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This article was published with modifications in Am J Epidemiol  2004; 159(2): 319-335

Ovarian Cancer and Polymorphisms in the Androgen and Progesterone Receptor Genes: A HuGE Review

Francesmary Modugno
From the Graduate School of Public Health,
University of Pittsburgh, Pittsburgh, PA.

Received for publication May 15, 2003
Accepted for publication August 5, 2003

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ABSTRACT

Ovarian cancer is the second most common gynecologic cancer among women and the second leading cause of death from gynecologic malignancy worldwide. Androgens, acting through androgen receptors (ARs), have been implicated in the disease, while progestins, acting through progesterone receptors (PGRs), may provide protection against the disease. The PGR gene contains several polymorphisms in the hormone-binding domain, three of which are in linkage disequilibrium (a complex referred to as PROGINS). PROGINS has been associated with increased risk of ovarian cancer. This association has not been found consistently, and it may be limited to women who do not use oral contraceptives. The AR gene contains a trinucleotide CAG repeat, the length of which has been inversely associated with the ability of the AR-ligand complex to transactivate androgen-responsive genes. Data on the association between the AR repeat length and ovarian cancer, both in general and among carriers of mutations in the breast cancer 1 and 2 ( BRCA1/2 ) genes, are inconclusive. There is insufficient evidence that polymorphisms in either the PGR gene or the AR gene may be a risk factor for ovarian cancer, alone or in combination with other factors. The sensitivity, specificity, positive and negative predictive values, and clinical validity of the PROGINS and AR CAG repeat assays are unknown. No recommendations for population-based screening can be made.

Key Words: epidemiology; genetics; ovarian neoplasms; polymorphism (genetics); receptors, androgen; receptors, progesterone; trinucleotide repeats

Abbreviations: AR, androgen receptor; BRCA, breast cancer; CI, confidence interval; OR, odds ratio; PCR, polymerase chain reaction; PGR, progesterone receptor.

GENES

It has recently been hypothesized that androgens and progestins may play a role in ovarian cancer etiology (1). In particular, there is emerging evidence for a protective role of progestins in ovarian cancer. The presence of progesterone receptors (PGRs) in normal ovarian epithelial cells (2) supports the premise of an activity of progesterone and its synthetic variants in the epithelial tissue of the organ. Progestins induce apoptosis in the ovarian surface epithelium of female cynomolgus macaques ( Macaca fascicularis ) (3), constituting an animal model for human ovarian cancer. In humans, persons with tumors that express PGR may have a better prognosis
(4). Epidemiologic data support the possibility of an inverse association of progestin levels with ovarian cancer. Oral contraceptives, which are associated with reduced risk of ovarian cancer, increase progesterone levels in vivo (5). Progestin-only oral contraceptives are as protective against ovarian cancer as estrogen-progestin formulations (6), and high-dose progestin oral contraceptive formulations may be more protective against the disease than low-dose formulations (7). Together, these data suggest that it is the progestin component of oral contraceptives that provides, at least in part, the protective effect. Finally, progestin-containing hormone replacement formulations used in a continuous regimen have recently been shown not to be associated with increased ovarian cancer risk, whereas estrogen-only formulations and formulations in which the progestin component was used sequentially were both associated with increased risk (8).

There is also emerging evidence that androgens may be associated with ovarian cancer risk (see review by Risch (1)). Androgens are produced by ovarian theca lutein cells, are present in ovarian follicular fluid, and are the principal sex steroid of growing follicles (9). Androgen receptors (ARs) are found in the normal surface epithelium of the ovaries (10), suggesting that androgens are active in the organ. Interestingly, the postmenopausal ovary is androgenic (11), as evidenced by 15-fold higher testosterone concentrations in the ovarian vein in comparison with serum from peripheral veins (11). Most ovarian cancers express AR, and antiandrogens inhibit ovarian cancer growth (12, 13). Epidemiologic evidence supports the possibility of an androgen-ovarian cancer link. Oral contraceptives, the most effective chemopreventive agent against the disease, suppress ovarian testosterone production by 35-70 percent (14-18). A prospective study (19) found significantly higher levels of androstenedione in the serum of case women than in control women. In the Cancer and Steroid Hormone Study, case women were more likely to have a history of polycystic ovary syndrome (odds ratio (OR) = 2.4, 95 percent confidence interval (CI): 1.0, 5.9) (20), a condition that causes elevated androgen levels (21-23). Finally, in a cohort study of 31,000 healthy women followed for more than 7 years, the risk of ovarian cancer increased with increasing waist-to-hip ratio (24), a marker of central obesity. Central obesity correlates with androgen levels in women (25-33).

In contrast, there is evidence that the AR gene may have an ovarian tumor suppressor function. AR mRNA and protein are down-regulated in ovarian cancer (10, 34). Moreover, loss of heterozygosity in the region containing the gene has been reported in approximately 40 percent of ovarian cancers (35-37). Finally, nonrandom X-inactivation (38) has been reported in invasive ovarian cancer (39), with expression potentially favoring the allele producing the less active receptor protein (40).

Progesterone receptor
The physiologic effects of progestins depend on the presence of human PGR, a member of the steroid-receptor superfamily of nuclear receptors (41). The PGR gene is located at 11q22-q23
(42-45). PGR exists in two isoforms produced by the single gene with two different promoter and translational start sites. PGR-B is the full-length receptor, while PGR-A is missing the first 165 amino acids (46, 47). The PGR protein consists of an amino-terminal domain containing a ligand-independent activation function; a DNA-binding domain and hinge region in the central part of the protein; and a carboxy-terminal, ligand-binding domain containing a second activation function that is ligand-dependent (48). Although PGR-A and -B share these structural domains, they function as two distinct transcription factors (49) with distinct physiologic effects
(50, 51). PGR-A has been shown to repress estrogen receptor and PGR -B gene activation, whereas PGR-B is a stronger activator of progesterone target genes (52).

Androgen receptor
Androgens exert their effects by first binding to ARs, members of the steroid hormone-thyroid hormone-retinoic acid family of nuclear receptors (48, 53). The resulting hormone-receptor complex then binds directly to DNA, thereby transactivating androgen-responsive genes. The AR gene, also known as dihydrotestosterone receptor, is located at Xq11.2-q12. It spans more than 90 kilobases and contains eight exons (54, 55). The AR protein consists of a highly acidic amino-terminal domain, which functions in transactivation and is located entirely in exon 1 (1,586 base pairs) (56); a highly conserved, cysteine-rich DNA-binding domain containing two DNA-binding fingers located in exons 2 (152 base pairs) and 3 (117 base pairs), respectively; and a mostly hydrophobic carboxy-terminal ligand-binding domain located in exons 4-8, which vary in size from 131 base pairs to 288 base pairs (57-60). The AR gene shares significant homology with both the estrogen receptor and PGR genes (54, 55, 61).

Two isoforms of AR have been identified in a variety of human tissues (62, 63). The two isoforms of AR are remarkably similar in structure to the A and B isoforms of PGR (62). AR-B is the full-length receptor, while AR-A lacks the normal N-terminus (62 , 63). AR-A is derived from internal translation initiation at methionine-188 in the AR open-reading frame and usually constitutes 20 percent or less of the immunoreactive AR present in any tissue (64). Despite the differences in structure and abundance, the two isoforms do not appear to differ in their regulation or in their ability to bind with ligands and activate target genes (64).

GENE VARIANTS

PGR gene
Several polymorphisms in the PGR gene have been identified (65). A Taq I restriction fragment length polymorphism in the hormone-binding domain was the first one reported (66). The polymorphism is the result of a small 309-base-pair Alu direct repeat insertion inherited in a Mendelian fashion (67). Although the functional significance of this insertion remains unknown, it may have consequences for the integrity of the regulatory functions of the gene. Hormone binding and subsequent transcriptional activation by PGR depend on the presence of a complete and intact hormone-binding domain. Alteration of part of this region induces a loss of hormone binding and transcriptional activity in vitro (68), as does the alternative splicing that may result from the Alu insertion (69). The Alu insertion has been associated with endometriosis (70) and breast cancer (71), both of which may be risk factors for ovarian cancer (72-81).

Two other polymorphisms, the Val660Leu polymorphism in exon 4 and the C -->T Hist770Hist polymorphism in exon 5, are in complete linkage disequilibrium with the Alu insertion (65). Together, these three polymorphisms form a complex referred to as PROGINS (82). Recently, a fourth polymorphism, S344T, was reported (65), which was shown to have a standardized pairwise linkage disequilibrium ( D ' = 0.99) with the PROGINS polymorphisms. This new single- nucleotide polymorphism in conjunction with the other three polymorphisms creates a linkage disequilibrium region of approximately 75 kilobases (65), which is consistent with the observed average length of linkage disequilibrium in US populations of Northern European descent (83).

