroid again, and some women will develop postpartum thyroiditis despite being fine during their pregnancy. 

Further treatment factors 

Although antithyroid drugs are ideally limited during pregnancy, other treatments are avoided altogether. Surgery and radioactive iodine — common treatments for general hyperthyroidism — are usually not feasible options during pregnancy. Radioactive iodine will cross the placenta, placing the fetus at an elevated risk for hypothyroidism, which is why it is never used during pregnancy.Surgery is also sparingly used. This option is something of a last resort to be turned to only if the patient is allergic or non-adherent to both methimazole and PTU, or if hyperthyroidism is uncontrolled. If necessary, it is safest in the second trimester. 

Summary recommendation 

Based on the currently available information, the best course of action to minimize the risk for mother and fetus is PTU treatment during the first trimester — strongly advising the patient on signs of liver injury and with careful monitoring — and then switch to methimazole following organogenesis. However, this recommendation is based on incomplete data and more studies in this area are needed.


Edited by Hanifullah Khan from an article by Matthew Brannon published in Endocrine Today on 1 September 2010

Editorial - The Avandia Saga Continues - NYTimes.com

A panel of expert advisers to the Food and Drug Administration delivered a confusing verdict on Wednesday after two days of hearings on the safety of the diabetes drug Avandia. A majority of the 33-member panel expressed concern that Avandia raises the risk of heart attacks compared with other diabetes drugs. But a majority also voted to leave the drug on the market anyway, with various degrees of restrictions or warnings. It will now be up to patients and their doctors to decide whether the risk is worth taking in particular cases.

In the crucial votes on Wednesday, the experts were asked to choose among five options for regulatory actions that the F.D.A. might take. Twelve voted to remove Avandia from the market. Ten voted to leave it on the market while further beefing up warning labels and adding restrictions on use, such as allowing only certain physicians to prescribe it or requiring special education for doctors and patients. Another 10 would settle for the current or somewhat stronger warnings. (One expert abstained.)

Some analysts see a victory for Glaxo, in that 20 of the panelists voted to retain the drug. But it is hardly reassuring that 22 of the panelists voted either for severe restrictions or complete banishment. The process doesn’t end here. The panel also voted to continue a large Glaxo-sponsored clinical trial to compare the cardiovascular risks of Avandia with those of Actos, its major rival, and with standard treatments for diabetes. Even if that trial is allowed to go forward, the results won’t be in for years. Right now, doctors and patients will have to think very hard before using a drug that a majority of these experts has deemed risky.

The clearest lesson to emerge from the hearings and other recent revelations is that GlaxoSmithKline, the maker of Avandia, can’t be trusted to report adverse clinical results fairly. The most troubling aspect of the Avandia saga is evidence — from internal company documents and investigations by a Senate committee and an F.D.A. investigator — that Glaxo sought to hide emerging indications of Avandia’s heart risks. Glaxo failed to report the results of a 1999 study that showed Avandia might be riskier for the heart than a competing drug (“these data should not see the light of day,” cautioned an internal e-mail message). And Glaxo made Avandia look good in a major clinical trial by failing to include in its tally of adverse events at least a dozen patients who suffered serious heart problems. The company found reasons to drop them from the study or misreport their ailments.

The company must be watched like a hawk as additional trials that it sponsors go forward.

New Position Statement on Menopausal Hormone Therapy

The Endocrine Society (USA) issued a scientific statement titled "Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement" that was published in the July 2010 issue of the Journal of Clinical Endocrinology & Metabolism (JCEM). This statement evaluates benefits and risks for postmenopausal hormone replacement therapy (HRT), now known as menopausal hormone therapy (MHT).

MHT was in widespread use in the 1990’s due to the belief that it prevented heart disease, fractures, memory loss and dementia in addition to its established role in relieving uncomfortable menopausal symptoms. This situation changed drastically in 2002 mainly due to the publication of the Women's Health Initiative (WHI) Study that showed that MHT was actually associated with an increased risk for heart disease, stroke, and breast cancer. It was reported then that MHT use declined as much as 80% from before.

