Menopausal hormone therapy association with breast cancer strengthened

In 2002, the Women's Health Initiative (WHI) randomized trial of placebo vs hormone therapy with estrogen and progestin was stopped early because of evidence of harm.¹ Sales of combined estrogen-progestin plummeted 32% between the period immediately before the study's release and the analogous period 1 year later, as the WHI trial had shown that hormone therapy increased a woman's risk of breast cancer and myocardial infarction.² The finding contradicted decades of case-control and observational cohort studies that had suggested that hormone therapy was associated with strong protective effects on the cardiovascular system. The WHI results also undermined a long and successful campaign by hormone replacement advocates to present hormone therapy as a panacea against heart disease, loss of femininity, and other perils of aging. In addition, the WHI documented numerous other negative effects of hormone therapy, including an increased risk of stroke and pulmonary embolism,¹ which are not strongly associated with the timing of hormone therapy initiation. Ultimately, the only long-term benefit of hormone therapy that the US Food and Drug Administration (FDA) allows the manufacturer to claim is reduction of risk of osteoporotic fractures.³

That breast cancer rates in the WHI increased among women receiving hormone therapy was not surprising. Epidemiological and biological studies had anticipated the effect,⁴ although the magnitude of risk was not known until the WHI, which showed that the effect of hormone therapy on breast cancer risk was about the same as the deleterious effect on cardiovascular health. Several years after use of hormone therapy plummeted in the United States, breast cancer incidence also declined.⁵

Chlebowski et al⁶ report results of an 11-year follow-up of WHI estrogen-progestin trial participants that address many of these questions. The authors found that hormone therapy increases the frequency of breast cancer and that the breast cancers are on average more advanced and may be larger. The authors found no evidence that the cancers had favourable prognostic features, such as more frequently being estrogen receptor positive or lacking HER2 /neu gene amplification. If anything, the results suggest a trend in the direction of less favourable cancers. In addition, the authors found strong evidence that the rate of breast cancer death is increased by hormone therapy. It is also probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study and that with longer follow-up, the deleterious effect will appear larger. This suggestion is based on several observations: the mortality curves appear to still be separating at the end of the current follow-up (Figure 4A in the article); the difference in cumulative breast cancer incidence between women in the hormone therapy and placebo groups is widening (Figure 2 in the article), which will ultimately lead to more deaths; and the breast cancers diagnosed among women who received hormone therapy are associated with a poorer prognosis.

Based on present data, the authors project that approximately 1.3 additional deaths from breast cancer per 10 000 person-years of follow-up have already occurred among the women who received hormone therapy in the study. Since this number is relatively small, clinicians might conclude that a brief period of hormone therapy for relief of menopausal symptoms is safe. Such a view would be consistent with some professional guidelines⁷ and with the FDA-approved label for combined estrogen-progestin therapy.³ However, the study by Chlebowski et al⁶ does not address the effect of short periods of hormone therapy on breast cancer risk (or other disease risk), and the current estimate of the deleterious effects of hormone therapy may be underestimated.

Therefore, the available data dictate caution in the current approach to use of hormone therapy, particularly because one of the lessons from the WHI is that physicians are ill-equipped to anticipate the effect of hormone therapy on long-term health. Clinicians who prescribe brief courses of hormone therapy for relief of menopausal symptoms should be aware that this approach has not been proven in rigorous clinical trials and that the downstream negative consequences for their patients are of uncertain magnitude. Given the substantial population of women who seek relief from menopausal symptoms and the large potential burden of disease that could be created if medications given to alleviate symptoms today cause cancer and other deaths tomorrow, it seems that additional randomized trials are needed specifically to determine whether lower doses or shorter durations of hormone therapy could alleviate menopausal symptoms without increasing cancer risk.

References

1. Rossouw JE, Anderson GL, Prentice RL; et al, Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

2. Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women's Health Initiative. JAMA. 2004;292(16):1983-1988.

