Luteinizing Hormone, Its ß-Subunit Variant, and Epithelial Ovarian Cancer: The Gonadotropin Hypothesis Revisited
Arslan Akhmedkhanov1,2,
Paolo Toniolo1,2,
Anne Zeleniuch-Jacquotte2,
Kim S. Pettersson3 and
Ilpo T. Huhtaniemi4
Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY.
Department of Environmental Medicine, New York University School of Medicine, New York, NY.
Department of Biotechnology, University of Turku, Finland.
Department of Physiology, University of Turku, Finland.
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ABSTRACT
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The gonadotropin hypothesis postulates that excessive gonadotropin stimulation results in increased proliferation and subsequent malignant transformation of ovarian epithelium. The authors evaluated this hypothesis by analyzing the association between serum levels of wild-type luteinizing hormone (LH) and ovarian cancer risk. They also examined the relation between a variant of LH containing two missense point mutations (Trp8Arg and Ile15Thr) in its ß-subunit and ovarian cancer risk. Fifty-eight cases of epithelial ovarian cancer and 116 controls matched on age, menopausal status, and date of blood donation were included in a case-control study nested within the New York University Women's Health Study, a prospective cohort enrolled between 1985 and 1991 in New York City. Wild-type serum levels and variant LH status were determined by immunofluorometric assays in which monoclonal antibodies specific for wild-type and variant LH were used. Compared with women in the lowest tertile of wild-type LH, women in the highest tertile had a lower risk of ovarian cancer, after adjustment for potential confounders (odds ratio = 0.42, 95% confidence interval: 0.09, 2.09). Women heterozygous for variant LH were not at increased risk (adjusted odds ratio = 0.95, 95% confidence interval: 0.27, 3.34). The results suggest that neither wild-type LH levels nor variant LH status is associated with increased risk of epithelial ovarian cancer.
gonadotropins; LH; ovarian neoplasms; polymorphism (genetics)
Abbreviations:
CI, confidence interval; FSH, follicle-stimulating hormone; LH, luteinizing hormone; OR, odds ratio
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INTRODUCTION
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In the United States, ovarian cancer is the second most common cancer of the female reproductive system and the leading cause of death from gynecologic neoplasms (1
). The lifetime risk of developing ovarian cancer is close to 2 percent. In 2000, an estimated 23,100 women were diagnosed with ovarian cancer, and 14,000 US women died from the disease (2
). Ovarian cancer is difficult to treat because about 70 percent of patients have advanced disease (spread beyond the pelvis) at initial presentation (3
). As a result, the prognosis is poor, with a 5-year relative survival rate of about 50 percent (3
).
While hereditary ovarian cancer is thought to account for 510 percent of all cases (4
), the etiology of ovarian cancer in the majority of cases remains poorly understood (5
). In 1983, Cramer and Welch (6
) summarized what was then known about its pathogenesis in a landmark paper that is still broadly cited. On the basis of experimental data suggesting that secretion of high levels of gonadotropin (luteinizing hormone (LH), follicle-stimulating hormone (FSH)) is associated with ovarian tumors in animals, they proposed the "gonadotropin hypothesis" of ovarian cancer pathogenesis. The hypothesis states that excessive gonadotropin and estrogen stimulation of the ovarian inclusion cysts (formed through repeated invaginations of ovarian epithelium during incessant ovulations) results in increased proliferation and malignant transformation of ovarian epithelium. In contrast, pregnancy and oral contraceptive use protect against ovarian cancer by lowering gonadotropin levels (6
).
Recently, a common variant of LH was identified (7
). The variant LH contains two missense point mutations (Trp8Arg and Ile15Thr) in its ß-subunit (8
, 9
) and is characterized by higher in-vitro bioactivity (10
, 11
), a shorter half-life in circulation (11
), and increased serum levels of estradiol and testosterone (12
), suggesting higher bioactivity at the ovarian level. Data also indicate suppressed bioactivity of the variant LH, as women homo- or heterozygous for the LH ß-subunit polymorphism have an increased frequency of infertility (9
, 13
). The variant LH seems to have altered bioactivity and a shorter half-life, suggesting different kinetics of LH action in variant LH carriers.