Despite its huge impact, WHI nevertheless had its criticisms.  The average age of the study group, 63 years, was rather advanced. Women typically contemplate initiating MHT between the ages of 50 to 54 years, and this group only made up 3.5% of the total participants in that study. WHI also did not consider menopausal symptom relief amongst these patients. Data from later studies evaluating the effects of MHT in women aged 50 to 55 years have thus been taken into consideration in issuing this latest scientific statement.

Recent evidence suggests that the afore mentioned health risks may not be applicable to all women using MHT. An important factor to consider is the time after onset of menopause when MHT is started, a factor not considered in the WHI assessment of MHT safety and efficacy.

According to the findings of Santen et al in their study published in the JCEM, women who begin MHT a short time after the onset of menopause at ages 50 to 59 years actually appear to benefit from that treatment. It is further evidenced that women in the short-time group using MHT for 5 years had a 30% to 40% reduction in mortality risk and no increased cardiovascular disease risk. In addition, they had a 90% decrease in hot flashes, overactive bladder, or other menopausal symptoms.

A very large portion of the anxiety among perimenopausal women is the risk of occurrence of breast cancer. Santen et al found that some patients who utilized MHT even in its short-time form nevertheless developed this dreaded disease. However, this only applied to those who used the combination of estrogen plus a progestogen and not with estrogen alone. They postulate that this may have been due to the stimulation and uncovering of very small, undiagnosed breast cancers, rather than de novo cancers.

In summary, the Endocrine Society states urges physicians and their patients to re-think the use of MHT based on data pertinent to the 50-55 year old age group and to individualize therapy based on symptoms and underlying risks of breast cancer and heart disease.

The Link Between Endometriosis and Cancer

         Women with endometriosis appear to be more likely to develop certain types of cancer. What scientists know about the link - and why it might occur - were the focus of a session at the inaugural symposium of the Endometriosis Foundation of America. Chief of the Hormonal and Reproductive Epidemiology branch at the National Cancer Institute, Louise Brinton’s interest in the long-term effects of endometriosis led her to Sweden about 20 years ago. Using the country's national inpatient register, she identified more than 20,000 women who had been hospitalized for endometriosis.[1] After an average follow-up of more than 11 years, the risk for cancer among these women was elevated by 90% for ovarian cancer, 40% for hematopoietic cancer (primarily non-Hodgkin's lymphoma), and 30% for breast cancer. Having a longer history of endometriosis and being diagnosed at a young age were both associated with increased ovarian cancer risk.

An increased risk for tumors with increasing years of follow-up was found. This made it unlikely that the ovarian cancer diagnoses were related to increased surveillance during endometriosis treatment. Also of special interest was the finding that women whose site of origin of endometriosis was the ovary had a particularly high risk for ovarian cancer. Dr. Brinton and colleagues published their research in 1997. A larger, more recent examination of the Swedish register, published in 2006 by Anna-Sofia Melin and colleagues, produced similar results.[2]

These 2 studies indicate a high risk related to follow-up time and site of origin of endometriosis, which suggests a biologic effect between the 2 diseases. On the other hand, confounding factors could be at work. For example, women being treated for endometriosis are more likely to be experiencing infertility, which affects risk because childbearing offers some protection against ovarian cancer. A 2002 pooled case-control study by Roberta B. Ness and colleagues found that the odds of developing ovarian cancer were 50% higher among women diagnosed with endometriosis, even after adjusting for factors such as duration of oral contraception use and number of births.[3] The risk was even higher -- a 3.5-fold increase -- for women with endometrioid or clear cell tumors, 2 subtypes of ovarian cancer. A 2005 case-control study by Brinton and colleagues also found a 2.5- to 3.5-fold increase in endometrioid and clear cell tumors among women with endometriosis.[4]