3. US Food and Drug Administration. Prempro prescribing information. 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020527s045lbl.pdf

4. Key TJA, Pike MC. The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol. 1988;24(1):29-43. 

5. Chlebowski RT, Kuller LH, Prentice RL; et al, WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573-587.

6. Chlebowski RT, Anderson GL, Gass M; et al, WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA.2010;304(15):1684-1692.  

7. US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the US Preventive Services Task Force. Ann Intern Med. 2005;142(10):855-860.

Edited by Hanifullah Khan from  Bach PB. Postmenopausal Hormone Therapy and Breast Cancer: An Uncertain Trade-off. JAMA  2010;304(15):1719-1720. doi:10.1001/jama.2010.1528

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

Individualized management important for perimenopausal symptoms

Women must be informed of the potential benefits and risks of all treatment options for menopausal symptoms and concerns and should receive individualized care, according to a review of the role of perimenopausal hormone therapy published in the April issue of Obstetrics & Gynecology.

Many therapeutic options are currently available for management of quality of life and health concerns in menopausal women. Treatment of vasomotor hot flushes and associated symptoms is the main indication for hormone therapy, which is still the most effective treatment of these symptoms and is currently the only US Food and Drug Administration–approved option. For healthy women with troublesome vasomotor symptoms who begin hormone therapy at the time of menopause, the benefits of hormone therapy generally outweigh the risks.

However, hormone therapy is associated with a heightened risk for coronary heart disease as evidenced by the results of the Women's Health Initiative (WHI) trial in 2002. Based on recent analyses, this higher risk is attributable primarily to older women and to those who reached menopause several years previously. Hormone therapy should not be used to prevent heart disease, based on these analyses. However, this evidence does offer reassurance that hormone therapy can be used safely in otherwise healthy women at the menopausal transition to manage hot flushes and night sweats.

Although hormone therapy may help prevent and treat osteoporosis, it is seldom used solely for this indication alone, particularly if other effective options are well tolerated.

Short-term treatment with hormone therapy is preferred to long-term treatment, in part because of the increased risk for breast cancer associated with extended use. The lowest effective estrogen dose should be given for the shortest duration required because risks for hormone therapy increase with advancing age, time since menopause, and duration of use.

Low-dose, local estrogen therapy is recommended vs systemic hormone therapy when only vaginal symptoms are present.

Alternatives to hormone therapy should be recommended for women with or at increased risk for disorders that are contraindications to hormone therapy use. These include breast or endometrial cancer, cardiovascular disease, thromboembolic disorders, and active hepatic or gallbladder disease.

In addition to estrogen therapy, progestin alone, and combination estrogen-progestin therapy, there are several nonhormonal options for the treatment of vasomotor symptoms. Lifestyle interventions include reducing body temperature, maintaining a healthy weight, stopping smoking, practicing relaxation response techniques, and receiving acupuncture.

Although efficacy greater than placebo is unproven, nonprescription medications that are sometimes used for treatment of vasomotor symptoms include isoflavone supplements, soy products, black cohosh, and vitamin E.

There are several nonhormonal prescription medications sometimes used off-label for treatment of vasomotor symptoms, but they are not approved by the Food and Drug Administration for this purpose. These drugs, and their accompanying potential adverse effects, include the following:

• Clonidine, 0.1-mg weekly transdermal patch, with potential adverse effects including dry mouth, insomnia, and drowsiness.
• Paroxetine (10 - 20 mg/day, controlled release 12.5 - 25 mg/day), which may cause headache, nausea, insomnia, drowsiness, or sexual dysfunction.
• Venlafaxine (extended release 37.5 - 75 mg/day), which is associated with dry mouth, nausea, constipation, and sleeplessness.
• Gabapentin (300 mg/day to 300 mg 3 times daily), with possible adverse effects of somnolence, fatigue, dizziness, rash, palpitations, and peripheral edema.

Women should be informed of the potential benefits and risks of all therapeutic options, and care should be individualized, based on a woman's medical history, needs, and preferences. For women experiencing an early menopause, especially before the age of 45 years, the benefits of using HT until the average age of natural menopause likely will significantly outweigh risks. The large body of evidence on the overall safety of oral contraceptives in younger women should be reassuring for those experiencing an early menopause, especially given the much lower estrogen and progestin doses provided by HT formulations.

