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Abstract

Objective: Uterine leiomyoma is associated with increased BMD in Caucasian women and is largely attributed to the state of hyperestrogenemia associated with disease. This relationship, however, has not been previously described in African–American women. We aim to assess BMD in African–American women with symptomatic uterine leiomyoma. Design: Case–control study. Materials & methods: 29 African–American women with uterine leiomyoma signed an Institutional Review Board (IRB) approved consent form at a reproductive clinic of an inner city hospital in Brooklyn, NY, USA. BMD and T-score of lumbar spine was compared with a controlled group matched for age, race and BMI. BMD of lumbar spine was measured using Hologic QDR 4200 in both groups. Data are presented as mean ± SEM. Results: For the entire study population the mean age (years) was 42.07 ± 1.15, and the BMI (kg/m²) was 29.37 ± 0.93 in patients with uterine leiomyoma and 30.07 ± 1.06 for the control group (p = 0.07). There was a significant difference in the mean BMD (cm²) between the uterine leiomyoma group (1.17 ± 0.03) compared with control (1.05 ± 0.02 p < 0.01). The T-score for the uterine leiomyoma group was significantly higher compared with the control group (0.31 ± 0.25 and −0.74 ± 0.21 with p < 0.01). The prevalence of osteopenia (T-score <-1) was lower for the leiomyoma group when compared with controls, (p < 0.02). Conclusion: Consistent with data from the white population with uterine leiomyoma, our data showed a significantly higher BMD in African–American women with uterine leiomyoma, compared with an age- and race-matched cohort. The implications of these findings remain to be investigated and further confirmed in future longitudinal studies.

Keywords

African–American bone mineral density estrogen GnRH agonist menopause osteopenia osteoporosis uterine leiomyomata

Uterine leiomyoma (ULM) arises from the uterine myometrium and is the most common tumor of the female reproductive tract. ULM, also more generally known as fibroids, is clinically diagnosed in 30% of reproductive-aged women and serves as a major source of gynecologic morbidity [1]. The clinical diagnosis of ULM are two- to three-times more common in black women than in white women [2 –5]. ULM growth has been shown to be dependent on estrogen [6]. Estrogen also blocks cytokine secretion, resulting in decreased bone resorption and hence preserved or higher BMD in premenopausal women [7]. The dependence of both ULM and BMD on estrogen makes the association of UML and high BMD an attractive hypothesis related to the presence of estrogen in premenopausal women.

It is hypothesized that due to their individual independent association with estrogen, leiomyomata and bone health (as measured by BMD) may be linked.

Estrogen is an essential steroidal hormone that is found both in men and women, and is necessary for normal development. Estrogen plays a major role in preventing bone resorption through its action on osteoclasts (cells responsible for the normal break down of bone), by decreasing their activity. In general, an excess of estrogen (which occurs more often in obese women and in women who have undergone postmenopausal hormone therapy) is inversely related to the risk of osteoporosis or bone fracture. The Women's Health Initiative (WHI), provided compelling evidence that estrogen reduces the risk of hip, vertebral and other bone fractures [8]. This observation suggests that BMD may indeed be a good marker of cumulative exposure to estrogen. Since the presence of ULM growth is indicative of a high estrogen environment [6], one may assume that the association of high BMD in leiomyomata patients occurs via estrogen-mediated mechanisms. The hyperestrogenic state of existing leiomyomata may well induce a protective effect against bone loss and fractures [9].

Increased BMD in black women, compared with that of white women, has been reported in several prospective studies [3], including perimenopausal and postmenopausal women. In spite of such findings, clinical investigations into whether leiomyomata are indeed adequate indicators of better bone health are still lacking. Studies of BMD in Caucasian women by Randell et al. [9] and Rozenburg et al. [10] found that patients with leiomyoma had significantly higher BMD in trabecular bone than in their respective reference population. However, this relationship, has not been elucidated in African–American women anywhere in the literature. This current investigation aims to assess BMD in African–American women with symptomatic uterine leiomyoma.