Other single-nucleotide polymorphisms in the PGR gene have been identified, including two variants in the coding region (S344T and G393G) and two in the promoter region (+44C/T and +331G/A) between the PGR-B and PGR-A transcriptional start sites (65). Interestingly, the +331G/A polymorphism creates a unique transcription start site and increases transcription of PGR, favoring the B isoform. Recently, the +331G/A polymorphism was found to be associated with endometrial cancer (65). No associations between the S344T, G393G, and +44C/T variants and endometrial cancer were found (65). To our knowledge, no studies have investigated these four PGR polymorphisms within the context of ovarian cancer.

Table 1 presents frequencies of the PROGINS alleles by ethnicity among relevant studies detected in a Medline (US National Library of Medicine) search of articles published between January 1, 1990, and March 30, 2003. We combined searches for the keywords "progesterone receptor," "polymorphisms," and "ovarian neoplasms" to identify relevant studies. We further searched the references of any identified paper to locate additional studies. Of the seven studies identified, three were conducted in North American (US) populations, three in European populations, and one in an Australian population. As Table 1 shows, the frequency of the more common allele ranged from 0.82 to 0.93 among healthy women and from 0.79 to 0.86 among women with ovarian cancer. Two studies were conducted in the US state of North Carolina: one population-based study (84) and one hospital-based study utilizing noncancer controls enrolled through hospital outpatient clinics (85). Allele distributions between the two case groups and the two control groups were similar, suggesting that the distributions within the cases and controls are representative of women with ovarian cancer in the region.

table Table 1
Results of studies of progesterone receptor gene PROGINS polymorphisms and epithelial ovarian cancer, 1995-2003

AR gene
The most widely studied variant in the AR gene is the highly polymorphic CAG trinucleotide repeat, located within a polyglutamine tract in exon 1. The length of the repeat is inversely associated with the ability of AR to transactivate genes (86, 87). Alleles with fewer CAG repeats appear to be more active, even when within the normal polymorphic range (11-38 repeats). Persons with X-linked spinal and bulbar muscular atrophy (Kennedy disease) have 40 or more AR CAG repeats and manifest clinical androgen insensitivity (88). In men, shorter AR CAG repeat tracts have been associated with prostate cancer, a disease linked to androgens (see review by Nelson and Witte (89)). In women, shorter repeat lengths have been associated with hirsutism
(90), alopecia (91), and acne (91), as well as with lower serum testosterone levels and anovulation among women with polycystic ovary disease (92). Conversely, longer repeat lengths have been associated with earlier age at onset of breast cancer among carriers of the breast cancer 1 ( BRCA1 ) gene mutation ( 93 ).

The AR-CAG repeat may be in linkage disequilibrium with other polymorphisms, including the Stu I mutation (94) and the GGC repeat in exon 1 (95), although these associations have not been confirmed.

There are well-established population differences in the length of the AR- CAG allele. Among African Americans, the most common allele length is 18, as compared with 21 for Caucasians
(96). Among Asian women, the most common allele length is 22 (92, 96).

Table 2 presents frequencies of AR CAG repeat lengths by ethnicity among relevant studies detected in a Medline search of articles published between January 1, 1990, and March 30, 2003. We combined searches for the keywords "androgen receptor," "trinucleotide repeats," and "ovarian neoplasms" to identify relevant studies. We further searched the references of any identified paper to locate additional studies. Only four studies identified (40, 97-99) have examined AR frequency: two Italian studies, one US study of Ashkenazi Jewish women, and one Australian study. Among the four studies, only two were case-control in design (40, 97). The remaining two studies (98, 99) were of case series. The mean length of the short AR repeat ranged from 17.0 to 20.5 repeats among women with ovarian cancer, and was 20.3 repeats among healthy control women from both case-control studies. The long AR repeat length ranged from 20.7 to 23.4 repeats among cases and from 22.8 to 23.6 repeats among controls. In the two studies conducted in Italy (40, 99), the mean number of long AR repeat lengths among cases was almost identical (23 vs. 23.4), while the mean number of short repeats was similar (19 vs. 20.3). The concordance of the findings of these studies, conducted by different investigators in different geographic locations in Italy, suggests that the findings are representative of Italian women with ovarian cancer.

table Table 2
Results of studies of androgen receptor gene polymorphisms and epithelial ovarian cancer, 1995-2003

DISEASE

Ovarian cancer incidence and mortality
In 2000, the worldwide incidence of ovarian cancer was 192.4 per 100,000 women, making the disease the sixth most common cancer among women (100). Worldwide, the highest incidence rates are found among White women in Europe and North America, and the lowest incidence rates are found in Asia. Rates in Central and South America lie between the two (101). In 2003, approximately 25,400 women in the United States will be diagnosed with ovarian cancer, accounting for almost 4 percent of all cancers in US women (102). From 1992 to 1999, the age-adjusted incidence rate among US women was 17.1 per 100,000 (103). The age-adjusted incidence rates for Caucasians, Hispanics, Asians/Pacific Islanders, African Americans, and Native Americans/Alaskans were 18.1, 13.5, 12.6, 12.2, and 10.2 per 100,000, respectively
(104). From 1989 to 1999, incidence rates declined by 0.7 percent per year (102). Although the rates among Asians and Hispanics in the United States are greater than the rates among women in Asia and Central/South America, they do not reach the rate of US Caucasians.

The lifetime risk of ovarian cancer in the population as a whole is approximately 1.4 percent. For women with a mutated BRCA1 gene, population-based studies estimate the risk to be 16-30 percent (105). Approximately 75 percent of women have advanced-stage disease at the time of diagnosis (102). Despite aggressive surgery and chemotherapy, the prognosis for these women is poor, with a 5-year survival rate of less than 40 percent ( 02 . This outcome is due, in large part, to a lack of effective prevention and early detection strategies; with current treatment modalities, the survival rate is approximately 95 percent when this cancer is diagnosed at an early stage (102).

Ovarian cancer is surpassed only by cervical cancer as the leading cause of death from gynecologic malignancy worldwide, with a mortality rate of 114.2 per 100,000 women (100). In the United States, ovarian cancer accounts for 5 percent of cancer deaths among women and is the leading cause of death from gynecologic malignancy (106). In 2003, approximately 14,300 US women will die from the disease. The overall age-adjusted mortality rate in the United States is 9.1 per 100,000 (104), with the highest mortality rates being observed among Whites (9.4/100,000), African Americans (7.7/100,000), and Hispanics (5.8/100,000).

Descriptive epidemiology
The most consistent protective factors for ovarian cancer are bearing children (107-126) and using oral contraceptives (107-114, 126-139). Tubal ligation and breastfeeding also appear to reduce risk (126, 140-142). Other factors shown to lower risk include physical activity (143), twinning (144), and the use of antiinflammatory agents, such as aspirin and the newer nonsteroidal antiinflammatory drugs (145), although data on these factors are inconsistent
(145-154).

Age is an important risk factor for ovarian cancer. The disease is uncommon before age 35 years, and incidence steadily increases until about age 80 years (103). The most consistent risk factor for ovarian cancer is family history. Women with one affected first-degree relative have a 5 percent lifetime risk (1 in 20, versus 1 in 70 for the general population). Those with two affected first-degree relatives have a 7 percent risk (155). Three hereditary syndromes have been defined: the very rare Lynch Syndrome II, which is associated with defects in DNA mismatch repair genes and hereditary nonpolyposis colorectal cancer; and hereditary site-specific ovarian cancer and hereditary breast/ovarian cancer, both of which are associated with mutations in breast cancer genes 1 and 2 ( BRCA1/2 ).

Other risk factors that have been less consistently associated with ovarian cancer include talc use (156), infertility (157), endometriosis (72), pelvic inflammatory disease (158), polycystic ovary syndrome (20), hormone replacement therapy (159), and central obesity (increased waist-to-hip ratio) (24). Cigarette smoking has also been shown to be a risk factor, but only for tumors of the mucinous subtype (160-163).

Genetic epidemiology
Approximately 5-10 percent of malignant epithelial tumors contain germline BRCA1/2 mutations (164-166), most of which are found in BRCA1 . Compared with sporadic disease, BRCA1/2- associated ovarian cancer is often diagnosed at a later stage (167, 168), although survival for BRCA1/2 -associated disease appears to be better than survival for sporadic disease (167-169 ).