Edited from an article by Laurie Barclay MD published in Medscape Medical News titled Hormone Therapy for Menopause Reviewed

Abstract

Obstet Gynecol. 2010 Apr;115(4):839-55.

Role of hormone therapy in the management of menopause.

Shifren JL, Schiff I.

Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, and Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. jshifren@partners.org

Abstract

There are many options available to address the quality of life and health concerns of menopausal women. The principal indication for hormone therapy (HT) is the treatment of vasomotor symptoms, and benefits generally outweigh risks for healthy women with bothersome symptoms who elect HT at the time of menopause. Although HT increases the risk of coronary heart disease, recent analyses confirm that this increased risk occurs principally in older women and those a number of years beyond menopause. These findings do not support a role for HT in the prevention of heart disease but provide reassurance regarding the safety of use for hot flushes and night sweats in otherwise healthy women at the menopausal transition. An increased risk of breast cancer with extended use is another reason short-term treatment is advised. Hormone therapy prevents and treats osteoporosis but is rarely used solely for this indication. If only vaginal symptoms are present, low-dose local estrogen therapy is preferred. Contraindications to HT use include breast or endometrial cancer, cardiovascular disease, thromboembolic disorders, and active liver disease. Alternatives to HT should be advised for women with or at increased risk for these disorders. The lowest effective estrogen dose should be provided for the shortest duration necessary because risks increase with increasing age, time since menopause, and duration of use. Women must be informed of the potential benefits and risks of all therapeutic options, and care should be individualized, based on a woman's medical history, needs, and preferences.

                                        

A Practical Approach to Diagnosing PCOS in the Adolescent

Hanifullah Khan

Women’s Health and Endometriosis Care Centre, Lumut, Malaysia

Introduction

Polycystic Ovary Syndrome (PCOS) has become the most common endocrine abnormality of women with a reported prevalence of 6% to 7%¹. It is frequently associated with ovulatory dysfunction that begins in the perimenarchal period. The classic symptoms are a result of a primarily ovarian overproduction of androgens, hyperinsulinaemia and chronic anovulation causing symptoms such as menstrual abnormalities, hirsutism and acne. Obesity can also be an associated feature. Additionally, the ovaries display a typical morphologic pattern that appears to be unique to the disorder.

From a reproductive point of view, puberty can be considered as the process by which hormonal changes take place in order to permit the expulsion of mature oocytes from the ovary, thus allowing fertilization to occur². For ovulation to happen however, a series of sequential hormonal events must take place in a highly synchronized manner. A healthy ovary will subsequently exhibit regular monthly ovulations, characterized by a 25 to 36 day cycle, although anovulatory cycles and irregular periods may occur during the first 2-5 years after menarche³. Irregular menstrual cycles that persist beyond these years may be a sign of an underlying hormonal disorder⁴. As previously stated, many women with PCOS recall the onset of their symptoms around the time of puberty or during the early adolescent period.

The metabolic syndrome is characterised by central adiposity, hypertension, increased triglycerides, low levels of high density lipoproteins, impaired glucose tolerance and diabetes mellitus. It is also associated with long term health risks such as cancer and cardiovascular disease. This syndrome has been shown to be very prevalent in women with PCOS⁵. Compared to a normal adolescent girl, adolescents with PCOS are at increased risk for the development of type 2 diabetes mellitus and the metabolic syndrome⁶. In fact, PCOS is now considered a major risk factor for the development of Type 2 diabetes mellitus. Because of the established link between PCOS and the metabolic syndrome, many have now begun to view PCOS as a premetabolic syndrome condition⁷. Establishing PCOS status in adolescence provides a unique opportunity for early intervention, the failure of which may result in delayed treatment and a lower quality of life⁸.

Although many issues surrounding the understanding and diagnosis of PCOS remain clouded, its management in adult women is now fairly well determined. Quite the reverse, the diagnosis and management of PCOS in adolescents leaves many questions requiring solutions. As most of the accepted clinical features of PCOS (menstrual irregularities, acne and hirsutism) are associated with a “normal” adolescence, definitive diagnostic criteria have become blurred. Typical biochemical features of PCOS such as increased androgen and insulin secretion can often be a feature of normal growing up.

