Polycystic ovary syndrome in younger women
At what stage do the risk factors for cardiovascular disease become apparent in women with PCOS? The majority of studies that have identified the risk factors of obesity and insulin resistance in women with PCOS have investigated adult populations, commonly including women who have presented to specialist endocrine or reproductive clinics. However, PCOS has been identified in much younger populations, in which women with increasing symptoms of PCOS, were found to be more insulin resistant. These data emphasize the need for long-term prospective studies of young women with PCOS in order to clarify the natural history, and to determine which women will be at risk of diabetes and cardiovascular disease later in life. A study of women with PCOS and a mean age of 39 years followed over a period of 6 years, found that 9% of those with normal glucose tolerance developed impaired glucose tolerance (IGT) and 8% developed noninsulin dependent diabetes (NIDDM). Fiftyfour per cent of women with IGT at the start of the study had NIDDM at follow-up. Not surprisingly, the risks of disease progression were greatest in those who were overweight.
Endometrial cancer
Endometrial adenocarcinoma is the second most common female
genital malignancy but only 4% of cases occur in women less than 40 years of
age. The risk of developing endometrial cancer has been shown to be adversely
influenced by a number of factors including obesity, long-term use of unopposed
estrogens, nulliparity and infertility. Women with endometrial carcinoma have
had fewer births compared with controls and it has also been demonstrated that
infertility per se gives a relative risk of 2. Hypertension and type 2
diabetes mellitus have long been linked to endometrial cancer, with relative
risks of 2.1 and 2.8, respectively—conditions that are now known also to be
associated with PCOS. The true risk of endometrial carcinoma in women with
PCOS, however, is difficult to ascertain. Endometrial hyperplasia may be a
precursor to adenocarcinoma, with cystic glandular hyperplasia progressing in
perhaps 0.4% of cases and adenomatous hyperplasia in up to 18% of cases over 2–10
years. Precise estimation of rate of progression is impossible to determine.
Some authors have reported conservative management of endometrial
adenocarcinoma in women with PCOS with a combination of curettage and high-dose
progestogens. The rationale is that cancer of the endometrium often presents at
an early stage, is well differentiated, with low risk of metastasis and,
therefore, is not perceived as being lifethreatening, whilst poorly
differentiated adenocarcinoma in a young woman has a worse prognosis and
warrants hysterectomy. In general, however, the literature on women with PCOS
and endometrial hyperplasia or adenocarcinoma suggests that this group of
patients has a poor prognosis for fertility. This may be because of the factors
that predisposed to the endometrial pathology—chronic anovulation combined
often with severe obesity—or secondary to the endometrium metrial pathology
disrupting potential embryonic implantation. Thus, a more traditional and radical
surgical approach (i.e. hysterectomy) is suggested as the safest way to prevent
progression of the cancer. Early-stage disease may permit ovarian conservation
and the possibility of pregnancy by surrogacy.
Although the degree of risk has not been clearly defined, it is
generally accepted that for women with PCOS who experience amenorrhea, or
oligomenorrhea, the induction of artificial withdrawal bleeds to prevent endometrial
hyperplasia is prudent management. There are no data on the frequency with
which women with PCOS should shed their endometrium. It seems prudent to induce
a withdrawal bleed either monthly or at least every 3 months, not only to prevent
endometrial hyperplasia but also to enable the bleed to be acceptable when it
occurs—as progressive endometrial development may lead to a prolonged and heavy
bleed when it does occur. For those with oligo-/amenorrhea who do not wish to use
cyclical hormone therapy we recommend an ultrasound scan to measure endometrial
thickness and morphology every 6–12 months (depending upon menstrual history).
An endometrial thickness greater than 10mm in an amenorrheic woman warrants an
artificially induced bleed, that should be followed by a repeat ultrasound scan
and endometrial biopsy if the endometrium has not been shed.
Another option is to consider a progestogen-releasing intrauterine
system, such as the Mirena.
Breast cancer
Obesity, hyperandrogenism, and infertility occur frequently in
PCOS, and are features known to be associated with the development of breast
cancer. However, studies examining the relationship between PCOS and breast
carcinoma have not always identified a significantly increased risk. The study
by Coulam and colleagues calculated a relative risk of 1.5 (95% CI 0.75–2.55) for breast
cancer in their group of women with chronic anovulation which was not statistically
significant. After stratification by age, however, the relative risk was found
to be 3.6 (95% CI 1.2–8.3) in the postmenopausal age group. More recently,
Pierpoint and associates reported a series of 786 women with PCOS in the UK who were traced
from hospital records after histological diagnosis of polycystic ovaries
between 1930 and 1979. Mortality was assessed from the national registry of
deaths and standardized mortality rates (SMR) calculated for patients with PCOS
compared with the normal population. The average follow-up period was 30 years.
The SMR for all neoplasms was 0.91 (95% CI 0.60–1.32) and for breast cancer 1.48
(95% CI 0.79–2.54). In fact, breast cancer was the leading cause of death in
this cohort.
Ovarian cancer
In recent years there has been much debate about the risk of ovarian cancer in women with infertility, particularly in relation to the use of drugs to induce superovulation for assisted conception procedures. Inherently, the risk of ovarian cancer appears to be increased in women who have multiple ovulations—that is those who are nulliparous (possibly because of infertility) with an early menarche and late menopause. Thus, it may be that inducing multiple ovulations in women with infertility will increase their risk—a notion that is by no means proven. Women with PCOS who are oligo-/anovulatory might therefore be expected to be at low risk of developing ovarian cancer if it is lifetime number of ovulations rather than pregnancies that is critical. Ovulation induction to correct anovulatory infertility aims to induce unifollicular ovulation and so, in theory, should raise the risk of a woman with PCOS to that of a normal ovulating woman. The polycystic ovary, however, is notoriously sensitive to stimulation and it is only in recent years, with the development of high-resolution transvaginal ultrasonography, that the rate of unifollicular ovulation has attained acceptable levels.The use of clomiphene citrate and gonadotropin therapy for ovulation induction in the 1960s—1980s resulted in many more multiple ovulations (and indeed multiple pregnancies) than in recent times and might therefore present with an increased rate of ovarian cancer when these women reach their sixties—the age of greatest incidence.
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