Approximately 1 in 800 women carries a BRCA1/2 mutation. In Ashkenazi Jewish women, the prevalence is about 1 in 50 ( 170 - 172 ). Among the Ashkenazim, approximately 45 percent of ovarian cancers arise from two BRCA1 mutations (185delAG and 5382insC) and a single BRCA2 mutation (6174delT) ( 173 - 176 ). These three mutations are commonly found in other ethnic groups. The penetrance of BRCA1 mutations for ovarian cancer is 36 percent by age 80 years
(177) and may depend on the location of the mutation (178, 179). In general, the penetrance of BRCA2 mutations is lower than that of BRCA1 mutations (177), and an ovarian cancer cluster region has been identified (180, 181).

Among women carrying a mutated BRCA1/2 gene, childbearing (182) and tubal ligation (182) appear to be protective against the disease. Whether oral contraceptives afford the same degree of protection to carriers as they do to noncarriers remains controversial (182-184).

ASSOCIATIONS AND INTERACTIONS

PGR polymorphisms and ovarian cancer risk
Table 3 shows the reported associations of PGR polymorphisms with epithelial ovarian cancer in the seven studies identified in the literature. The first study (66), comprising a small convenience sample, suggested a possible increase in ovarian cancer risk associated with the PROGINS allele. However, more recent studies using larger data sets (84, 185) have failed to establish any statistically significant associations, and no consistent pattern of increased risk has emerged. Only one population-based study has addressed the question (84), with a modest association of borderline significance found only among women who had never used oral contraceptives (OR = 1.8, 95 percent CI: 1.0, 3.3; adjusted for age, tubal ligation, and race). A similar finding was reported among women with BRCA1/2 mutations (186).

table Table 3
Association of the progesterone receptor gene PROGINS polymorphism with epithelial ovarian cancer in various studies

There are several reasons for the negative findings. Small sample sizes limit the power of any one study; convenience samples may introduce bias into the study results; and selection of controls who are not representative of the population from which the cases were ascertained may generate selection bias. Data on other important factors, such as the response rates of cases and controls, were not reported in most of the published articles. This made it difficult to adequately assess other biases or flaws that may have been introduced into individual studies.

Several studies have examined the association of PROGINS with tumor behavior (84, 185, 187) No significant associations have been reported for tumor grade, stage, histologic subtype, invasiveness, or age at onset. Again, the small sample sizes and the limited details provided by the reports make it difficult to assess the validity of these findings.

PGR polymorphisms, oral contraceptive use, and ovarian cancer risk 
No studies have investigated formal interactions between PROGINS and ovarian cancer risk factors. However, Runnebaum et al. (186) examined the association of PROGINS with oral contraceptive use and ovarian cancer risk among women with a BRCA1/2 mutation. They reported no association overall between disease status and the presence of the PROGINS allele and no modifying effect of PROGINS in women who reported ever using oral contraceptives. However, in women who had never been exposed to oral contraceptives, the presence of at least one PROGINS allele was associated with increased risk of ovarian cancer (unadjusted OR = 2.4, 95 percent CI: 1.4, 4.3). The association was even stronger (though not statistically significant) when the analysis was limited to women carrying two PROGINS alleles (unadjusted OR = 3.3, 95 percent CI: 0.7, 14.2). The authors reported a similar association after adjustment for year of birth and ethnicity. No other adjustments were mentioned.

Lancaster et al. (84) recently reported no association between PROGINS and ovarian cancer risk in general or among oral contraceptive users and nonusers. However, in their data set, the PROGINSallele was less common among cases who had ever used oral contraceptives in comparison with controls (OR = 0.8, 95 percent CI: 0.5, 1.2; adjusted for age, race, and tubal ligation) but more common among cases who had never used oral contraceptives in comparison with controls (adjusted OR = 1.8, 95 percent CI: 1.0, 3.3). This difference between ever users and never users of oral contraceptives was even stronger when the analysis was limited to women carrying two PROGINS alleles: The adjusted odds ratio was 0.4 for oral contraceptive users and 2.2 for never users. Together, the data of Runnebaum et al. (186) and Lancaster et al. (84) suggest a possible interaction between oral contraceptive use and carriage of the PROGINS allele.

AR CAG repeat length and ovarian cancer risk
Two case series (98, 99) examined the association of repeat length with age of disease onset. Levine and Boyd (98) studied 179 Ashkenazi Jewish ovarian cancer patients consecutively diagnosed at a single hospital in New York City (85 BRCA1/2 mutation carriers, 94 sporadic cases). Independent of BRCA1/2 carriage, women who carried a short AR allele, defined as fewer than 20 repeats, were diagnosed an average of 7.2 years (95 percent CI: 2.3, 12.1) earlier than patients who did not carry a short allele ( p = 0.0004). In contrast, Menin et al. (99) reported that among 50 women from high-risk families (14 of whom were BRCA1/2 carriers), cases with fewer than 19 repeats had a median age at diagnosis of 58 years, as compared with 52 years for cases with 19 or more repeats ( p = 0.03).

Two case-control studies have examined the association of CAG repeat length with ovarian cancer risk (Table 4). Spurdle et al. (97) found no association between ovarian cancer risk and AR CAG repeat length in a population-based case-control study. When CAG repeat length was analyzed as a continuous variable, there were no differences between incident cases and either population controls or controls from a study of monozygotic twins (in which only one twin from each pair was included in the control group) for smaller, larger, and average allele sizes of CAG repeat length, before or after adjustment for age. Moreover, no differences between cases and controls were found when repeat length was analyzed as a dichotomous variable based on median length (22 or more repeats) or based on the length reported to act as a modifier of breast cancer risk (29 or more repeats) (188). However, there was a borderline-significant suggestion that alleles of at least 27 repeats may be weakly protective against ovarian cancer (for cases versus the pooled control group, unadjusted OR = 0.64, 95 percent CI: 0.41, 0.99). This latter finding is consistent with the hypothesis that increased androgen exposure is a risk factor for ovarian cancer (1), because functional studies suggest that longer CAG repeat alleles are associated with decreased AR hormone action (189).

table Table 4
Association of the androgen receptor gene CAG repeat with epithelial ovarian cancer in two studies

In contrast, in a hospital-based case-control study, Santarosa et al. (40) observed an increase in ovarian cancer risk among women carrying at least one allele with 22 or more CAG repeats (OR = 2.17, 95 percent CI: 1.10, 4.27; adjusted for age). This association was more pronounced in women with a family history of the disease (adjusted OR = 3.52, 95 percent CI: 1.18, 10.47) and in women carrying at least two alleles with 22 or more repeats (adjusted OR = 3.45, 95 percent CI: 1.42, 8.37) (40). Interestingly, 18 of the 27 tumors (six hereditary and 21 sporadic) examined showed preferential expression of the long AR allele, with five of the six hereditary tumors expressing the long allele. Thus, while these data do not support a role for androgens in the etiology of ovarian cancer, they do support the hypothesis that the AR gene may serve as a tumor suppressor gene.

Although the contradictory findings of these two studies might be attributed to ethnic or environmental differences in ovarian cancer etiology between the two populations, it is likely that the differing study designs contributed to the differing results. In particular, although both studies employed a case-control design, in one study, controls were recruited from the general population (97), while in the other, controls were recruited from women donating blood at the hospital from which the cases were identified (40). However, in both studies, the mean age of the controls was significantly lower than that of the cases. Thus, it is possible that the contrasting findings of the two studies can be attributed to differences in the control populations. In particular, while the distribution of allele lengths was almost identical for both studies' case groups, the distribution of allele lengths between the two studies' control groups differed substantially (Table 4). Hence, because the biology of ovarian carcinogenesis is likely to be independent of ethnic origin, the differences in allele distributions in the control groups may represent a bias in one of the studies rather than a true ethnic difference in allele frequency.

AR CAG repeat length, BRCA1/2 carriage, and ovarian cancer risk
Only one study (98) has examined the interaction between BRCA1/2carriage and AR CAG repeat length. Among the 179 consecutive Ashkenazi Jewish cases, no differences in short, long, or average allele length were found between women with one of the three Ashkenazi founder mutations and women without any founder mutations. This result contrasts with results that have been reported for breast cancer (188), in which AR CAG repeat length modified the age at onset and the risk associated with BRCA1/2 carriage. The finding also does not support in vitro studies showing that in breast and prostate cancer cell lines, BRCA1 binds to the AR in the N-terminal region (where the CAG repeat is found) and serves as a coactivator for the gene (190), possibly playing a role in androgen-induced apoptosis (191).