It is apparent that a greater appreciation of initial symptomatology is essential to allow for early therapeutic intervention to minimize the acute and chronic consequences of PCOS. Generally speaking, the diagnosis of this disorder can be indicated by the clinical presentation, although laboratory testing and imaging is necessary to exclude other possible conditions that may mimic it. The following review is an attempt to aid in the reliable clinical diagnosis of PCOS in adolescent and young adult women based on the historical and physical signs and a cost-effective use of investigational procedures.

Diagnostic quandry

            Difficulties in the diagnosis of PCOS and controversies in definition arise from the heterogeneous nature of the disorder. Girls and women may present with a variety of concerns and symptoms, including irregular periods, excess hair growth, acne, and obesity. Numerous attempts have been made to define and quantify PCOS from its earliest description in 1935⁹. So far, 3 sets of criteria have been proposed for the diagnosis of PCOS in adult women; the NIH, Rotterdam and Androgen Excess Society criteria. No set criteria exist for such a diagnosis in adolescents and teenagers.

In the United States, diagnosis has been based on the findings of irregular cycles (oligo/anovulation) and clinical or biochemical evidence of androgen excess with the absence of any tumour or adrenal enzymatic defect. These criteria came from a conference held at the US National Institute of Health (NIH) in 1991¹⁰. Although the original descriptor of this condition, these criteria did not include the presence of a particular ovarian morphology for diagnosis. It also did not allow for the inclusion of women who ovulate and have PCOS, a fact that had been previously documented.

On the other hand, the European definition of PCOS is highly reliant on the demonstration of polycystic morphology on ultrasound scanning. To reconcile these differences, a meeting in Rotterdam crafted compromise criteria which now carry the name of that city, and requires any two features from irregular cycles, hyperandrogenism and ultrasound demonstration of polycystic ovaries to diagnose PCOS¹¹. This definition results in four subsets of PCOS: (1) irregular menstrual pattern plus polycystic ovary morphology plus (clinical or laboratory) hyperandrogenism, (2) irregular menses plus hyperandrogenism, (3) hyperandrogenism plus polycystic ovary morphology, and (4) irregular menses plus polycystic ovary morphology¹². Importantly, the Rotterdam criteria allows for the previously excluded ovulatory women with features of PCOS, as well as for women who have irregular cycles and polycystic ovaries but no evidence of androgen excess. This latter phenotype of patients remains the centre of debate, as there is strong sentiment that androgen excess is key to the pathophysiology of PCOS.

Not surprisingly, the Androgen Excess Society (AES) Task Force on the Phenotype of PCOS in 2006 narrowed the Rotterdam consensus to exclude women who did not have androgen excess¹³. This criteria defines PCOS as a condition with hyperandrogenism (clinical or biochemical) and ovarian dysfunction (either oligo-anovulation and/or polycystic ovarian morphology on ultrasound) with the obvious exclusion of other disorders. This seems to be the most adequate for the diagnosis of PCOS in adolescence.

Some factors underlie the basis of this diagnostic quandary. Many of the features of PCOS may be a normal occurrence in the young woman. For example, menstrual cycles are frequently anovulatory; acne and mild hirsutism are common and obesity prevalent. Ultrasound scanning can be contradictory as polycystic-type ovaries can occur in healthy asymptomatic adolescents¹⁴, whereas only about half of adolescents with PCOS demonstrate polycystic ovaries¹⁵. Inaccuracies in current assay systems, coupled with limited laboratory data on androgen levels in pubertal and adolescent girls do not allow for a clear cut diagnosis of androgen excess. Furthermore, documented hyperandrogenemia amongst these patients has been associated with later normal ovulatory cycles¹⁶.

It is thus painfully apparent that quantifying PCOS in an adolescent girl is a challenging exercise. Understanding the clinical features with optimal use of investigative procedures would go a long way towards identifying the adolescent patient who might have PCOS.

