Newsletter

Table of Contents

20.07.2002

Newsletter Nr. 16

Oral contraceptives and the risk of breast cancer
Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity
Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome
Ovarian reserve after uterine artery embolization for leiomyomata

1. Oral contraceptives and the risk of breast cancer

It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. Therefore, a population-based, case-control study to determine the risk of breast cancer among former and current users of oral contraceptives was conducted. Women who were 35 to 64 years old were interviewed. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral-contraceptive use at a young age. Thus, among women from 35 to 64 years of age, current or former oral-contraceptive use was not associated with a significantly increased risk of breast cancer.

Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, Bernstein L, Malone KE, Ursin G, Strom BL, Norman SA, Wingo PA, Burkman RT, Berlin JA, Simon MS, Spirtas R, Weiss LK. (2002) Oral contraceptives and the risk of breast cancer. N Engl J Med. 346:2025-2032.

Davidson NE, Helzlsouer KJ. (2002) Good news about oral contraceptives. N Engl J Med. 346:2078-2079. No abstract available.

2. Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women and is defined by hyperandrogenic chronic anovulation with the exclusion of secondary causes, such as congenital adrenal hyperplasia or an androgen secreting tumor. PCOS women are uniquely insulin resistant. It is estimated that 5% of the female population is affected. The underlying genetic defect in insulin action is unknown. Obesity aggravates the underlying predisposition to insulin resistance. Diagnostic criteria which focus on menstrual irregularity are more likely to identify insulin resistant women. About 40% of PCOS women display glucose intolerance (either impaired glucose tolerance or type 2 diabetes) in response to an oral glucose challenge. The study was performed to determine whether the sisters of women with polycystic ovary syndrome have evidence for insulin resistance. Three hundred and thirty-six women with PCOS, 307 sisters of these probands, and 47 control women were studied. The sisters were grouped by phenotypes: PCOS [hyperandrogenemia (HA) with chronic oligo- or amenorrhea, n = 39], HA with regular menses (n = 36), unaffected (UA; n = 122), and unknown (n = 110). The analyses were adjusted for age and body mass index. PCOS and HA sisters of women with PCOS had similar and significantly elevated fasting insulin levels (P = 0.001) as well as similar and significantly decreased fasting glucose/insulin ratios (P < 0.001) suggestive of insulin resistance compared with UA sisters and control women. Markers of insulin resistance were associated with hyperandrogenemia and not with menstrual irregularity. PCOS sisters also had decreased levels of SHBG (P = 0.02) suggestive of higher ambient insulin levels. PCOS sisters had increased levels of proinsulin (P = 0.04) compared with control women, which suggested pancreatic beta-cell dysfunction in this group of sisters. The magnitude of obesity also differed significantly among the groups of sisters. The PCOS sisters were significantly more obese than all the other groups, and the HA sisters were more obese than the UA sisters. It is concluded that markers of insulin resistance are associated with hyperandrogenemia rather than menstrual irregularity in the sisters of women with PCOS. Insulin resistance per se does not cause menstrual irregularities, however, menstrual irregularity may be related to the magnitude of insulin sensitivity or insulin secretion or to other factors associated with obesity.

Legro RS, Bentley-Lewis R, Driscoll D, Wang SC, Dunaif A. (2002) Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin Endocrinol Metab. 87:2128-2133.

Legro, R.S. (2002) Polycystic ovary syndrome. Long term sequelae and management. Minerva Ginecol. 54:97-114.

3. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome

There is an inherited susceptibility to polycystic ovary syndrome (PCOS). Some investigators have suggested that premature male-pattern balding is a male phenotype in PCOS families, but this remains controversial. The authors recently reported evidence for an autosomal monogenic abnormality in ovarian and adrenal steroidogenesis in the sisters of women with PCOS. This study was performed to determine whether a clinical or biochemical phenotype could be identified in the brothers of women with PCOS. One hundred nineteen brothers of 87 unrelated women with PCOS and 68 weight- and ethnicity-comparable unrelated control men were examined and had fasting blood samples obtained. The odds of balding (Hamilton score > or = V) did not differ in the brothers of PCOS women compared with control men. Brothers of women with PCOS had significantly elevated dehydroepiandrosterone sulfate (DHEAS) levels [brothers 3035 +/- 1132 ng/ml (mean +/- SD) vs. control men 2494 +/- 1172 ng/ml; P < 0.05]. There was a significant positive linear relationship between DHEAS levels in PCOS probands and their brothers (r = 0.35; P = 0.001). There was no significant bimodal distribution in DHEAS levels, and there were no significant differences in other parameters in brothers of PCOS women with high DHEAS levels compared with those with low DHEAS levels. There is familial clustering of elevated DHEAS levels in the brothers of women with PCOS, suggesting that this is a genetic trait. This might reflect the same underlying defect in steroidogenesis that was found in the sisters of women with PCOS. Balding was not increased in the brothers of women with PCOS. It is therefore concluded that there is a biochemical reproductive endocrine phenotype in men in PCOS families.

Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A (2002). Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 87:2134-2148.

4. Ovarian reserve after uterine artery embolization for leiomyomata

One of the newest treatments of uterine leiomyomata is uterine artery embolization. However, several women have become menopausal after this procedure. It seems that premature menopause after embolization occurs predominantly in older women. Whether uterine artery embolization decreases ovarian function in younger women is unknown. Therore,it was sought to evaluate ovarian reserve and ovarian stromal blood flow before and after uterine artery embolization.
From January 2000 to June 2001, 48 premenopausal women with symptomatic uterine myomata underwent bilateral uterine artery embolization. Twenty-three of these women had baseline serum FSH levels < 10 mIU/mL. Uterine artery embolization was performed bilaterally in all cases by using 350- to 500-m polyvinyl alcohol particles (Boston Scientific, Target Therapeutics Division, Fremont, CA). Before uterine artery embolization, samples of blood were drawn for FSH and E2 measurement.
The volume of the myomata, ovarian volume, antral follicle count, and ovarian stromal blood flow were measured. All scans were performed by one investigator (TJC) by using a 5-MHz transvaginal transducer with color and pulsed Doppler facilities. All of these tests were done on day 3 of the menstrual cycle before embolization and in the first and third cycle after embolization. Data were analyzed by using the Student t-test and Mann-Whitney test. Two-tailed P<.05 was considered statistically significant. The mean age of the participants was 44.1Â±2.4 years. The volume of the largest myoma was 196.4Â±36.6 cm3 before embolization, 129.7Â±25.3 cm3 1 month after embolization, and 91.3Â±18.4 cm3 3 months after embolization, respectively. The diameter of the largest myoma had decreased significantly 3 months after embolization (P<.01). Serum FSH levels gradually increased over time. A level >10 mIU/mL was found in seven women 1 month after uterine artery embolization and in 9 women 3 months after the procedure. The highest levels were 22.8 mIU/mL and 33.8 mIU/mL at 1 month and 3 months after the procedure, respectively. No significant difference in E2 levels, ovarian volume, number of antral follicles, and ovarian stromal blood flows before, 1 month after, and 3 months after uterine artery embolization was observed.
Day 3 serum FSH level is an indirect measure of ovarian reserve. In agreement with a previous observation, basal FSH levels increased after uterine artery embolization. There was also a trend toward increasing serum E2 levels. These changes suggest a decreasing ovarian reserve. The high E2 levels indicate accelerated follicular recruitment in response to elevated FSH secretion. The declining ovarian reserve is also indicated by the decreasing number of antral follicles.
The most likely mechanism of declining ovarian reserve and premature menopause after uterine artery embolization is embolization of the utero-ovarian collateral circulation. This effect compromises blood supply to the ovaries. Transient ovarian failure after uterine artery embolization has been described. Uterine artery embolization may hasten ovarian failure. In this series, the FSH levels 3 months after embolization were higher than the levels at 1 month after uterine artery embolization and the baseline levels in all patients. Whether ovarian function will return to normal 6 or 12 months after embolization is unknown. Ravina et al. reported 12 pregnancies after uterine artery embolization. Of these, 5 resulted in miscarriage and 3 in preterm deliveries. This high rate of miscarriage is of concern. Although it has not been reported, the decrease in uterine blood flow after uterine artery embolization can also lead to intrauterine growth restriction. To date, reports of pregnancy after uterine artery embolization are anecdotal and descriptions of live birth are still limited. The results of the study suggest that uterine artery embolization decreases ovarian reserve. Because of concern about loss of ovarian function and risks of premature menopause, this procedure should be reserved for women who do not desire future fertility.

Tulandi T, Sammour A, Valenti D, Child TJ, Seti L, Tan SL. (2002) Ovarian reserve after uterine artery embolization for leiomyomata. Fertil Steril. 78:197-198. No abstract available.

Gerhard Leyendecker