LABORATORY TESTING

PGR gene
Early genotyping studies (66) used Southern blot analysis of Taq I-digested genomic DNA hybridized with a PGR cDNA probe. In more recent studies, undigested genomic DNA from peripheral blood leukocytes or banked tissue specimens has been amplified by polymerase chain reaction (PCR). In several studies ( 66, 84, 85, 186, 192), the region flanking the Alu insertion was amplified. Alleles lacking the insertion appear as smaller bands compared with alleles with the insertion (175 base pair fragments vs. 481) when resolved on agarose gel. Spurdle et al.
(185) used the Sequence Detection System allelic discrimination assay (PE Applied Biosystems, Foster City, California) to detect the G and T alleles of the exon 4 Val660Leu polymorphism. Tong et al. (187) used fluorescein-labeled PCR primers to amplify DNA fragments containing the polymorphic sites in exons 4 and 5. They then designed 5-biotin-labeled probes to hybridize either to the wild-type PCR product or the polymorphic PCR product. Allele detection was performed with the ViennaLab Universal Gene Mutation Detection Kit (ViennaLab Labordiagnostika GmbH, Vienna, Austria), in which denatured PCR product is added to oligonucleotide-specific streptavidin-coated wells. The captured oligonucleotides for the polymorphisms in exons 4 and 5 hybridize specifically with either wild-type or polymorphic PCR products, generating genotype-specific color signals. No data on the sensitivity, specificity, or positive and negative predictive values of any of the PROGINS assays have been presented. Moreover, there are no data on the clinical validity of any of these assays.

AR gene
Molecular methods for determining AR CAG repeat length were summarized by Nelson and Witte
(89). Briefly, PCR is utilized to amplify the CAG trinucleotide repeat in exon 1 using primers that are labeled with [ gamma33 P]-adenosine triphosphate. The amplified products are then size-separated and analyzed on a denaturing polyacrylamide sequencing gel. The number of repeats can be determined by comparing the gel band to a series of CAG size standards. More recently, fluorescein-labeled primers have been used and the sizes of the PCR products have been determined automatically (97). No data on the sensitivity, specificity, or positive and negative predictive values of the CAG repeat assays have been presented, although Nelson and Witte stated that because "the primers for this test are designed specifically for the CAG repeat,... the sensitivity and specificity are extremely high" (89, p. 888). No data on the clinical validity of the CAG repeat assay have been presented.

POPULATION TESTING

There is insufficient evidence to justify testing for the PROGINS , the +44C/T and +331G/A PGR polymorphisms, or the AR CAG trinucleotide repeat in a screening program for ovarian cancer in the general population. Neither is there sufficient evidence to justify testing for these polymorphisms in a screening program for high-risk women, including BRCA1/2 mutation carriers.

OTHER POTENTIAL PUBLIC HEALTH APPLICATIONS

At this time, the data are insufficient to support any public health recommendations.

CONCLUSIONS AND RECOMMENDATIONS FOR RESEARCH

The mounting evidence for a role of both progestins and androgens in ovarian cancer supports the hypothesis that polymorphisms in the PGR and AR genes may act as risk factors for ovarian cancer and/or as modifiers of risk associated with exposure to hormonal factors. However, the data thus far have been inconclusive. Only two studies have examined the association of the AR CAG repeat with ovarian cancer, with contradictory findings. As was discussed above, differences in the study designs may explain these disparate findings. This suggests a need for large, well-designed studies specifically aimed at addressing the association of the polymorphism with ovarian cancer. Additionally, more research is needed to understand the AR CAG polymorphism and its interaction with known risk factors and protective factors, including oral contraceptive use, parity, hormone replacement therapy, and BRCA1/2 mutation status.

While there have been a greater number of studies on PROGINS and ovarian cancer, the results thus far have been predominantly negative. Although the lack of an association may be real, it is possible that methodological issues, such as small sample sizes, may be obscuring any true association. In addition, the association of PROGINS with a subset of women not using oral contraceptives and with those carrying a BRCA1/2 mutation is intriguing and underscores the need for further investigation into the gene-gene and gene-environment interactions that may partially explain the etiology of ovarian cancer.

In addition to large-scale, population-based studies examining the AR CAG repeat and PROGINS as independent risk factors and as risk-modifying factors for ovarian cancer, studies of emerging polymorphisms in these genes are also needed. Notably, the four recently identified PGR polymorphisms (S344T, G393G, +44C/T, and +331G/A) (65) warrant further investigation, especially because the S344T and G393G polymorphisms are located in the coding region of the gene and the +331G/A polymorphism, which has been found to be associated with an almost twofold increase in risk of endometrial cancer (65), favors increased receptor transcription. In particular, the +331G/A polymorphism is 3' of the PGR-A and -B transcriptional start sites and favors production of the B isoform (65). Highly malignant forms of ovarian cancer have been correlated with overexpression of PGR-B (193). An association with the +331G/A polymorphism is therefore plausible.

This review has focused on common polymorphisms in the AR and PGR genes. However, polymorphisms in genes along the sex steroid biosynthesis and metabolism pathways also warrant investigation as ovarian cancer risk factors, either alone or, more likely, in combination with lifestyle/environmental exposures and other genetic polymorphisms. In particular, polymorphisms in the estrogen receptor gene as well as in enzymes involved in the conversion of cholesterol to progesterone, androgens, and estrogens must be considered (Figure 1) To date, only a handful of studies have examined the association of ovarian cancer with single polymorphisms in enzymes involved in this pathway (194-197), and no studies have examined the interaction of several of these polymorphisms together or between these polymorphisms and environmental exposures. Moreover, only one study has examined the association of genotypes with specific histologic subtypes of ovarian cancer (197). The results of these few studies have been mostly negative; only one study reported a significant association between carriage of the cytochrome P-450 17 A2 variant and ovarian cancer (OR = 1.86, 95 percent CI: 1.26, 2.75) (197). The increased risk was most apparent in women over age 50 years and in women with invasive serous carcinoma. The same investigators reported an inverse association with carriage of a valine/methionine variant of the catechol- O -methyltransferase gene, especially for women with mucinous tumors (197).

figure  Figure 1
  General scheme of the sex steroid synthesis pathway and the associated  hormone receptors. For simplicity, only some of the enzymes and some of  the potential receptor-hormone complexes are shown. CYP, cytochrome  P- 450; 17HSD, 17ß-hydroxysteroid dehydrogenase; OH, hydroxy; DHEA,  dehydroepiandrosterone; 3HSD, 3 alpha-hydroxysteroid dehydrogenase; SDR,  steroid 5 alpha-reductase II; DHT, dihydroxytestosterone; PR, progesterone  receptor; AR, androgen receptor; ER, estrogen receptor. Solid arrows  indicate conversion pathways; dotted lines represent potential  hormone- receptor complexes; boxes represent hormone receptors.

Investigations of multiple polymorphisms in the steroid metabolism pathway are critical, because the high degree of interaction among these gene products, such as the cross-talk between the estrogen receptor and both AR (198) and PGR 199), makes it is unlikely that any one polymorphism alone will confer a substantial individual risk of ovarian cancer. As an example of the effect of multiple polymorphisms in this pathway on cancer risk, one recent study showed that although a polymorphism in the estrogen receptor gene was not a risk factor for prostate cancer, it substantially modified the risk of prostate cancer associated with a short AR CAG repeat (200).

Because the steroid hormone system both influences and is influenced by the insulin and insulin-like growth factor pathways (201-204), these latter pathways and the factors affecting them must also be considered. For example, polymorphisms in insulin-like growth factor I and its binding proteins may alter the availability of insulin-like growth factors (205, 206), which in turn can alter steroid hormone levels (202-204).

Hence, researchers must consider not only the individual effects of genetic polymorphisms but also the joint effects of several genes interacting. Moreover, because an environmental and lifestyle factor, such as alcohol drinking, may exert its effect on both the sex steroid and insulin-like growth factor pathways, genotype combinations must also be considered in conjunction with such factors.

These studies should include ethnically diverse populations in order to capture data on potential lifestyle and cultural factors, as well as other genetic factors, that may modify risk. For identification of specific risk modifiers, the PGR and AR polymorphisms should be examined in combination with specific hormonal exposures, such as oral contraceptive use and hormone replacement therapy regimens. Additional putative risk modifiers include hormone-altering host and dietary/lifestyle factors. Examples of such host factors include body mass index and central obesity, which correlate with hormone levels, especially androgen levels (25). Lifestyle factors that may alter circulating hormone levels include the use of alcohol and certain supplements (such as soy). Alcohol intake has been shown to alter progestin and androgen levels in both oral contraceptive users and nonusers (207).