The aim of this study was to examine the association between serum levels of wild-type LH and risk of epithelial ovarian cancer. We also assessed the role of a common variant of LH in ovarian cancer.
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MATERIALS AND METHODS
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Study population
The New York University Women's Health Study is a prospective cohort study that has been described in detail elsewhere (14
, 15
). Briefly, between March 1985 and June 1991, 14,275 healthy women were enrolled at a breast-cancer-screening center in New York City. Women aged 3465 years, who in the preceding 6 months had neither used hormonal medications nor been pregnant, were eligible for enrollment. Blood was drawn between 9:00 a.m. and 3:00 p.m. from nonfasting subjects. After centrifugation, serum was divided into 1-ml aliquots and was stored at -80°C for subsequent biochemical analyses. Written informed consent was obtained from all cohort members. The study is reviewed and approved annually by the Institutional Board of Research Associates of the New York University School of Medicine, New York, New York.
Nested case-control study
Ovarian cancer cases were identified by active follow-up either during annual mammographic screenings (until 1991) or through questionnaires mailed to each cohort member every 18 months, as well as by computer linkages with tumor registries in the states of New York, New Jersey, Connecticut, and Florida. From an initial cohort of 14,275 women, 187 (1.3 percent) had been lost to follow-up and 832 (5.8 percent) had withdrawn their collaboration by January 1, 1998. As of that date, 60 cases of ovarian cancer (58 epithelial and 2 stromal) had been identified and confirmed by review of individual clinical and pathology records.
Two controls per case were selected at random among cohort members who were alive and free of cancer at diagnosis of the case and who met the matching criteria, which included age, menopausal status at blood donation, and date of blood donation. Women were classified as premenopausal if they reported at least one menstrual cycle during the preceding 6 months at the time of the baseline blood draw. Premenopausal women also were matched by day and phase of the menstrual cycle. The number of days prior to the next menses and the phase of the cycle were calculated by using calendars that the study subjects were instructed to mark and return following their next menses after enrollment.
Laboratory methods
Serum samples from each case and her matched controls were analyzed in the same batch by a laboratory technician who was unaware of their disease status. LH levels were measured at the University of Turku with an immunofluorometric assay for serum LH determination (Delfia; Wallac Oy, Turku, Finland). Variant LH status was determined with a combination of two immunofluorometric assays in which different monoclonal antibodies are used. This is a common, indirect method in which the ratio of LH phenotypes in serum is used to determine LH status (10
, 16
).
The first assay uses
/ß-subunit-specific monoclonal antibodies and detects only the wild-type LH molecules (7
). The second assay uses two LH ß-subunit-specific antibodies and detects both wild-type and variant LH (reference method) (17
). The ratios of the LH levels measured by these two assays (assay 1/assay 2) were divided into three separate categories indicating LH status: 1)
1.0 (normal ratio), indicating that the subject had two normal LHß alleles; 2) 0.150.99 (low ratio), the subject was heterozygous for the mutant LHß gene; and 3) 00.14 (zero ratio), the subject was homozygous for the variant LHß gene (10
, 16
). The intra- and interassay coefficients of variation of the first and second assays were less than 4 and 5 percent, respectively, at LH levels at and above the lowest standard concentration of 0.6 IU/liter of International Reference Preparation 80/552 (LH Human International Standard; World Health Organization, Geneva, Switzerland). Comparison of the immunofluorometric assay technique with DNA hybridization assay showed identical results regarding variant LH status, and either method can be used as an alternative to determine LH status (18
).
Statistical methods
To test for differences in continuous variables between cases and controls, we used mixed-effects regression models to take into account the matched design and to adjust for any residual correlation between cases and controls within the matched set (19
). For categorical variables, the chi-square test was used.
Conditional univariate and multivariate logistic regression analyses appropriate for matched case-control data were used to assess the association between LH serum levels, LH status, and epithelial ovarian cancer. Potentially confounding variables, including Quetelet index (weight in kilograms divided by height in meters squared), race/ethnicity, parity, and use of oral contraceptives, were included in multivariate logistic models. Results were expressed as odds ratios and 95 percent confidence intervals. All reported p values were two-tailed, and p values of less than 0.05 were considered statistically significant.
