Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Menopause. Author manuscript; available in PMC 2010 August 24.
Published in final edited form as:
PMCID: PMC2927106

ALOX12 gene is associated with the onset of natural menopause in white women



Natural menopause is a key physiological event in a woman’s life. Timing of menopause affects risk for many postmenopausal systemic disorders and may thus influence life expectancy. Age at natural menopause (ANM) is largely determined genetically, but a list of candidate genes is far from complete. This study investigated the ALOX12 gene for its possible association with ANM.


Six single-nucleotide polymorphisms (SNPs) of the gene (rs9904779, rs2073438, rs11571340, rs434473, rs2307214, and rs312462) were genotyped in a random sample of 210 unrelated white women. The SNPs and common haplotypes were then analyzed for their association with ANM. Smoking, alcohol consumption, and duration of breast-feeding were used as covariates.


Two SNPs, rs9904779 and rs434473 (encodes a replacement of asparagine by serine in the protein), were significantly associated with ANM (P = 0.022 and 0.033, respectively). The minor alleles of both SNPs seem to promote about 1.3- to 1.5-year earlier menopause and confer a 1.6 to 1.8 times higher risk for early menopause. All SNPs indicated significant or nearly significant interactions with alcohol use and duration of breast-feeding. Five common haplotypes were also associated with ANM.


The ALOX12 gene seems to be associated with the timing of natural menopause in white women.

Keywords: Age at natural menopause, Association, ALOX12, Polymorphisms, Haplotypes

Natural menopause is one of the most important physiological events: it is related to the cessation of ovarian function and the end of the reproductive cence. Average age at natural menopause (ANM) in white women is about 50 years.1,2 Entering the menopausal transition is often associated with various psychological problems,3,4 which are especially pronounced under premature menopause.5 Early onset of natural menopause increases risk for many postmenopausal health complications, such as osteoporosis,68 ischemic disease,9 and ovarian cancer,10,11 whereas later menopause is a risk factor for endometrial12,13 and breast14 cancer. In such a way, timing of menopause may affect life expectancy.15 Therefore, knowing the factors that underlie ANM may potentially help to forecast onset of menopause, contribute to the prophylaxis of postmenopausal health problems, and thus increase overall longevity.

According to various estimates, genetic factors may account for up to 63% to 74% of ANM variation.16,17 Recent studies identified several genes and genomic regions that may contribute to ANM,1821 but they constitute only a small portion of quantitative tract loci underlying ANM.

Arachidonate 12-lipoxygenase (ALOX12; EC is an important enzyme of lipid metabolism. It catalyzes the transformation of arachidonic acid into 12(S)-hydroperoxyeicosatetraenoic acid by oxygenating its 12-position. Several considerations are in favor of the ALOX12 gene being a possible contributor to the onset of menopause. First, several studies provided evidence that menopause may increase risk for obesity and affect body fat distribution.2225 This suggests that genes involved in fat metabolism (including ALOX12) may be associated with menopause. Second, the reaction catalyzed by ALOX12 is a step in the biosynthesis of leukotriene, a hormone playing an important role in inflammation and immunity.26 ALOX12 and its metabolites stimulate cell proliferation and were therefore implicated in the etiology of various tumors,2729 including breast cancer.3033 Because breast cancer and some other cancers are associated with ANM,1214 it is suggested that ALOX12 may also contribute to ANM. Third, in addition to its role in cancers, the gene was reported as a candidate for other primarily postmenopausal disorders, osteoporosis34,35 and Alzheimer’s disease.36 Finally, more evidence for a possible association of ALOX12 with menopause comes from the data about its expression in female reproductive organs and tissues, uterus,37 and thecal and granulosa layers of preovulatory follicles.38

Here, we present the results of the analysis of six ALOX12 single-nucleotide polymorphisms (SNPs) for their possible association with ANM in white women.



The female participants in this study were recruited as part of our large-scale project on the genetic basis of osteoporosis. This study was approved by the institutional review board of Creighton University, and each participant signed an informed consent document before entering the study. The sample was composed of 210 randomly selected white women. All participants identified themselves as being of European origin. The exclusion criteria that were used for the participant recruitment have been described previously.39 Based on these exclusion criteria, women with systemic metabolic diseases (eg, diabetes, hypoparathyroidism and hyper-parathyroidism, hyperthyroidism), chronic diseases of vital organs (brain, lung, heart, liver, kidney), malnutrition conditions (eg, chronic diarrhea, chronic ulcerative colitis), and surgical menopause (hysterectomy or oophorectomy) in their medical history were not included in the study. The participants also provided data about their age at menarche and menopause, smoking and alcohol consumption status, parity, breast-feeding status, and oral contraceptive use before menopause by answering a questionnaire.