In addition, detailed data on the timing of host and lifestyle factors, such as weight throughout the life span, should be obtained in order to identify critical time periods in which exposure to certain factors could modify the risk of ovarian cancer associated with the AR or PROGINS polymorphisms. Similarly, detailed data on exposure levels should be recorded in order to identify potential threshold effects.

More advanced approaches to identifying those polymorphisms involved in ovarian cancer are also warranted. In particular, knowledge of the haplotype map will enable researchers to focus on identifying those functional polymorphisms that influence risk, age at onset, clinical course, and response to treatment. In addition, more advanced analytical techniques aimed at uncovering higher-order interactions (208) will prove useful in increasing our knowledge and understanding of the complex interactions between multiple genes along a single pathway, such as the steroid synthesis pathway, or along related pathways, such as the insulin and insulin-like growth factor pathways. These techniques will probably apply to interactions with environmental and lifestyle exposures as well.

In conclusion, although currently the data do not support a definite role for the AR CAG and PROGINS polymorphisms in ovarian cancer etiology, there is sufficient evidence of a possible association to warrant further investigation. Studies collecting detailed data on lifestyle and host factors throughout the life span, together with additional genetic data on not only the steroid hormone pathways but also related pathways such as those of the insulin-like growth factors, are needed. Collection of such detailed data in large, diverse populations will enable scientists to identify more precisely the individual and joint roles of genetic factors and environmental exposures in the etiology of ovarian cancer.

ACKNOWLEDGMENTS

This research was supported by grants K07-CA80668 and R03-CA92776 from the National Cancer Institute and grant DAMD17-001-0569 from the US Department of Defense (Ovarian Cancer Research Program).

The authors thank Dr. Jeffrey L. Eppinger for his comments on this work. They also thank Dr. Julia Greer and Randi E. Koenig for their help with the manuscript.

NOTES

Correspondence to Dr. Francesmary Modugno, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, 516A Parran Hall, Pittsburgh, PA 15261 (e-mail: fm@cs.cmu.edu).

 