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RESULTS
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The majority of study subjects were Caucasian (86 percent), 7 percent were African American, 4 percent were Hispanic, and 3 percent reported other ethnicity. This ethnic composition reflected the characteristics of the patient population at the screening clinic at the time of recruitment. Review of the pathology reports revealed that the majority of cases had common epithelial-type ovarian tumors, such as serous (n = 28), mucinous (n = 6), endometrioid (n = 3), clear cell (n = 2), and not-otherwise-specified adenocarcinoma (n = 19). Two cases had nonepithelial ovarian tumors (one granulosa cell tumor and one dysgerminoma). These two cases were excluded, resulting in a total of 58 ovarian cancer cases and 116 controls for final analysis. The median age at diagnosis of epithelial ovarian cancer was 61.5 years, and the median period between blood donation and diagnosis was 5.6 years (range, 0.912.1).
Descriptive characteristics of the study subjects are given in table 1. Of 58 cases, 22 were premenopausal and 36 were postmenopausal at blood donation. Cases and controls did not differ appreciably in age at menarche or age at first full-term pregnancy. Women diagnosed with epithelial ovarian cancer less frequently reported pregnancy and oral contraceptive use (table 1). Women of Caucasian/Jewish origin were significantly overrepresented among epithelial ovarian cancer cases as compared with controls (65.5 vs. 31.9 percent, p = 0.05). Ovarian cancer cases had a lower median Quetelet index than controls (23.6 vs. 25.4 kg/m2, p = 0.003).
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TABLE 1. Characteristics of epithelial ovarian cancer cases and controls, New York University Women's Health Study, New York City, 19851998
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Information on serum LH levels determined by assay 1 (wild-type LH only) and assay 2 (wild-type and variant LH) is presented in table 2. The LH levels determined by using the two different assays were highly correlated (Pearson's r = 0.90). As expected, LH levels in premenopausal women were highest during the ovulatory phase, intermediate during the follicular phase, and lowest during the luteal phase of the menstrual cycle. Serum LH levels were on average 1316 percent lower in premenopausal cases compared with premenopausal controls and 1213 percent higher in postmenopausal cases than in postmenopausal controls, but these differences were not statistically significant (table 2).
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TABLE 2. Mean serum levels of luteinizing hormone, by menopausal and case-control status, New York University Women's Health Study, New York City, 19851998
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Table 3 shows the distribution of variant LH in epithelial ovarian cancer cases and controls. Subjects for whom the assay 1/assay 2 ratio was 0.150.99 were considered heterozygous for the variant LHß allele (11
, 17
). Of the 174 subjects included in the analysis, 21 had a low (heterozygous) LH ratio. We found no homozygous (LH ratio of less than 0.15) subjects in the study population. Overall, the proportions of LH-variant heterozygous women were identical among epithelial ovarian cancer cases and controls (12.1 percent). The proportion of variant LH was higher for premenopausal cases (13.6 percent) compared with premenopausal controls (9.1 percent) and slightly lower for postmenopausal cases (11.1 percent) than postmenopausal controls (13.9 percent) (table 3). Among cases, there were no evident differences in age at cancer diagnosis between women with wild-type LH (mean age, 59.6 years) and those with variant LH (mean age, 60.6 years).
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TABLE 3. Luteinizing hormone status of epithelial ovarian cancer cases and controls, New York University Women's Health Study, New York City, 19851998
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In logistic regression analyses, we computed the odds ratios of epithelial ovarian cancer associated with wild-type LH serum levels by tertile and variant LH status (table 4). When LH levels were introduced in the regression model as tertiles, unadjusted and adjusted analyses showed that LH serum levels were inversely associated with risk of epithelial ovarian cancer. However, the observed trend was not statistically significant (table 4). Variant LH status was not associated with an altered risk of epithelial ovarian cancer in unadjusted (except for matching criteria) analysis (odds ratio (OR) = 1.00, 95 percent confidence interval (CI): 0.39, 2.60). Adjustment for potential confounders, including age at menarche, parity, oral contraceptive use, race/ethnicity, Quetelet index, and cigarette smoking, did not substantially change the risk estimate (OR = 0.95, 95 percent CI: 0.27, 3.34).