ANM was determined as the age at the last menses (years) followed by one calendar year with no menses. To eliminate the probability of including women with premature ovarian failure, only data collected from women who experienced ANM after 40 years of age were analyzed. Early menopause was defined as ANM lower than the mean for the studied population. Data on the participants are given in Table 1.

Characteristics of the participants in this study


Genomic DNA was isolated from peripheral blood using a Puregene kit (Gentra Systems, Inc, Minneapolis, MN) according to the manufacturer’s protocol. The SNPs were selected using dbSNP ( The following criteria were adopted for the SNP selection: (1) position in or around the gene, (2) minor allele frequencies greater than 0.05, (3) validation status in white women, and (4) being reported to dbSNP by various sources. The polymorphisms were genotyped using the Integrated Bead-Array System (Illumina, Inc).

Statistical analyses

All genotypes were tested for their correspondence to the Hardy-Weinberg equilibrium using PLINK software,40 which is available online at PedCheck41 was used to verify whether genotype data are consistent with the Mendelian segregation.

Because of the very low frequencies of their minor allele homozygotes, the genotypes of three SNPs (rs11571340, rs2307214, and rs312462) were divided into two groups (with or without the minor allele, respectively) to increase the power of the analyses. The participants were also categorized according to the number of pregnancies and months of breast-feeding (Table 1).

Multiple linear and univariate regression analyses were applied to estimate the effects of the lifestyle factors and the studied SNPs on ANM. Each marker was investigated independently in the univariate analysis. This analysis was applied also to estimate pairwise SNP-SNP and SNP-environment interactions on ANM. To exhaustively exploit haplotype information, we subjected alleles (contiguous sets of markers) from sliding windows of all sizes to haplotype association tests. The haplotype-specific analysis that tests each haplotype at one time (each vs all others) was performed with the χ2 test, with 1 degree of freedom. All statistical analyses were conducted using PLINK40 and SPSS, version 16.0.1 (SPSS Inc, Chicago, IL).


Study participants’ characteristics

The study participants were, on average, 63.7 ± 0.7 years old. Their mean ± SE age at menarche was 13.0 ± 0.1 years, and the mean ± SE ANM was 49.4 ± 0.3 years (Table 1). The skewness and kurtosis of the ANM values were −0.081 and 0.789, respectively, that is, slightly deviated from the normal distribution parameters. According to the multiple regression analysis, cigarette smoking (P = 0.037), alcohol consumption (P = 0.021), and duration of breast-feeding (P = 0.014) were determined to influence ANM significantly in this sample and were thus used as covariates in the analyses.

SNP association analyses

All studied polymorphisms were in concordance with Hardy-Weinberg equilibrium (Table 2). Two SNPs, rs9904779 (SNP1) and rs434473 (SNP4), were significantly associated with ANM (P = 0.022 and 0.033, respectively; Table 3). The minor alleles of these SNPs seem to confer a higher risk for early menopause. Women who carry a minor allele C of SNP1 have, on average, 1.3 years earlier menopause (48.9 ± 0.5 y) than do the major allele homozygotes (50.2 ± 0.5 y) and 1.6 times higher relative odds for entering menopause before the mean ANM for the studied population, that is, 49.4 years (95% CI, 0.914–2.770). Likewise, carriers of the SNP4 minor allele (G) experience menopause about 1.5 years earlier (48.8 ± 0.5 y) than do homozygotes for the major allele (50.3 ± 0.5 y) and have 1.8 times higher relative odds for earlier menopause than the average ANM (95% CI, 1.032–3.213).

Summary information about the studied SNPs in the total sample
Results of the association analyses for the SNPs of the ALOX12 gene with age at natural menopause (mean ± SE) in white women

In addition to the individual SNPs, five haplotypes were associated with ANM (Table 4). Four of them include either allele of SNP4. Importantly, haplotypes B and D, carrying a major allele A of SNP4, seem to confer later ANM (variable β; Table 4), whereas haplotypes C and E, carrying a minor allele G of this SNP, confer earlier ANM. Haplotype A, although including a minor allele of SNP1 (which supposedly confers lower ANM), is nevertheless associated with later ANM. This is due to the combined effects of alleles at SNP1 and SNP2.