Menstrual irregularity

Normal puberty is a gradual process which takes several years to be completed. During this time, certain developmental events such as acceleration of growth in height, breast budding and enlargement, appearance of sexual hair and menstrual bleeding occur. The onset of ovarian steroidogenesis is linked to hypothalamic Gonadotrophin Releasing Hormone (GnRH) and pituitary gonadotrophin secretion which in turn stimulate ovarian follicular maturation and subsequent menarche. Normal menstruation, however, does not commence immediately as there is a period of transition of between 1 to 3 years before regular ovulatory and menstrual cyclicity is achieved, although this itself can be very variable¹⁷. During this time, the bleeding pattern can be irregular and unpredictable as a result of anovulation. In addition, even if normal cycles do occur, they may not signify ovulation. This period of time may be referred to as one of physiologic anovulation.

As menstrual dysfunction occurs in about two thirds of adolescents with PCOS, and since the inception of irregular menses is frequently traced to menarche, it may be difficult initially to distinguish between PCOS and physiologic anovulation. The spectrum of anovulatory symptoms includes primary or secondary amenorrhea, oligomenorrhea (defined as irregular infrequent menses), dysfunctional uterine bleeding (due to endometrial hyperplasia) and anovulatory regular menses. What is important to know is that this disruption of menstrual bleeding is not uniform in all women with PCOS. It is now also recognized that some affected individuals can have normal ovulatory function, which implies that the presence of regular menses does not preclude the possibility of PCOS.

Because of the similarity of irregular, infrequent, or absent menstrual bleeding between those with normal puberty and those with PCOS, it may not be wise to base the diagnosis of PCOS solely on menstrual irregularity. Nevertheless, certain features of menstruation may suggest the presence of anovulation, if not PCOS. Irregular menstruation not typically preceded by premenstrual symptomatology is highly suggestive of anovulation. An irregular bleeding pattern that persists for more than 2 years after menarche also makes it likely that it is due to hyperandrogenemia. Apart from the aforementioned cycle irregularity, complete history taking for provisional identification of PCOS should also include age of menarche and presence of menstrual cramps and other symptoms of premenstrual stress.

Hyperandrogenism

Hyperandrogenism is one of the most common endocrine abnormalities in women of reproductive age and is most often caused by PCOS. It is characterized by excessive androgen production by the ovary and/or the adrenal glands. The increased circulating androgen levels affect mainly the pilosebaceous unit and the reproductive system, leading to diverse clinical conditions, ranging from acne, hirsutism, male pattern baldness, diffuse alopecia, seborrhoea to frank virilisation¹⁸. Hirsutism can be the most distinctive and visible sign of PCOS, especially in combination with acne. Although prolonged exposure to elevated circulating androgen levels may lead to mild virilising signs such as temporal balding and a change in body habitus, extreme expressions of androgen excess such as virilisation and clitoromegaly are not typical findings in this syndrome. Needless to say, these common manifestations of hyperandrogenism are a cause of acute embarrassment to young girls and prime reasons for seeking help.

Hirsutism

Hirsutism is defined as the presence of sexual hair in a male pattern (increase in the number of terminal hairs on the face, back, chest, abdomen and inner thighs) and often graded with the Ferriman and Gallwey scoring system¹⁹. Excessive facial hair may be common soon after puberty, gradually increasing and involving the side of the face, chin and neck. Abdominal hair growth can be similar to the male pattern with hair extending from the mons pubis to the umbilicus. Initially thin and lightly pigmented, this excess hair will eventually become abundant, dark and thick. Unabated PCOS may lead to further hair growth over the back, chest and upper arms.

It is important to emphasize that the hair growth is gradual and slowly progressive and any hirsutism of rapid onset and growth (over a few months) should raise the concern of an androgen secreting tumour or intersex state. A concise history should thus include the timing, location, and rate of progression and recent changes in the amount of hair.