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TABLE 4. Epithelial ovarian cancer odds ratios, by luteinizing hormone status, New York University Women's Health Study, New York City, 19851998
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Because of the concern that a different ethnic composition of the case and control groups could affect our results, we repeated the analyses by restricting them to Caucasian subjects only. These results showed a nonsignificant protective effect of variant LH against epithelial ovarian cancer (table 4). Exclusion of eight epithelial ovarian cancer cases diagnosed within 2 years of blood draw did not substantially alter the risk estimates (data not shown).
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DISCUSSION
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In a case-control study nested within a prospective cohort of mostly Caucasian women in New York City, we found that serum levels of wild-type LH were not associated with an increased risk of epithelial ovarian cancer. We also did not observe any evidence for the role of a recently identified common variant of LH in epithelial ovarian cancer.
This study has its strengths and limitations. Among its strong points is that serum samples were collected prior to a diagnosis of cancer, thus eliminating the effect of disease on LH levels. The potential for selection bias was minimized because cases and controls were chosen from the same source population, ensuring exceptional comparability. The prospective design of the study also eliminated the potential for survivor bias, which is important for diseases characterized by a poor prognosis, such as ovarian cancer.
Among the limitations is that, with 58 cases and 116 controls, it had limited power to detect small associations, even though it remains one of the largest prospective studies of epithelial ovarian cancer reported to date. Furthermore, only LH levels were measured; therefore, relations with other hormones, including FSH and steroid hormones, could not be assessed.
We observed a higher proportion of women of Caucasian/Jewish origin among ovarian cancer cases than among controls, which raises the possibility that some of the ovarian cancers in Caucasian/Jewish women in our study could have been due to germ-line mutations (BRCA1, BRCA2) characterized by relatively early-onset ovarian cancer (20
). Unfortunately, we could not test this assumption because specific consent from subjects to test for these high-penetrance mutations was not available.
In the only known previous study that examined directly the role of gonadotropins in ovarian cancer, Helzlsouer et al. (21
) analyzed LH, FSH, and other hormones in a population-based serum bank in Washington County, Maryland. Of 20,305 participants who were followed up for more than 15 years after providing blood samples, 31 developed ovarian cancer. Cases were matched to 62 controls on age, menopausal status, and, for premenopausal women, number of days from the beginning of the last menstrual period. Contrary to the gonadotropin hypothesis, LH levels were found to be marginally lower in cases with ovarian cancer than in controls (16.3 vs. 17.9 IU/liter, respectively), and the risk of ovarian cancer decreased with increasing levels of LH and FSH (21
).
Similar to the Helzlsouer et al. study (21
), we found an inverse association between serum levels of wild-type LH and risk of ovarian cancer. The odds ratio for the high compared with the low third of LH was 0.42 (95 percent CI: 0.09, 2.09) in our study, which is very similar to the corresponding estimate of 0.4 from the Helzlsouer et al. study (95 percent CI: 0.1, 2.0).
The gonadotropin hypothesis postulates that critical events in the pathogenesis of ovarian cancer are entrapment of surface epithelium in inclusion cysts followed by stimulation of the entrapped epithelium by estrogens in the presence of high and persistent levels of LH (6
). Several observations provide arguments that the gonadotropin hypothesis may not be an adequate model for the pathogenesis of epithelial ovarian cancer.
First, the rationale for the gonadotropin hypothesis is based on experimental techniques that induce increased gonadotropin production and development of ovarian tumors in rats whose ovaries were autotransplanted to the spleen (22
, 23
). However, in these animal models, ovarian tumors originate exclusively from the stromal cells (luteomas and granulosa cell tumors) and do not reflect the tumors of epithelial origin most commonly observed in humans.