Haplotypes of the ALOX12 gene showing significant or nearly significant association with ANM

All studied SNPs showed a significant or nearly significant interaction effect with alcohol consumption and duration of breast-feeding on ANM (Table 5). In addition, SNP1 and SNP4 indicated significant interaction with parity (P = 0.05 and 0.02, respectively). On the other hand, no significant interactions between the polymorphisms were detected.

Results of the univariate analysis (P values) for interaction effect between the SNPs of the ALOX12 gene and lifestyle factors on ANM


Despite the apparent importance of timing of menopause for health in the later part of a woman’s life and, respectively, for longevity,42 only a few studies have been done to determine the genetic basis of this physiological event. The present study adds ALOX12 to the list of candidate genes for ANM.1820,4345

The exact role of ALOX12 in the onset of menopause is not clear. Flatman et al37 were among the first who reported a lower activity of ALOX12 in the uterine cervix of postmenopausal women as compared with premenopausal women. This suggests that ALOX12 expression level is related to the menopause status of a woman, and thus, the respective gene may be associated with menopause. Some more assumptions may be drawn from the available data about the relationship between menopause and arachidonic acid status. Several studies reported an effect of natural menopause on the content of arachidonic acid in female tissues, although the data were controversial. Specifically, postmenopausal women were reported to have either a decreased46 or an increased47,48 level of arachidonic acid as compared with premenopausal women. On the other hand, surgical menopause (ovariectomy) did not affect the fatty acid composition of platelets but significantly increased the serum concentration of thromboxane B2, a metabolite of arachidonic acid.49

In a quite recent study of induced ovulation using a murine model, Kurusu et al38 provided evidence that inhibition of ALOX12 resulted in impaired ovulation. This suggests that ALOX12 is likely to have an important role in ovary function and, respectively, a potential contribution to the cessation of this function, that is, menopause.

One of the most pronounced effects of menopause is estrogen depletion, which is considered a key cause of post-menopausal adverse health consequences.5052 Because catechol estrogens have a strong inhibitory effect on arachidonic acid metabolism, their lower concentration after menopause may promote increased synthesis of leukotriene and higher risk for associated disorders.53 However, this assumption still needs to be examined further: the other studies either support54 or reject55 it.

Interestingly, all genetic variants (SNPs and haplotypes) identified here as those promoting earlier menopause have a lower population frequency as compared with the variants associated with later ANM. If earlier menopause indeed increases mortality,42 then this may be a reason for the lower population frequency of the slightly deleterious genetic variants, which confer early menopause.

Importantly, the above studies, are essentially in favor of this effect per se although the exact mode of the ALOX12 effect on menopause is controversial. The body of evidence suggests that ALOX12 probably affects ANM by regulating the level of arachidonic acid and respective metabolites. With reference to this, two SNPs that are significantly associated with ANM may be functionally important. SNP1 (rs9904779) is located in the 5′-flanking region of the gene, 822 bp upstream the first codon, and may be within a regulatory area. SNP4 (rs434473) is a missense mutation resulting in the substitution of asparagine by serine at position 322 of the ALOX12 protein. Although asparagine and serine are similar in their physiochemical properties, the substitution may nonetheless affect the protein activity. For example, replacement of arginine by similar glutamine at position 261 results in a significant increase in ALOX12 enzyme activity in platelets and a higher risk for esophageal squamous cell carcinoma.56

The difference in menopause onset of only 1.3 to 1.5 years between the genotypes (Table 3) may look clinically irrelevant. However, it should be noted that ANM is a complex trait determined by many genes and environmental factors. As such, the contribution of any single candidate gene is expected to be modest. However, a cumulative effect of several such genes, including possible gene-gene interactions, may be quite noticeable.

There are data suggesting a potential role of ALOX12 in aging processes. Specifically, the higher expression of the gene was associated with the diagnosed Alzheimer disease36,57 and cardiovascular problems.5860 As the proportion of older people in the human population steadily increases, proper managing of healthy aging becomes more and more important. In these terms, identifying lifestyle and genetic factors that contribute to ANM helps to accomplish this task and improve overall quality of life.

The present study has several limitations that should be acknowledged. The observed significant interactions should be treated with certain caution because the sample size is small and, respectively, statistical power to detect interactions is limited. However, because several SNPs and lifestyle factors were analyzed, this might bring about a problem of multiple testing. We did not adjust for multiple testing for several reasons. First, this is a candidate gene study with previous knowledge, and the number of analyzed SNPs was small. Second, all six SNPs in our study were in strong linkage disequilibrium (data not shown), and therefore, the tests were highly correlated. Therefore, although a risk for false-positives still exists, it seems to be low. In addition, because simple correction for multiple testing is conservative, it may result in a further decrease in power to detect real effects.