The diagnosis of clinical hyperandrogenism by the assessment of excess hair is not without its challenges. The Ferrimen Gallwey system was established by the study of only white women, the majority of which where over 24 years of age. Ethnic variations, time since puberty and varying androgen levels make its use impossible as a sensitive gauge in adolescents.  Furthermore, adolescents who experience transient hyperandrogenemia run the risk of being prematurely labelled as PCOS. Biochemical assays can be of only limited assistance due to significant interlaboratory variability.

Nevertheless, persistent and progressively increasing hair growth should be investigated, given the rather common occurrence of PCOS, and any evidence of increased hair growth warrants consideration of the diagnosis in early adolescence. It may also be helpful to enquire on methods employed for hair removal to fully appreciate the degree of hirsutism.

Acne

Chronic inflammatory lesions of the pilosebaceous unit are called acne vulgaris. It is a multifactorial disorder most common in adolescents and young adults with prevalence rates of up to 90% among teenagers²⁰. The lesions of acne include open and closed comedones, papules, pustules, and nodules usually distributed over the face, chest, arms and upper back. A characteristic feature is the varying stages of formation and resolution of the lesions which makes diagnosing this condition quite straightforward.

The reasons for the occurrence of acne remain unclear although a strong link to androgens is plainly demonstrated. The inciting event is believed to be stimulation of the pilosebaceous units by circulating androgens evidenced by the appearance of acne during puberty and its attendant sex hormone surge. The increased androgen levels at this time cause excess sebum production and the shedding of hyperkeratinized epithelium to occlude the hair follicle. Hyperandrogenic states such as the menstrual and premenstrual period and corticosteroid and androgen drug therapy are also associated with acne flare-ups. Even the use of contraceptives such as depo-provera and progestin containing intrauterine devices have been known to exacerbate it^21,22.

Having established this link between hyperandrogenism and acne, it has to be pointed out that the majority of women with acne have normal circulating androgen levels without any evidence of an endocrine problem. This means to say that acne as an isolated symptom should not be considered a sign of PCOS; other signs and symptoms of androgen excess or insulin resistance should be present prior to pursuing a workup for an endocrinopathy. However, an underlying hyperandrogenic state has to be excluded in cases of early or late onset of acne, persistent acne and severe acne requiring treatment. Recalcitrant acne despite hormonal manipulation is another reason for further investigation²³.

Insulin resistance

Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. It appears to be the key etiologic feature in the development of PCOS and is noted in the majority of women²⁴. 50% of all women with PCOS have been estimated to have insulin resistance²⁵.

The clinical recognition of insulin resistance in PCOS is based on associated physical features that accompany the disorder. Obesity and acanthosis nigricans are both markers for insulin resistance, such that in the presence of these findings, insulin resistance may be strongly suspected unless proven otherwise. By comparison, identification of insulin resistance by laboratory testing has been inaccurate and difficult as most patients exhibit normal circulating insulin and fasting blood glucose levels. As a result, the clinical determination of insulin resistance relies mainly on its physical manifestations.

Obesity

It is a well-documented fact that more than half of women with PCOS are obese²⁶. This relationship between obesity and androgen secretion also holds true among adolescent PCOS patients. The notion that obesity facilitates androgen excess is borne out by the exhibition of significantly more hyperandrogenemia in overweight peripubertal girls as compared to those with normal weight. Although present in both lean and obese patients, obesity has an additive role on the severity of insulin resistance that is seen in PCOS²⁷. The importance of obesity lies in its association with insulin resistance and hyperinsulinaemia and their contribution to potential long-term health consequences for young individuals with PCOS, with the demonstration of increased likelihoods of dyslipidemia, cardiovascular disease and diabetes mellitus²⁸.

The characteristic pattern of fat distribution in young PCOS women has been termed android obesity. There is increased upper body adiposity with a preponderance of visceral fat that gives rise to a raised waist to hip ratio. In contrast, obese girls without PCOS usually display enhanced accumulation of fat in the hips, buttocks, and thighs, frequently termed truncal obesity, and resulting in a waist to hip ratio of less than one

Although the relationship between android obesity and adolescent girls with PCOS is consistently demonstrated, it is worth highlighting that such a pattern of fat distribution does not in itself confer a diagnosis.