REFERENCES

  1. Risch HA. Hormonal etiology of epithelial ovarian cancer, with hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998;90:1774-86.
  2. Zeimet AG, Muller-Holzner E, Marth C, et al. Immunocytochemical versus biochemical receptor determination in normal and tumorous tissues of the female reproductive tract and the breast. JAMA 1994;49:365-72.
  3. Rodriguez GC, Walmer DK, Cline M, et al. Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis? J Soc Gynecol Investig 1998;5:271-6.
  4. Sevelda P, Denison U, Schemper M, et al. Oestrogen and progesterone receptor content as a prognostic factor in advanced epithelial ovarian carcinoma. Br J Obstet Gynaecol 1990;97:706-12.
  5. King RJ. Biology of female sex hormone action in relation to contraceptive agents and neoplasia. Contraception 1991;43:527-42.
  6. Rosenberg L, Palmer JR, Zauber AG, et al. A case-control study of oral contraceptive use and invasive epithelial ovarian cancer. Am J Epidemiol 1994;139:654-61.
  7. Schildkraut JM, Calingaert B, Marchbanks PA, et al. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst 2002;94:32-8.
  8. Riman T, Dickman PW, Nilsson S, et al. Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst 2003;94:497-504.
  9. McNatty KP, Makris A, Reinhold VN, et al. Metabolism of androstenedione by human ovarian tissues in vitro with particular reference to reductase and aromatase activity. Steroids 1979;34:429-43.
  10. Lau KM, Mok SC, Ho SM. Expression of human estrogen receptor alpha and beta, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells. Proc Natl Acad Sci U S A 1999;96:5722-7.
  11. Judd HL, Judd GE, Lucas WE, et al. Endocrine function of the post-menopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 1974;39:1020-4.
  12. Slotman BJ, Rao BR. Response to inhibition of androgen action of human ovarian cancer cells in vitro. Cancer Lett 1989;45:312-20.
  13. Chadha S, Rao BR, Soltman BE, et al. An immunohistochemical evaluation of androgen and progesterone receptors in ovarian cancer. Hum Pathol 1993;24:90-5.
  14. Godwin AK, Testa JR, Handel LM, et al. Spontaneous transformation of rat ovarian surface epithelial cells: association with cytogenetic changes and implications of repeated ovulation in the etiology of ovarian cancer. J Natl Cancer Inst 1992;84:592-601.
  15. Browning MC, Anderson J. Effect of oral contraceptives on plasma testosterone concentration. (Letter). Br Med J (Clin Res Ed) 1977;1:107.
  16. Murphy A, Cropp CS, Smith BS, et al. Effect of low-dose oral contraceptive on gonadotropins, androgens, and sex hormone binding globulin in nonhirsute women. Fertil Steril 1990;53:35-9.
  17. van der Vange N, Blankenstein MA, Kloosterboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and testosterone. Contraception 1990;41:345-52.
  18. Kuhnz W, Sostarek D, Gansau C, et al. Single and multiple administration of a new triphasic oral contraceptive to women: pharmacokinetics of ethinyl estradiol and total testosterone levels in serum. Am J Obstet Gynecol 1991;165:596-602.
  19. Helzlsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-30.
  20. Schildkraut J, Schwingl PJ, Bastos E, et al. Epithelial ovarian cancer risk among women with polycystic ovarian syndrome. Obstet Gynecol 1996;88:549-54.
  21. Insler V, Luenfeld B. Pathophysiology of polycystic ovarian disease: new insights. Int J Cancer 1991;6:1025-9.
  22. Abdel Gadir A, Khatim MS, Mowafi RS, et al. Implications of ultrasonically diagnosed polycystic ovaries: correlations with basal hormonal profiles. Hum Reprod 1992;7:453-7.
  23. Robinson S, Rodin DA, Deacon A, et al. Which hormone tests for the diagnosis of polycystic ovary syndrome? Br J Prev Soc Med 1992;99:232-8.
  24. Mink PJ, Folsom AR, Sellers TA, et al. Physical activity, waist-to-hip ratio and other risk factors for ovarian cancer: a follow-up study of older women. Epidemiology 1996;7:38-15.
  25. Ballard-Barbash R. Anthropometry and breast cancer. Body size-a moving target. Cancer 1994;74:1090-100.
  26. Barrett-Conner E, Ferrara A. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and non- insulin-dependent diabetes in post menopausal women: The Rancho Bernardo Study. J Clin Endocrinol Metab 1996;81:59-64.
  27. De Pergola G, Triggiani V, Giorgino F, et al. The testosterone to dehydroepiandrosterone sulphate molar ratio as a marker of visceral fat accumulation in premenopausal obese women. Int J Obes Relat Metab Disord 1994;18:659-64.
  28. Evans DJ, Hoffman RG, Kalkhoff RK, et al. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 1983;57:304-10.
  29. Kaye SA, Folsom AR, Soler JT, et al. Associations of body mass and fat distribution with sex hormone concentration in post-menopausal women. Int J Epidemiol 1991;20:151-6.
  30. Kirschner MA, Samojlik E. Sex hormone metabolism in upper and lower body obesity. Int J Obes 1991;15:101-8.
  31. Luthold WW, Borges MF, Marcondes JA, et al. Serum testosterone fractions in women: normal and abnormal clinical states. Metabolism 1993;42:638-43.
  32. Mantzoros CS, Georgiadis EI, Evangelopoulou K, et al. Dehydroepiandrosterone sulfate and testosterone are independently associated with body fat distribution in premenopausal women. Epidemiology 1996;7:513-16.
  33. Williams DP, Boyden TW, Pamenter RW, et al. Relationship of body fat percentage and fat distribution with dehydroepiandrosterone sulfate in premenopausal females. J Clin Endocrinol Metab 1993;77:80-5.
  34. van Doorn HC, Burger CW, van der Valk P, et al. Estrogen, progesterone, and androgen receptors in ovarian neoplasia: correlation between immunohistochemical and biochemical receptor analyses. J Clin Pathol 2000;53:201-5.
  35. Davis M, Hitchcock A, Foulkes WD, et al. Refinement of two chromosome 11q regions of loss of heterozygosity in ovarian cancer. Cancer Res 1996;56:741-4.
  36. Edelson MI, Lau CC, Colitti CV, et al. A one centimorgan deletion unit on chromosome Xq12 is commonly lost in borderline and invasive epithelial ovarian tumors. Oncogene 1998;16:197-202.
  37. Gabra H, Watson JE, Taylor KJ, et al. Definition and refinement of a region of loss of heterozygosity at 11q23.3-q24.3 in epithelial ovarian cancer associated with poor prognosis. Cancer Res 1996;56:950-4.
  38. Lyon MF. Gene action in the X-chromosome of the mouth. Nature 1961;190:372-3.
  39. Buller RE, Sood AK, Lallas T, et al. Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. J Natl Cancer Inst 1999;91:339-46.
  40. Santarosa M, Bidoli E, Gallo A, et al. Polymorphic CAG repeat length within the androgen receptor gene: identification of a subgroup of patients with increased risk of ovarian cancer. Oncol Rep 2002;9:639-44.
  41. Lydon JP, DeMayo FJ, Funk CR, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 1995;9:2266-78.
  42. Law ML, Kao FT, Wei Q, et al. The progesterone receptor gene maps to human chromosome band 11q13, the site of the mammary oncogene int -2. Proc Natl Acad Sci U S A 1987;84:2877-81.
  43. Mattei MG, Krust A, Stropp U, et al. Assignment of the human progesterone receptor to the q22 band of chromosome 11 using in situ hybridization. Cytogenet Cell Genet 1987;46(suppl):658.
  44. Mattei MG, Krust A, Stropp U, et al. Assignment of the human progesterone receptor to the q22 band of chromosome 11. Hum Genet 1988;78:96-7.
  45. Rousseau-Merck MF, Misrahi M, Loosfelt H, et al. Localization of the human progesterone receptor gene to chromosome 11q22-q23. Hum Genet 1987;77:280-2.
  46. Sartorius CA, Melville MY, Hovland AR, et al. A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol 1994;8:1347-60.
  47. Wen DX, Xu YF, Mais DE, et al. The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol 1994;14:8356-64.
  48. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell 1995;83:835-9.
  49. Giangrande PH, Kimbrel EA, Edwards DP, et al. The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol 2000;20:3102-15.
  50. Richer JK, Jacobsen BM, Manning NG, et al. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 2002;277:5209-18.
  51. Horwitz KB. The molecular biology of RU486: is there a role for antiprogestins in the treatment of breast cancer? Endocr Rev 1992;13:146-63.
  52. Vegato E, Shahbaz MM, Wen DX, et al. Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol 1993;7:1244-55.
  53. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988;240:889-95.
  54. Brinkmann AO, Faber PW, van Rooij HC, et al. The human androgen receptor: domain structure, genomic organization and regulation of expression. J Steroid Biochem 1989;34:307-10.
  55. Kuiper GG, Faber PW, van Rooij HC, et al. Structural organization of the human androgen receptor gene. J Mol Endocrinol 1989;2:R1-4.
  56. Faber PW, Kuiper GG, van Rooij HC, et al. The N-terminal domain of the human androgen receptor is encoded by one, large exon. Mol Cell Endocrinol 1989;61:257-62.
  57. Chang C, Kokontis J, Liao S. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 1988;240:324-6.
  58. Lubahn DB, Joseph DR, Sullivan PM, et al. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 1988;240:327-30.
  59. Tilley WD, Marcelli M, Wilson JD, et al. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci U S A 1989;86:327-31.
  60. Trapman J, Klaassen P, Kuiper GG, et al. Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commununmun 1988;153:241-8.
  61. Kuper H, Titus-Ernstoff L, Harlow BL, et al. Population based study of coffee, alcohol and tobacco use and risk of ovarian cancer. Int J Cancer 2000;88:313-18.
  62. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci U S A 1994;91:1234-8.
  63. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol 1996;120:51-7.
  64. Gao T, McPhaul MJ. Functional activities of the A and B forms of the human androgen receptor in response to androgen receptor agonists and antagonists. Mol Endocrinol 1998;12:654-63.
  65. De Vivo I, Huggins GS, Hankinson SE, et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A 2002;99:12263-8.
  66. McKenna NJ, Kieback DG, Carney DN, et al. A germline Taq I restriction fragment length polymorphism in the progesterone receptor gene in ovarian carcinoma. Br J Cancer 1995;71:451-5.