As an important component of the key biochemical process (metabolism of arachidonic acid and, more generally, lipids), ALOX12 may potentially contribute to various post-menopausal metabolic disorders, which is indeed evidenced by many studies3436,5760. However, the exact role of the gene in these health complications is largely unknown. It may be associated with the ALOX12 contribution to the onset of menopause. Despite the previously mentioned limitations, our study, along with the other independent observations mentioned here, provides support for this statement. However, further studies on larger samples and various ethnicities are needed to corroborate or reject this assumption.


Funding/support: Financial support for this study was provided by the National Institutes of Health (grants R01 AR050496, K01 AR02170-01, R01 AR45349-01, and R01 GM60402-01A1), the State of Nebraska (grant LB595) the National Science Foundation of China, Huo Ying Dong Education Foundation, HuNan Province, Xi’an Jiaotong University, and the Ministry of Education of China.


Financial disclosure/conflicts of interest: None reported.


1. Meschia M, Pansini F, Modena AB, et al. Determinants of age at menopause in Italy: results from a large cross-sectional study. ICARUS Study Group. Italian Climacteric Research Group Study. Maturitas. 2000;34:119–125. [PubMed]
2. Nichols HB, Trentham-Dietz A, Hampton JM, et al. From menarche to menopause: trends among US women born from 1912 to 1969. Am J Epidemiol. 2006;164:1003–1011. [PubMed]
3. Towey M, Bundy C, Cordingley L. Psychological and social interventions in the menopause. Curr Opin Obstet Gynecol. 2006;18:413–417. [PubMed]
4. Deeks AA. Psychological aspects of menopause management. Best Pract Res Clin Endocrinol Metab. 2003;17:17–31. [PubMed]
5. Liao KL, Wood N, Conway GS. Premature menopause and psychological well-being. J Psychosom Obstet Gynaecol. 2000;21:167–174. [PubMed]
6. Gallagher JC. Effect of early menopause on bone mineral density and fractures. Menopause. 2007;14:567–571. [PubMed]
7. Francucci CM, Romagni P, Camilletti A, et al. Effect of natural early menopause on bone mineral density. Maturitas. 2008;59:323–328. [PubMed]
8. Kritz-Silverstein D, Barrett-Connor E. Early menopause, number of reproductive years, and bone mineral density in postmenopausal women. Am J Public Health. 1993;83:983–988. [PubMed]
9. Jacobsen BK, Knutsen SF, Fraser GE. Age at natural menopause and total mortality and mortality from ischemic heart disease: the Adventist Health Study. J Clin Epidemiol. 1999;52:303–307. [PubMed]
10. Cramer DW. Epidemiologic aspects of early menopause and ovarian cancer. Ann N Y Acad Sci. 1990;592:363–375. [PubMed]
11. Schildkraut JM, Cooper GS, Halabi S, Calingaert B, Hartge P, Whittemore AS. Age at natural menopause and the risk of epithelial ovarian cancer. Obstet Gynecol. 2001;98:85–90. [PubMed]
12. Wernli KJ, Ray RM, Gao DL, De Roos AJ, Checkoway H, Thomas DB. Menstrual and reproductive factors in relation to risk of endometrial cancer in Chinese women. Cancer Causes Control. 2006;17:949–955. [PubMed]
13. Purdie DM, Green AC. Epidemiology of endometrial cancer. Best Pract Res Clin Obstet Gynaecol. 2001;15:341–354. [PubMed]
14. Velie EM, Nechuta S, Osuch JR. Lifetime reproductive and anthropometric risk factors for breast cancer in postmenopausal women. Breast Dis. 2005;24:17–35. [PubMed]
15. Ossewaarde ME, Bots ML, Verbeek AL, et al. Age at menopause, cause-specific mortality and total life expectancy. Epidemiology. 2005;16:556–562. [PubMed]
16. Snieder H, MacGregor AJ, Spector TD. Genes control the cessation of a woman’s reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab. 1998;83:1875–1880. [PubMed]
17. Murabito JM, Yang Q, Fox C, Wilson PW, Cupples LA. Heritability of age at natural menopause in the Framingham Heart Study. Obstet Gynecol Surv. 2005;60:656–657.