Materials & methods

In a case–controlled study of 29 African–American women with symptomatic (i.e., abnormal uterine bleeding) ULM who had signed an IRB-approved consent form at a reproductive clinic of an inner-city hospital in Brooklyn, NY, USA. BMD and BMD of the lumbar spine were compared with that of a control group matched for age, race and BMI. The control group was obtained from our database for premenopausal women referred for screening BMD. Menopausal status was obtained only by menstrual history through a questionnaire provided prior to BMD measurements as routine to prevent pregnant women from inadvertent exposure to radiation. Persons with risk factors for osteoporosis were excluded from the analysis. These risk factors included: personal history of fracture, family history of osteoporosis, maternal fracture, cigarette smoking, steroid use, the use of antiseizure medications, excessive alcohol intake (>2 drinks per day), vitamin D deficiency, low calcium intake and a sedentary lifestyle. BMD of lumbar spine was measured using Hologic QDR 4200 in both groups. We used BMD at the lumbar spine, which consists mainly of trabecular bone, since this is more reflective of changes that occur in menopause compared with other areas such as the hip and the forearm (i.e., areas of high cortical bone). This is why spine fractures occur much earlier in postmenopausal women compared with hip fracture that occurs mainly in the elderly.

Prior to each study, the bone densitometer was calibrated with quality control as per the manufacturer's specification with a coefficient of variation equal to 1%.

Diagnosis of ULM was made with abdominal and endovaginal sonograms. All except one had multiple leiomyoma and there was no history of fibroids obtained from the control group.

Descriptive statistics and the applied student t-test were used to compare the study population of interest with the control group for continuous variables such as BMD and BMI. χ² analysis was also utilized to compare categorical variables between the two groups. Data are presented as mean ± standard error of the mean (except for percentage of osteopenia [T-score <-1]).

Results

For the entire study population the mean age (years) was 42.07 ± 1.15. The mean BMI (kg/m²) was 29.37 ± 0.93 in patients with ULM, which is not significant from that of 30.07 ± 1.06 for the control group (p = 0.07). There was a significant difference in BMD (g/cm²) between the uterine leiomyoma group (1.17 ± 0.3) compared with controls (1.05 ± 0.02), at a p value of less than 0.01 (Figure 1). The mean T-score for the ULM group was also significantly higher when compared with that of the controls (0.31 ± 0.25 and −0.74 ± 0.21 respectively), at the p value of less than 0.01 (Figure 2). There was also a higher prevalence of osteopenia (T-score <-1.0) in the control group compared with the ULM group (53.6 vs 14.3%) for the control and the ULM group respectively (p = 0.02). (Figure 3). Prevalence of osteopenia (T-score <-1) was lower for leiomyoma group when compared with the control group (p < 0.02) (Figure 3).

Figure 1.

Bone mineral density (g/cm²) in the uterine leiomyoma and control groups (p < 0.01).

Figure 2.

T-score in the uterine leiomyoma and control group (p < 0.01).

Figure 3.

Prevalence of osteopenia in the uterine leiomyoma and control groups (p = 0.02).

Discussion

Uterine leiomyoma arises from the uterine myometrium and is the most common tumor of the female reproductive tract. ULM (also known as fibroids) is clinically recognized in approximately 30% of reproductive-aged women [1] and is responsible for a significant amount of gynecologic morbidity. ULM is the fifth leading cause of hospitalizations for gynecologic conditions unrelated to pregnancy in women aged 15–44 years [11] and is the primary indication for hysterectomy among women of all ages in the USA [2,12]. Leiomyomas are the number one cause of hysterectomy in reproductive-aged women, accounting for more than 200,000 of these types of surgeries annually in the USA alone [1].

The clinical diagnosis of ULM are two- to three-times more common in black women than in white women [2 –5] in the USA. Black women have an earlier age at diagnosis [3,5,12] and more numerous and symptomatic tumors compared with white women [5,13]. In recent years, the USA registration data from hospital discharge and hysterectomy records have confirmed strong associations between race/ethnicity and the frequency of ULM [2,4,11]. In addition, a 3.3-fold increased risk of ULM was observed prospectively among an African–American cohort in the Nurses' Health Study II [3]. Black women are significantly more likely to have leiomyomata since they have a higher prevalence of estrogen receptor-α genotype, which has been shown to be strongly associated with an increased risk of ULM [13].

Estrogen has traditionally been proposed as the primary promoter of ULM growth. Clinical observations have shown that fibroids occur only after menarche, then develop during the reproductive years, may enlarge during pregnancy and then frequently regress following menopause. The estrogen hypothesis has also been supported by numerous clinical trials evaluating the medical treatment of leiomyomata with gonadotropin-releasing hormone agonists, the effective result of which is hypoestrogenism accompanied by the regression of the fibroids [14].