  67. Rowe SM, Coughlan SJ, McKenna NJ, et al. Ovarian carcinoma-associated Taq I restriction fragment length polymorphism in intron G of the progesterone receptor gene is due to an Alu sequence insertion. Cancer Res 1995;55:2743-5.
  68. Dobson AD, Conneely OM, Beattie W, et al. Mutational analysis of the chicken progesterone receptor. J Biol Chem 1989;264:4207-11.
  69. Vegato E, Allan GF, Schrader WT, et al. The mechanism of RU486 antoagonism is dependent upon the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell 1992;69:703-13.
  70. Wieser F, Schneeberger C, Tong D, et al. PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril 2002;77:309-12.
  71. Wang-Gohrke S, Chang-Claude J, Becher H, et al. Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50. Cancer Res 2000;60:2348-50.
  72. Brinton LA, Gridley G, Persson I, et al. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol 1997;176:572-9.
  73. Harvey EB, Brinton LA. Second cancer following cancer of the breast in Connecticut, 1935-82. Natl Cancer Inst Monogr 1985;68:99-112.
  74. Teppo L, Pukkala E, Saxen E. Multiple cancer-an epidemiologic exercise in Finland. J Natl Cancer Inst 1985;75:207-17.
  75. Volk N, Pompe-Kirn V. Second primary cancers in breast cancer patients in Slovenia. Cancer Causes Control 1997;8:764-70.
  76. Schenker JG, Levinsky R, Ohel G. Multiple primary malignant neoplasms in breast cancer patients in Israel. Cancer 1984;54:145-50.
  77. Tanaka H, Tsukuma H, Koyama H, et al. Second primary cancers following breast cancer in the Japanese female population. Jap J Cancer Res 2001;92:1-8.
  78. Ewertz M, Storm HH. Multiple primary cancers of the breast, endometrium and ovary. Eur J Cancer Clin Oncol 1989;25:1927-32.
  79. Schottenfeld D, Berg J. Incidence of multiple primary cancers. IV. Cancers of the female breast and genital organs. J Natl Cancer Inst 1971;46:161-70.
  80. Schoenberg BS, Greenberg RA, Eisenberg H. Occurrence of certain multiple primary cancers in females. J Natl Cancer Inst 1969;43:15-32.
  81. Ewertz M, Mouridsen HT. Second cancer following cancer of the female breast in Denmark, 1943-80. Natl Cancer Inst Monogr 1985;68:325-9.
  82. Kieback DG, Tong X-W, Weigel NL, et al. A genetic mutation in the progesterone receptor ( PROGINS) leads to an increased risk of non-familial breast and ovarian cancer causing inadequate control of estrogen receptor driven proliferation. . J Soc Gynecol Investig 1998;5(suppl):40A.
  83. Reich DE, Cargill M, Bolk S, et al. Linkage disequilibrium in the human genome. Nature 2001;411:199-204.
  84. Lancaster JM, Wenham RM, Halabi S, et al. No relationship between ovarian cancer risk and progesterone receptor gene polymorphism in a population-based, case-control study in North Carolina. Cancer Epidemiol Biomarkers Prev 2003;12:226-7.
  85. Lancaster JM, Berchuck A, Carney ME, et al. Progesterone receptor gene polymorphism and risk for breast and ovarian cancer. (Letter). Br J Cancer 1998;78:277.
  86. Tut TG, Ghadessy FJ, Trifiro MA, et al. Long polyglutamine tracts in the androgen receptor are associated with reduced transactivation, impaired sperm production and male infertility. J Clin Endocrinol Metab 1997;82:3777-82.
  87. Grierson AJ, Mootoosamy RC, Miller CC. Polyglutamine repeat length influences human androgen receptor/C Jun mediated transcription. Neurosci Lett 1999;277:9-12.
  88. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77-9.
  89. Nelson KA, Witte JS. Androgen receptor CAG repeats and prostate cancer. Am J Epidemiol 2002;155:883-90.
  90. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853-61.
  91. Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg 1998;3:9-15.
  92. Mifsud A, Ramirez S, Yong EL. Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metab 2000;85:3484-8.
  93. Rebbeck TR, Kantoff PW, Krithivas K, et al. Modification of BRCA1 -associated breast cancer risk by polymorphic androgen-receptor CAG repeat. Am J Hum Genet 1999;64:1371-7.
  94. Ross RK, Pike MC, Coetzee GA, et al. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res 1998;58:4497-504.
  95. Irvine RA, Yu MC, Ross RK, et al. The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 1995;55:1937-40.
  96. Edwards A, Hammond HA, Jin L, et al. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 1992;12:241-53.
  97. Spurdle AB, Webb PM, Chen X, et al. Androgen receptor exon 1 CAG repeat length and risk of ovarian cancer. Int J Cancer 2000;87:637-43.
  98. Levine DA, Boyd J. The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series. Cancer Res 2001;61:908-11.
  99. Menin C, Banna GL, De Salvo G, et al. Lack of association between androgen receptor CAG polymorphism and familial breast/ovarian cancer. Cancer Lett 2001;168:31-6.
  100. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-6.
  101. Bray F, Ferlay J, Parkin DM, et al. GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide. (IARC Cancer Base no. 5). Lyon, France: International Agency for Research on Cancer, 2001.
  102. American Cancer Society. American Cancer Society facts and figures 2003. Washington, DC: American Cancer Society, 2003:1-52.
  103. Ries LA, Eisner MP, Kosary CL, et al. SEER cancer statistics review, 1973-1999. Bethesda, MD: National Cancer Institute, 2002.
  104. Ries LA, Eisner MP, Kosary CL, et al. SEER cancer incidence and mortality rates by race/ethnicity, 1992-1999. Bethesda, MD: National Cancer Institute, 2002.
  105. Claus EB, Schildkraut JM, Thompson WD, et al. Attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-24.
  106. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5-26.
  107. Wu ML, Whittemore AS, Paffenbarger RS Jr, et al. Personal and environmental characteristics related to epithelial ovarian cancer. I. Reproductive and menstrual events and oral contraceptive use. Am J Epidemiol 1988;128:1216-27.
  108. Tzonou A, Day NE, Trichopoulos D, et al. The epidemiology of ovarian cancer in Greece: a case-control study. Eur J Clin Oncol 1984;20:1045-52.
  109. Newhouse ML, Pearson RM, erton JM, et al. A case-control study of the ovary. Br J Prev Soc Med 1977;31:148-53.
  110. McGowan L, Parent L, Lednar W, et al. The women at risk for developing ovarian cancer. Gynecol Oncol 1979;7:325-44.
  111. Booth M, Beral V, Smith P. Risk factors for ovarian cancer: a case-control study. Br J Cancer 1989;60:592-8.
  112. Hildreth NG, Kelsey JL, LiVolsi VA, et al. An epidemiologic study of epithelial carcinoma of the ovary. Am J Epidemiol 1981;114:398-405.
  113. Casagrande JT, Louie EW, Pike MC, et al. "Incessant ovulation" and ovarian cancer. Lancet 1979;2:170-3.
  114. Rosenberg L, Shapiro S, Slone D, et al. Epithelial ovarian cancer and combination oral contraceptives. JAMA 1982;247:3210-12.
  115. Mori M, Kiyosawa H, Miyake H. Case-control study of ovarian cancer in Japan. Cancer 1984;53:2746-52.
  116. Kvale G, Heuch I, Nilssen S, et al. Reproductive factors and risk of ovarian cancer: a prospective study. Int J Cancer 1988;42:246-51.
  117. Joly DJ, Lilienfeld AM, Diamond EL, et al. An epidemiologic study of the relationship of reproductive experience to cancer of the ovary. Am J Epidemiol 1974;99:190-209.
  118. Cramer DW, Hutchison GB, Welch WR, et al. Determinants of ovarian cancer risk. J Natl Cancer Inst 1983;71:711-16.
  119. Franceschi S, La Vecchia C, Helmrich SP, et al. Risk factors for epithelial ovarian cancer in Italy. Am J Epidemiol 1982;115:714-19.
  120. La Vecchia C, Decarli A, Franceschi S, et al. Age at first birth and the risk of epithelial ovarian cancer. J Natl Cancer Inst 1984;73:663-6.
  121. Nasca PC, Greenwald P, Chorost S, et al. An epidemiologic case-control study of ovarian cancer and reproductive factors. Am J Epidemiol 1984;119:705-13.
  122. Risch HA, Weiss NS, Lyon JL, et al. Events of reproductive life and the incidence of epithelial ovarian cancer. Am J Epidemiol 1983;117:128-39.
  123. Voight LF, Harlow BL, Weiss NS. The influence of age at first birth and parity on ovarian cancer risk. Am J Epidemiol 1986;124:490-1.
  124. Wydner EL, Dodo H, Barber HR. Epidemiology of cancer of the ovary. Cancer 1969;23:352-70.
  125. Mori M, Harabuchi I, Miyake H, et al. Reproductive, genetic, and dietary risk factors for ovarian cancer. Am J Epidemiol 1988;128:771-7.
  126. Gwinn ML, Lee NC, Rhodes PH, et al. Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol 1990;43:559-68.
  127. Stanford JL. Oral contraceptives and neoplasia of the ovary. Contraception 1991;43:543-56.
  128. Weiss NS, Homonchuk TA, Young JL Jr. Incidence of the histologic types of ovarian cancer: the U.S. Third National Cancer Survey, 1969-1971. Gynecol Oncol 1977;5:161-7.
  129. Weiss NS, Lyon JL, Liff JM, et al. Incidence of ovarian cancer in relation to the use of oral contraceptives. Int J Cancer 1981;28:669-71.
  130. Vessey M, Metcalfe A, Wells C, et al. Ovarian neoplasms, functional ovarian cysts, and oral contraceptives. Br Med J (Clin Res Ed) 1987;294:1518-20.
  131. La Vecchia C, Decarli A, Fasoli M. Oral contraceptives and cancers of the breast and female genital tract: interim results from a case-control study. Br J Cancer 1986;54:311-17.
  132. Harlow BL, Weiss NS, Roth GJ, et al. Case-control study of borderline ovarian tumors: reproductive history and exposure to exogenous female hormones. Cancer Res 1988;48:5849-52.
  133. Hartge P, Schiffman MH, Hoover R, et al. A case-control study of epithelial ovarian cancer. Am J Obstet Gynecol 1989;161:10-16.
  134. Cramer DW, Hutchison GB, Welch WR, et al. Factors affecting the association of oral contraceptives and ovarian cancer. N Engl J Med 1982;307:1047-51.
  135. Beral V, Hannaford P, Kay C. Oral contraceptive use and malignancies of the genital tract. Lancet 1988;2:1331-4.
  136. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral-contraceptive use. N Engl J Med 1987;316:650-5.
  137. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Epithelial ovarian cancer and combined oral contraceptives. Int J Epidemiol 1987;18:538-45.
  138. Shu WO, Brinton LA, Gao YT, et al. Population-based case-control study in Shanghai. Cancer Res 1989;49:3670-4.
  139. Willet WC, Bain C, Hennekens CH, et al. Oral contraceptives and the risk of ovarian cancer. Cancer 1981;48:1684-7.