18. He LN, Recker RR, Deng HW, Dvornyk V. A polymorphism of apolipoprotein E (APOE) gene is associated with age at natural menopause in Caucasian females. Maturitas. 2009;62:37–41. [PMC free article] [PubMed]
19. Hefler LA, Grimm C, Heinze G, et al. Estrogen-metabolizing gene polymorphisms and age at natural menopause in Caucasian women. Hum Reprod. 2005;20:1422–1427. [PubMed]
20. Long JR, Shu XO, Cai Q, et al. Polymorphisms of the CYP1B1 gene may be associated with the onset of natural menopause in Chinese women. Maturitas. 2006;55:238–246. [PubMed]
21. Murabito JM, Yang Q, Fox CS, Cupples LA. Genome-wide linkage analysis to age at natural menopause in a community-based sample: the Framingham Heart Study. Fertil Steril. 2005;84:1674–1679. [PubMed]
22. Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes. 2008;32:949–958. [PMC free article] [PubMed]
23. Pasquali R, Casimirri F, Labate AM, et al. Body weight, fat distribution and the menopausal status in women. The VMH Collaborative Group. Int J Obes Relat Metab Disord. 1994;18:614–621. [PubMed]
24. Toth MJ, Tchernof A, Sites CK, Poehlman ET. Menopause-related changes in body fat distribution. Ann N Y Acad Sci. 2000;904:502–506. [PubMed]
25. Ijuin H, Douchi T, Oki T, Maruta K, Nagata Y. The contribution of menopause to changes in body-fat distribution. J Obstet Gynaecol Res. 1999;25:367–372. [PubMed]
26. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237:1171–1176. [PubMed]
27. Uchide K, Sakon M, Ariyoshi H, Nakamori S, Tokunaga M, Monden M. Cancer cells cause vascular endothelial cell (vEC) retraction via 12(S)HETE secretion; the possible role of cancer cell derived microparticle. Ann Surg Oncol. 2007;14:862–868. [PubMed]
28. Bednar W, Holzmann K, Marian B. Assessing 12(S)-lipoxygenase inhibitory activity using colorectal cancer cells overexpressing the enzyme. Food Chem Toxicol. 2007;45:508–514. [PubMed]
29. Timar J, Raso E, Dome B, et al. Expression, subcellular localization and putative function of platelet-type 12-lipoxygenase in human prostate cancer cell lines of different metastatic potential. Int J Cancer. 2000;87:37–43. [PubMed]
30. Kristensen VN, Edvardsen H, Tsalenko A, et al. Genetic variation in putative regulatory loci controlling gene expression in breast cancer. Proc Natl Acad Sci U S A. 2006;103:7735–7740. [PubMed]
31. Mohammad AM, Abdel HA, Abdel W, Ahmed AM, Wael T, Eiman G. Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. Indian J Cancer. 2006;43:163–168. [PubMed]
32. Natarajan R, Esworthy R, Bai W, Gu JL, Wilczynski S, Nadler J. Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor. J Clin Endocrinol Metab. 1997;82:1790–1798. [PubMed]
33. Jiang WG, Douglas-Jones A, Mansel RE. Levels of expression of lipoxygenases and cyclooxygenase-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids. 2003;69:275–281. [PubMed]
34. Mullin BH, Spector TD, Curtis CC, et al. Polymorphisms in ALOX12, but not ALOX15, are significantly associated with BMD in postmenopausal women. Calcif Tissue Int. 2007;81:10–17. [PubMed]
35. Ichikawa S, Koller DL, Johnson ML, et al. Human ALOX12, but not ALOX15, is associated with BMD in white men and women. J Bone Miner Res. 2006;21:556–564. [PubMed]
36. Pratico D, Zhukareva V, Yao Y, et al. 12/15-Lipoxygenase is increased in Alzheimer’s disease: possible involvement in brain oxidative stress. Am J Pathol. 2004;164:1655–1662. [PubMed]
37. Flatman S, Morgan A, Donald-Gibson RG, Davey A, Jonas GE, Slater TF. 12-Lipoxygenase activity in human uterine cervix. Prostaglandins Leukot Essent Fatty Acids. 1988;32:87–94. [PubMed]
38. Kurusu S, Jinno M, Ehara H, Yonezawa T, Kawaminami M. Inhibition of ovulation by a lipoxygenase inhibitor involves reduced cyclooxygenase-2 expression and prostaglandin E2 production in gonadotropin-primed immature rats. Reproduction. 2009;137:59–66. [PubMed]