Studies have shown that growth hormone (GH), which exerts important influences on maintaining BMD, may influence the development of leiomyoma. The incidence of myoma is increased in women with acromegaly [15]. By the use of radioimmunoassay the spellacy measured fasting and stimulated GH level after insulin-induced hypoglycemia in women with and without ULM. Although fasting levels were not different between the two groups, the peak GH level 1 h after insulin administration was significantly increased in ULM group [Muneyyirci-Delale O et al. Pers. Comm.] [16].

Since the growth of leiomyomata has been shown to be dependent on ovarian steroid hormones, it raises the question of whether there is any association between ULM and bone health. Bone mass is influenced by endogenous and exogenous estrogens. Estrogen is the dominant sex steroid regulating bone resorption. It plays a major role in preventing bone resorption by its action on the osteoclasts [17]. In general, an excess of estrogen such as may occur in obese women [18] and with postmenopausal hormone therapy, is inversely related to the risk of osteoporosis or fracture [19]. Ravn et al. have reported that premenopausal hysterectomy did not reduce ovarian function, and led to increased bone turnover and bone loss due to trunkal fat and higher serum estradiol levels seen in these women [20]. The WHI study provided compelling evidence that estrogen reduced the risk of hip, vertebral and other fractures. This observation suggests that bone mass may be a marker of cumulative exposure to estrogen. Increased BMD in black women compared with white women has been reported in several studies across the lifespan, including at menopause and postmenopause [21 –25]. Differences in urinary calcium excretion have been proposed as a possible contributor to these differences in BMD, with black females excreting less calcium, thus increasing the calcium incorporated into bone [26,27]. In addition, bone turnover seems to be slower in black women than in white women and bone loss is slower overall during early menopause [28,29].

This study demonstrates that African–American women with symptomatic ULM have a significant increase in BMD and lower prevalence of osteopenia. Biomedical research into whether leiomyomata serves as an adequate marker of better bone health continues to be rare. Our results were consistent with that of a retrospective analysis conducted by Rozenburg [10], who found that subjects with ULM had significantly higher BMD in the vertebra compared with the reference population. Our investigation is also in strong agreement with that of Randell et al. [9], who have concluded that peri- and early postmenopausal women with a history of leiomyoma seem to have higher BMD and less fractures compared with those without leiomyoma. However, this relationship, has not been described in African–American women until now.

The investigation had some limitations. First, the study group was relatively small (n = 58). We did not evaluate the hormonal status of the participants. The hormonal status of a woman, particularly estrogen levels, plays a major role. A possible reason for why one group presented higher BMD is that the other group was hypoestrogenic because they are in the menopausal transition.

Furthermore, we did not control for other factors such as GH level, age of menarche, as well as parity and breastfeeding. These factors may have influenced the results. While we considered family history for osteoporosis as well as maternal fractures, genetic testing for heredity osteoporosis was outside of the scope of this study. None of the patients were using hormonal contraceptive prior to bone density determination, nevertheless, prior use was not controlled for. Most patients had multiple leiomyomata uteri, and only one had a single fibroid. However, the size of fibroids was not documented since there is no evidence in the literature that they correlate with BMD. It is also important to note that patients with vitamin-D deficiency were excluded from cases as well as control groups based only on history. This by no means can ascertain the absence of vitamin-D deficiency in either group.

Our data on African–American women are consistent with that obtained in white women and highlights the association of higher BMD with ULM that is probably due to hyperestrogenemia. However we cannot from our study conclude a causal relationship between hyperestrogenemia and higher BMD observed in ULM patients owing to the lack of measurement of estrogen level in this study.

The implications of these findings remain to be investigated and further confirmed in future longitudinal studies.

Future perspective

Future studies in women with leiomyoma might reveal that not only higher estrogen environment causes high BMD, but other factors in these women contribute to this problem such as increased growth hormone levels.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Executive summary

Consistent with data from white populations with uterine leiomyoma (ULM), this study showed significantly higher BMD in African–American women with uterine leiomyoma compared with age-and race-matched cohort.

While the exact mechanisms for increased BMD in ULM population compared with controls is not known, hyperestrogenemia associated with ULM as well as increased growth hormone might play a role in the pathogenesis of ULM and increased BMD.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Bone Mineral Density in African–American Women with Symptomatic Uterine Leiomyoma

Abstract

Keywords

Materials & methods

Results

Discussion

Future perspective

Ethical conduct of research

Footnotes

References