Second, serum gonadotropins reach maximal levels during the perimenopausal and postmenopausal years. If the 2530-year latency period estimated by Risch (24
) is assumed, the majority of ovarian cancer cases should arise after age 70 years. In reality, the mean age of ovarian cancer occurrence is the mid- to late fifties, and the majority (75 percent) of cases of the disease arise before age 70 years (24
).
Third, according to the hypothesis, the higher gonadotropin levels observed in premature ovarian failure or early menopause should increase the risk of ovarian cancer. However, there is little evidence that age at natural menopause influences risk (25
, 26
).
Fourth, postmenopausal estrogens reduce gonadotropin levels and should reduce the risk of ovarian cancer, as indicated by the gonadotropin hypothesis. On the contrary, postmenopausal estrogen use is associated with a moderately increased risk of ovarian cancer (27
).
Fifth, according to the gonadotropin hypothesis, one mechanism leading to excessive gonadotropin production is exposure to medications affecting the normal inhibitory feedback between ovary and pituitary (psychotropic drugs, barbiturates, antihistamines, and anti-inflammatory drugs). However, there is no consistent evidence that such medications increase the risk of ovarian cancer. Although Harlow et al. reported that psychotropic medications may be associated with an increased risk of ovarian cancer (28
), anti-inflammatory drugs may actually reduce the risk (29

32
).
Several new hypotheses regarding ovarian carcinogenesis were introduced recently. Ghahremani et al. (33
) proposed that dysregulation of apoptosis, specifically, failure of the Fas/Fas ligand apoptotic system to eliminate inclusion cysts within the ovarian stroma, may play a role in ovarian tumor formation. Experimental data from monkeys indicate that progestin-containing oral contraceptives induce apoptosis in the ovarian epithelium (34). Since combined oral contraceptives confer significant protection against subsequent epithelial ovarian cancer (35
, 36
), induction of apoptosis could be responsible for this effect (34
).
On the basis of data from a large case-control study, Ness et al. (37
, 38
) proposed that chronic epithelial ovarian inflammation could play a key role in the pathogenesis of ovarian cancer. Supporting this hypothesis are findings that factors that enhance local inflammation (ovarian endometriosis, pelvic inflammatory disease, talc and asbestos exposure) are associated with an increased risk of ovarian cancer (38
). On the other hand, factors that reduce local inflammation, such as hysterectomy without oophorectomy, tubal ligation, and use of anti-inflammatory medications, have a protective effect (38
). The inflammation hypothesis may also explain the protective effect observed with a reduced lifetime number of ovulations (39
, 40
). Mammalian ovulation has many characteristics of an inflammatory reaction, including local elevation of levels of proinflammatory cytokines, prostaglandins, and leukotrienes (41
). Therefore, a decreased number of ovulations (because of pregnancy, lactation, or oral contraceptive use) may result in less ovarian epithelium exposure to proinflammatory cytokines, which could play a role in the pathogenesis of ovarian cancer (42
).
In conclusion, results from the prospective New York University Women's Health Study suggest that neither serum levels of wild-type LH nor a common variant of LH is associated with an increased risk of epithelial ovarian cancer. On the contrary, compared with women in the lowest tertile of LH levels, women in the highest tertile appear to have a lower risk of epithelial ovarian cancer. A review of relevant evidence suggests a lack of support for the long-held gonadotropin hypothesis of ovarian carcinogenesis. New leads should be explored, including emerging hypotheses on the role of apoptosis and inflammation in epithelial ovarian cancer.
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ACKNOWLEDGMENTS
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Supported by research grant DAMD17-97-1-7226 from the US Department of Defense and by Public Health Service grants R01 CA34588 and P30 CA16087 from the National Cancer Institute.
The authors thank Lynne Quinones, Daniela Masciangelo, Aila Metsävuori, and Tarja Laiho for technical assistance and Yelena Afanasyeva for computer programming assistance.
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NOTES
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Reprint requests to Dr. Arslan Akhmedkhanov, Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Avenue, NB 9E2, New York, NY 10016 (e-mail: akhmea01{at}med.nyu.edu).
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Received for publication June 21, 2000.
Accepted for publication August 20, 2000.