39. Deng HW, Xu FH, Liu YZ, et al. A whole-genome linkage scan suggests several genomic regions potentially containing QTLs underlying the variation of stature. Am J Med Genet. 2002;113:29–39. [PubMed]
40. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575. [PubMed]
41. O’Connell JR, Weeks DE. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet. 1998;63:259–266. [PubMed]
42. Jansen SC, Temme EH, Schouten EG. Lifetime estrogen exposure versus age at menopause as mortality predictor. Maturitas. 2002;43:105–112. [PubMed]
43. He LN, Xiong DH, Liu YJ, Zhang F, Recker RR, Deng HW. Association study of the oestrogen signalling pathway genes in relation to age at natural menopause. J Genet. 2007;86:269–276. [PubMed]
44. Zhang F, Xiong DH, Wang W, et al. HDC gene polymorphisms are associated with age at natural menopause in Caucasian women. Biochem Biophys Res Commun. 2006;348:1378–1382. [PMC free article] [PubMed]
45. Kevenaar ME, Themmen AP, Rivadeneira F, et al. A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Hum Reprod. 2007;22:2382–2388. [PubMed]
46. Maynar M, Mahedero G, Maynar I, Maynar JI, Tuya IR, Caballero MJ. Menopause-induced changes in lipid fractions and total fatty acids in plasma. Endocr Res. 2001;27:357–365. [PubMed]
47. Abbadia Z, Vericel E, Mathevet P, Bertin N, Panaye G, Frappart L. Fatty acid composition and CD36 expression in breast adipose tissue of premenopausal and postmenopausal women. Anticancer Res. 1997;17:1217–1221. [PubMed]
48. Rhee Y, Paik MJ, Kim KR, et al. Plasma free fatty acid level patterns according to cardiovascular risk status in postmenopausal women. Clin Chim Acta. 2008;392:11–16. [PubMed]
49. Punnonen R, Seppala E, Punnonen K. Effect of ovariectomy in humans on serum 6-keto-PGF1 a and TXB2 concentrations and platelet fatty acids. Prostaglandins Leukot Med. 1987;26:85–89. [PubMed]
50. Overlie I, Moen MH, Morkrid L, Skjaeraasen JS, Holte A. The endocrine transition around menopause—a five years prospective study with profiles of gonadotropines, estrogens, androgens and SHBG among healthy women. Acta Obstet Gynecol Scand. 1999;78:642–647. [PubMed]
51. Riggs BL, Khosla S, Melton LJ., III A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 1998;13:763–773. [PubMed]
52. Gandy S, Duff K. Post-menopausal estrogen deprivation and Alzheimer’s disease. Exp Gerontol. 2000;35:503–511. [PubMed]
53. Alanko J, Sievi E, Lahteenmaki T, Mucha I, Vapaatalo H, Parantainen J. Catechol estrogens as inhibitors of leukotriene synthesis. Biochem Pharmacol. 1998;55:101–104. [PubMed]
54. Ranganath LR, Christofides JA, Wright JW, Marks V. Effects of hormone replacement therapy on platelet membrane fatty acid composition. J Endocrinol. 1996;148:207–212. [PubMed]
55. Lewis-Barned NJ, Sutherland WH, Walker RJ, et al. Plasma cholesteryl ester fatty acid composition, insulin sensitivity, the menopause and hormone replacement therapy. J Endocrinol. 2000;165:649–655. [PubMed]
56. Guo Y, Zhang X, Tan W, et al. Platelet 12-lipoxygenase Arg261Gln polymorphism: functional characterization and association with risk of esophageal squamous cell carcinoma in combination with COX-2 polymorphisms. Pharmacogenet Genomics. 2007;17:197–205. [PubMed]
57. Lebeau A, Terro F, Rostene W, Pelaprat D. Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide. Cell Death Differ. 2004;11:875–884. [PubMed]
58. Poch E. Role of lipoxygenase metabolites in cardiovascular disease. Curr Hypertens Rep. 2003;5:1–2. [PubMed]
59. Nozawa K, Tuck ML, Golub M, Eggena P, Nadler JL, Stern N. Inhibition of lipoxygenase pathway reduces blood pressure in renovascular hypertensive rats. Am J Physiol. 1990;259:H1774–H1780. [PubMed]
60. Gonzalez-Nunez D, Claria J, Rivera F, Poch E. Increased levels of 12(S)-HETE in patients with essential hypertension. Hypertension. 2001;37:334–338. [PubMed]