The overall lifetime risk for ovarian cancer is 1.4%, according to the American Cancer Society.[5] Endometriosis affects as many as 7% to 15% of women of reproductive age. Regarding the link between epithelial ovarian cancer and endometriosis, according to a 2000 study of women with ovarian cancer by Hiroyuki Yoshikawa and colleagues, endometriosis was present in 39% of the women with clear cell tumors and 21% of those with endometrioid tumors, vs just 3% of those with serous or mucinous tumors.[6] Nezhat and colleagues also identified a link between endometriosis and ovarian cancer.[7] A pathology review of samples from 76 patients with stage 1 ovarian cancer revealed that most were associated with endometriosis or endometrioma. Most patients presented with pelvic pain or adnexal mass, supporting the idea that healthcare providers should be alert to the possibility of ovarian cancer in women with a history of endometriosis.

Studies have been inconsistent on whether endometriosis is linked to breast cancer or non-Hodgkin's lymphoma. Anecdotal evidence has linked endometriosis to melanoma, brain and endocrine cancers, and thyroid cancer. Large epidemiologic studies are required to examine these associations.

The Pathogenesis of Endometriosis and Cancer

Both endometriosis and ovarian cancer are progressive diseases and depend on estrogen for their growth. Studies have shown that endometrial tissue shows elevated activity of aromatase, an enzyme used for a key step in the biosynthesis of estrogens.

Another factor that appears to play a role in both diseases is inflammation. Inflammation can cause cancer, as seen in hepatitis of the liver and asbestosis of the lung. Endometriosis is characterized by a chronic inflammatory state, which leads to the release of cytokine. These cytokines may promote the growth of tumours by causing unregulated mitotic division, growth, and differentiation. The combination of inflammation with estrogen can be a vicious circle.

The 2 diseases share numerous other characteristics. For example, both are related to early menarche and late menopause, infertility, and nulliparity. Factors that relieve or offer protection against both conditions include tubal ligation, oral contraceptives, hysterectomy, and progesterone exposure.

Mutations in genes that are known to suppress tumors, such as PTEN, p53, and bcl, have been found in both ovarian tumors and adjacent endometriotic lesions.

Of course, links between the 2 diseases don't prove that one causes the other. But there's reason to believe that endometriosis contributes to ovarian cancer, as evidenced by Dr. Brinton's finding that cancer risk increases with duration of endometriosis. If endometriosis does increase the risk for ovarian cancer, then treating it might reduce the risk

Advice to Surgeons and Patients

Surgeons who operate on women with endometriosis, which includes fertility specialists performing in vitro fertilization (IVF), need to be alert to the possibility of ovarian cancer. Ultrasound scanning should be carried out during the preoperative evaluation and the follow-up. Surgeons are also cautioned to biopsy any ovarian cysts instead of just draining them. Every adnexal mass has to be thoroughly evaluated.

Although the elevated risk for ovarian cancer appears to be real, women with endometriosis should not become too anxious about it. Even though a 2- to 3-fold increase in the risk for ovarian cancer is noted, it's still a very rare condition with the absolute risk being low.

References

1.      Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol. 1997;176:572-529. Abstract
2.      Melin A, Sparén P, Persson I, Bergqvist A. Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Hum Reprod. 2006;21:1237-1242. Abstract
3.      Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol. 2002;155:217-224. Abstract
4.      Brinton LA, Sakoda LC, Sherman ME, et al. Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors. Cancer Epidemiol Biomarkers Prev. 2005;14:2929-2935. Abstract
5.      US National Institutes of Health. National Cancer Institute Fact Sheet. BRCA1 and BRCA2: cancer risk and genetic testing. Available at: http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA Accessed May 24, 2010.
6.      Yoshikawa H, Jimbo H, Okada S, et al. Prevalence of endometriosis in ovarian cancer. Gynecol Obstet Invest. 2000;50(suppl 1):11-17. Abstract

7.      DeLigdisch L, Pénault-Llorca F, Schlosshauer P, Altchek A, Peiretti M, Nezhat F. Stage I ovarian carcinoma: different clinical pathologic patterns. Fertil Steril. 2007;88:906-910. Abstract

 Edited from an article by Devon Schuyler on  Medscape Ob/Gyn & Women's Health