Acanthosis nigricans

Acanthosis nigricans arises from epidermal hyperkeratosis and dermal fibroblast proliferation. It is a velvety rash which can be found on the nape of the neck, the axilla, the area beneath the breasts and other intertrigenous areas, as well as on exposed surfaces such as the elbows and knuckles. It is supposedly more common among obese women with PCOS.

Differential diagnoses and confirmatory tests

The diagnosis of PCOS has become one of exclusion due to the unavailability of reliable hormone assays, especially those for androgens. The goals of laboratory assessment are threefold. First and foremost, androgen excess has to be documented since elevated levels are part of the criteria for making a diagnosis of this disorder. Secondly, other causes of androgen excess and irregular menses such as late onset variant of congenital adrenal hyperplasia (CAH), Cushing’s syndrome, prolactinoma, hyper- and hypothyroidism and premature ovarian failure have to be ruled out. Finally, metabolic abnormalities commonly seen with PCOS such as dyslipidemia and glucose intolerance have to be looked for. Only the most helpful tests for the assessment of PCOS should be ordered and a cost effective evaluation strategy developed.

From among the differential diagnoses of PCOS previously alluded to, it may be pertinent to further elaborate on two of these. CAH and Cushing’s syndrome need particular attention due their similarities in clinical presentation to PCOS. Furthermore, confirmation of these conditions requires detailed laboratory and radiological testing which is usually unnecessary if practicality is to be employed in diagnosing PCOS.

Whilst the cause of disordered adrenal steroidogenesis may be due to several different enzyme defects, the 21-hydroxylase deficiency is of particular interest due to its frequency of occurrence and its ability to simulate the features of PCOS. This non-classical CAH form presents in adolescence and early adulthood with a clinical presentation, complete with polycystic ovarian morphology, that may be indistinguishable from PCOS. Several clinical features of CAH that may suggest the diagnosis include severe hirsutism, clitoromegaly, regular menses, familial tendency, short stature and hyperandrogenemia of adrenal origin.

Excessive cortisol or adrenocorticotropin (ACTH) production results in the features of Cushing’s syndrome, of which obesity, hirsutism, acne, and menstrual irregularity may be mistaken for PCOS. However, the additional presence of moonlike facies, a buffalo hump, abdominal striae and hypertension should indicate a problem of cortisol excess. This should elicit a search for an adrenal or pituitary neoplasm although rare ectopic sources of ACTH such as adenocarcinoma of the lung may also be causal. An important and early differential might be the absence of the typical polycystic features of the ovaries. More elaborate biochemical testing will be able to confirm this rare syndrome.

Blood tests can be obtained at the time of the first clinic visit. Testosterone, free testosterone, and dehydroepiandrosterone sulphate (DHEAS) all determine circulating androgen levels, with DHEAS being of importance in localising hyperandrogenemia of adrenal origin. It has been demonstrated that between 60-90% of PCOS patients have elevated androgen levels¹². Although measurement of androgens is important in the evaluation of PCOS, it should be kept in mind that interpretation of results is not all that easy²⁹.

Hyperprolactinaemia can be excluded by drawing blood for serum prolactin and similarly a thyroid stimulating hormone (TSH) level can indicate over or under performance of the thyroid gland. If suspicion of non-classical CAH is entertained due to the presence of virilisation (especially if marked), then a serum 17 hydroxyprogesterone (17-OHP) test in the follicular phase between 7 and 8 AM (to assess 21-Hydroxylase function in the adrenal gland) can be obtained. Elevated serum levels of follicular stimulating hormone (FSH) and luteinising hormone (LH) help determine ovarian failure and may add to clinical suspicion of PCOS if an LH:FSH ratio of more than 2 is found.

On the metabolic side, a lipid panel including cholesterol and high density lipoprotein (HDL-C) can be carried out to assess for dyslipidemia. Fasting glucose and 2 hour glucose level after 75 g oral glucose, in essence, the oral glucose tolerance test (OGTT), is the most reliable screening method for impaired glucose tolerance and diabetes mellitus. About one third of adolescents with PCOS may be thus impaired³⁰. Relying on a fasting glucose level alone is inadequate as it is a poor predictor of impaired glucose tolerance or diabetes³¹. Based on this evidence, some groups have recommended routine OGTT in adolescents diagnosed with PCOS³².