  140. Whittemore AS, Harris R, Intyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:1184-203.
  141. Rosenblatt KA, Thomas DB. Lactation and the risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Epidemiol 1993;22:192-7.
  142. Rosenblatt KA, Thomas DB. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. Cancer Epidemiol Biomarkers Prev 1996;5:933-5.
  143. Cottreau CM, Ness RB, Kriska AM. Physical activity and reduced risk of ovarian cancer. Obstet Gynecol 2000;96:609-14.
  144. Whiteman DC, Murphy MF, Cook LS, et al. Multiple births and risk of epithelial ovarian cancer. J Natl Cancer Inst 2000;92:1172-7.
  145. Cramer DW, Harlow BL, Titus-Ernstoff L, et al. Over-the-counter analgesics and risk of ovarian cancer. Lancet 1998;351:104-7.
  146. Tavani A, Gallus S, La Vecchia C, et al. Aspirin and ovarian cancer: an Italian case-control study. Ann Oncol 2000;11:1171-3.
  147. Moysich KB, Mettlin C, Piver MS, et al. Regular use of analgesic drugs and ovarian cancer risk. Cancer Epidemiol Biomarkers Prev 2001;10:903-6.
  148. Akhmedkhanov A, Toniolo P, Zeleniuch-Jacquotte A, et al. Aspirin and epithelial ovarian cancer. Prev Med 2001;33:682-7.
  149. Bertone ER, Willett WC, Rosner BA, et al. Prospective study of recreational physical activity and ovarian cancer. J Natl Cancer Inst 2001;93:942-8.
  150. Bertone ER, Newcomb PA, Willett WC, et al. Recreational physical activity and ovarian cancer in a population-based case-control study. Int J Cancer 2002;99:431-6.
  151. Fairfield KM, Hunter DJ, Fuchs CS, et al. Aspirin, other NSAIDs, and ovarian cancer risk (United States). Cancer Causes Control 2002;13:535-42.
  152. Meier CR, Schmitz S, Jick H. Association between acetaminophen or non-steroidal anti-inflammatory drugs and risk of developing ovarian, breast, or colon cancer. Pharmacotherapy 2002;22:303-9.
  153. Mink PJ, Folsom AR, Sellars TA, et al. Physical activity, waist-to-hip ratio, and other risk factors for ovarian cancer: a follow-up study of older women. Epidemiology 1996;7:38-45.
  154. Rosenberg L, Palmer JR, Rao RS, et al. A case-control study of analgesic use and ovarian cancer. Cancer Epidemiol Biomarkers Prev 2000;9:933-7.
  155. Gabra H, Smyth JF. Ovarian cancer-an introduction. In: Langdon S, Miller W, Berchuck A, eds. Biology of female cancers. New York, NY: CRC Press, 1997.
  156. Cook LS, Kamb ML, Weiss NS. Perineal powder exposure and the risk of ovarian cancer. Am J Epidemiol 1997;145:459-65.
  157. Brinton LA, Melton LJ III, Malkasian GD Jr, et al. Cancer risk after evaluation for infertility. Am J Epidemiol 1989;129:712-22.
  158. Shu XO, Brinton LA, Gao YT, et al. Population-based case-control study of ovarian cancer in Shanghai. Cancer Res 1989;49:3670-4.
  159. Weiss NS, Lyon JL, Krishnamurthy S, et al. Non-contraceptive estrogen use and the occurrence of ovarian cancer. J Natl Cancer Inst 1982;68:95-8.
  160. Marchbanks PA, Wilson H, Bastos E, et al. Cigarette smoking and epithelial ovarian cancer by histologic type. Obstet Gynecol 2000;95:255-60.
  161. Modugno F, Ness RB, Cottreau CM. Cigarette smoking and the risk of mucinous and non-mucinous epithelial ovarian cancer. Epidemiology 2002;13:467-71.
  162. Purdie DM, Webb PM, Siskind V, et al. The different etiologies of mucinous and nonmucinous epithelial ovarian cancers. Gynecol Oncol 2003;88(suppl):S145-8.
  163. Risch HA, Marrett LD, Jain M, et al. Differences in risk factors for epithelial ovarian cancer by histologic type: results of a case-control study. Am J Epidemiol 1996;144:363-72.
  164. Stratton JF, Gayther SA, Russell P, et al. Contributions of BRCA1 mutations to ovarian cancer. N Engl J Med 1997;336:1125-30.
  165. Takahashi H, Behbakht K, McGovern PE, et al. Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res 1995;55:2998-3002.
  166. Mutsushima M, Kobayashi K, Emi M, et al. Mutational analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation. Hum Mol Genet 1995;4:1953-6.
  167. Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA -linked and sporadic ovarian cancer. JAMA 2000;283:2260-5.
  168. Rubin SC, Benjamin I, Behbakht K, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1 . N Engl J Med 1996;335:1413-16.
  169. Ben DY, Chetrit A, Hirsh-Yechezkel G, et al. Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 1915;20:463-6.
  170. Struewing JP, Abeliovich D, Peretz T, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 1995;11:198-200.
  171. Roa BB, Boyd AA, Volcik K, et al. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2 . Nat Genet 1996;14:185-7.
  172. Oddoux C, Struewing JP, Clayton CM, et al. The carrier frequency of BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 1996;14:188-90.
  173. Levy-Lahad E, Catane R, Eisenberg S, et al. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet 1997;60:1059-67.
  174. Moslehi R, Chu W, Karlan B, et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 2000;66:1259-72.
  175. Lu KH, Cramer DW, Muto MG, et al. A population-based study of BRCA1 and BRCA2 mutations in Jewish women with epithelial ovarian cancer. Obstet Gynecol 1999;93:34-7.
  176. Abeliovich D, Kaduri L, Lerer I, et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 1997;60:505-14.
  177. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001;68:700-10.
  178. Van Der Looij M, Szabo C, Besznyak I, et al. Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary. Int J Cancer 2000;86:737-40.
  179. Thompson D, Easton D. Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 2002;11:329-36.
  180. Gayther SA, Mangion J, Russell P, et al. Variations of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 1997;15:103-5.
  181. Gayther SA, Warren W, Mazoyer S, et al. Germline mutation of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 1995;11:428-33.
  182. Modan B, Hartge P, Hirsh-Yechezkel G, et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and non-carriers of a BRCA1 or BRCA2 mutation. N Engl J Med 1926;345:235-40.
  183. Modugno F, Moslehi R, Ness RB, et al. Reproductive factors and ovarian cancer risk in Jewish BRCA1 and BRCA2 mutation carriers. Cancer Causes Control 2003;14:439-46.
  184. Narod SA, Risch HA, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424-8.
  185. Spurdle AB, Webb PM, Purdie DM, et al. No significant association between progesterone receptor exon 4 Val660Leu G/T polymorphism and risk of ovarian cancer. Carcinogenesis 2001;22:717-21.
  186. Runnebaum IB, Wang-Gohrke S, Vesprini D, et al. Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives. Pharmacogenetics 2001;11:635-8.
  187. Tong D, Fabjani G, Heinze G, et al. Analysis of the human progesterone receptor gene polymorphism progins in Austrian ovarian carcinoma patients. Int J Cancer 2001;95:394-7.
  188. Rebbeck TR, Kantoff PW, Krithivas K, et al. Modification of BRCA1 -associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet 1999;64:1371-7.
  189. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994;22:3181-6.
  190. Park JJ, Irvine RA, Buchanan G, et al. Breast cancer susceptibility gene 1 ( BRCA1 ) is a coactivator of the androgen receptor. Cancer Res 2000;60:5946-9.
  191. Yeh S, Hu YC, Rahman M, et al. Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells. Proc Natl Acad Sci U S A 2000;97:11256-61.
  192. Manolitsas TP, Englefield P, Eccles DM, et al. No association of a 306-bp insertion polymorphism in the progesterone receptor gene with ovarian and breast cancer. Br J Cancer 1997;75:1397-9.
  193. Fujimoto J, Ichigo S, Hirose R, et al. Clinical implication of expression of progesterone receptor form A and B mRNAs in secondary spreading of gynecologic cancers. J Steroid Biochem Mol Biol 1997;62:449-54.
  194. Spurdle AB, Chen X, Abbazadegan M, et al. CYP17 promoter polymorphism and ovarian cancer risk. Int J Cancer 2000;86:436-9.
  195. Spurdle AB, Hopper JL, Chen X, et al. The steroid 5 alpha-reductase type II TA repeat polymorphism is not associated with risk of breast or ovarian cancer in Australian women. Cancer Epidemiol Biomarkers Prev 2001;10:1287-93.
  196. Goodman MT, McDuffie K, Guo C, et al. CYP17 genotype and ovarian cancer: a null case-control study. Cancer Epidemiol Biomarkers Prev 2001;10:563-4.
  197. Garner EI, Stokes EE, Berkowitz RS, et al. Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol- O -methyltransferase and risk of epithelial ovarian cancer. Cancer Res 2002;62:3058-62.
  198. Yeh S, Miyamoto H, Shima H, et al. From estrogen to androgen receptor: a new pathway for sex hormones in prostate. Proc Natl Acad Sci U S A 1998;95:5527-32.
  199. Katzenellenbogen BS. Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways. J Soc Gynecol Investig 2000;7(suppl):S33-7.
  200. Modugno F, Weissfeld J, Trump DL, et al. Allelic variants of aromatase and the androgen and estrogen receptors: toward a multigenic model of prostate cancer risk. Clin Cancer Res 2001;7:3092-6.
  201. Poretsky L, Cataldo N, Rosenks Z, et al. The insulin-related ovarian regulatory system in health and disease. Endocr Rev 1999;20:535-82.
  202. Mason HD, Willis D, Holly JM, et al. Inhibitory effects of insulin-like growth factor-binding proteins on steroidogenesis by human granulosa cells in culture. Mol Cell Endocrinol 1992;89:R1-4.
  203. Erickson GF, Garzo VG, Magoffin DA. Progesterone production by human granulosa cells cultured in serum medium: effects of gonadotrophins and insulin-like growth factor I (IGF-I). Hum Reprod 1991;6:1074-81.
  204. Bergh C, Olsson JH, Hillensjo T. Effect of insulin-like growth factor I on steroidogenesis in cultured human granulosa cells. Acta Endocrinol 1991;125:177-85.
  205. Rosen CJ, Kurland ES, Vereault D, et al. Association between serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density. J Clin Endocrinol Metab 1998;83:2286-90.
  206. Deal C, Ma J, Wilkin F, et al. Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J Clin Endocrinol Metab 2001;86:1274-80.
  207. Eriksson CJ, Fukunaga T, Lindman R. Sex hormone response to alcohol. (Letter). Nature 1994;369:711.
  208. Moore JH, Williams SM. New strategies for identifying gene-gene interactions in hypertension. Ann Med 2002;34:88-95

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