Imaging

The role of imaging must be elaborated at this point. Both the Rotterdam and AES criteria include the assessment of ovarian morphology for identification of polycystic ovaries. This can be achieved by the use of transvaginal ultrasound (TVS), computed tomography (CT) scan or magnetic resonance imaging (MRI). TVS is a cost effective, sensitive and specific tool and most gynaecologists are trained in its use. It is most useful in the clinic setting but is not widely employed in the adolescent population because of religious and cultural sensitivities. As an alternative, transabdominal ultrasound is limited by its inability to visualize the ovaries in a majority of women.

The ultrasound image of the ovary in PCOS has been described rather specifically as ovarian enlargement with increased central stroma and 10 or more antral follicles ranging from 2 to 10 mm in diameter arranged in a peripheral distribution^33,34. A distinction must be made from the multifollicular ovary which is normal sized and contains 6 or more follicles without any specific arrangement or increase in central stroma, and which can arise as a consequence of hormonal manipulation for fertility treatment35. The value of pelvic ultrasound scanning lies not so much in its ability to make a diagnosis of PCOS, but in the rapid and relatively easy exclusion of an ovarian neoplasm.

In the presence of rapidly progressive hirsutism or virilisation with high testosterone levels, the added cost and time of employing a CT scan or MRI may be warranted to rule out an adrenal or pituitary tumour. Utilisation of similar imaging techniques are also relevant in the evaluation of elevated prolactin levels.

Summary recommendation

The early detection and management of PCOS provides the advantage of allowing for the institution of interventional therapies against such consequences of this condition as the metabolic syndrome, fertility and quality of life issues. Although there exist 3 sets of criteria for diagnosis of adult PCOS, all unite in the necessity to exclude other disorders. Bearing this in mind, the Androgen Excess Society criteria of 2006 seem the most suited for the diagnosis of PCOS in adolescence, underscoring the presence of primary hyperandrogenaemia and ovarian dysfunction. 

Irregular, infrequent, or absent menstrual bleeding may suggest the presence of anovulation, especially if the irregular menstruation is not typically preceded by premenstrual symptoms. Irregular bleeding that persists for more than 2 years after menarche increases the likelihood of hyperandrogenemia. Hirsutism with a preponderance of terminal hairs over the face, back, chest, abdomen and inner thighs may be the most visible sign of PCOS. Essentially, this occurrence is gradual after puberty and slowly progressive, without signs of overt virilisation and clitoromegaly. In concert with this pattern of hair growth, persistent or severe acne requiring treatment should prompt an evaluation for hyperandrogenism. More than half of women with PCOS present with increased upper body and visceral fat for which the waist to hip ratio is an objective assessment. Presence of acanthosis nigricans may provide the strongest suspicion of insulin resistance and PCOS.

Laboratory screening test should include measurement of serum Testosterone, free testosterone, and DHEAS both to document hyperandrogenemia and exclude an adrenal cause for it. Similarly, serum prolactin and TSH can screen for prolactinoma and thyroid causes respectively. If CAH is suspected, an early morning specimen of blood may be obtained during the follicular phase of the menstrual cycle to check for 17-OHP. At this same sitting, blood for serum LH and FSH levels may be helpful in determining ovarian failure as well as confirming PCOS. Determination of metabolic status via a lipid panel and an OGTT may also be carried out, or deferred to a later time.

A pelvic ultrasound scan, preferably a transvaginal one, may conveniently aid in the determination of typical polycystic ovarian morphology as well as ruling out pelvic tumours. If warranted, CT scanning or MRI can be ordered to exclude neoplasms in the pelvis, abdomen, brain and elsewhere.

Although adolescents with PCOS may appear normal without any signs of hyperandrogenism or hyperinsulinism, this diagnosis should be considered in any adolescent girl who presents with irregular menstrual bleeding, hirsutism, persistent acne or obesity, especially if these features occur in concert.

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