Lifetime endogenous estrogen exposure and electrocardiographic frontal T axis changes in postmenopausal women.

Maturitas. 2009 Jun 29; Atsma F, van der Schouw YT, Grobbee DE, Kors JA, Bartelink MLOBJECTIVE: The protective effect of endogenous estrogens in cardiovascular disease may in part originate from effects of circulating estrogens on the electrophysiological properties of the myocardium. The aim of this study was to investigate the relation between reproductive factors and the electrocardiographic frontal T axis in postmenopausal women. DESIGN: Cohort study. SETTING: The study was conducted at the University Medical Center Utrecht. PATIENTS: In total, 998 postmenopausal women were included. MAIN OUTCOMES: Information of women's reproductive life was obtained by a questionnaire. Electrocardiographic frontal T axes were categorized as normal (25-65 degrees ) or abnormal (-180 degrees to 24 degrees and 66-180 degrees ). Logistic regression analysis was used to assess the relationship between reproductive factors and the frontal T axis. Moreover, the effect of the lifetime cumulative number of menstrual cycles, a composite measure of all reproductive factors, on the frontal T axis was investigated. RESULTS: The mean age was 66.0 (+/-5.6) years and 15.3% had T-axes abnormalities. Later menopausal age decreased the risk on frontal T-axis abnormalities; the multivariable adjusted odds ratio was 0.97 (95% CI: 0.94-0.99) per year increasing menopause. For the lifetime cumulative number of menstrual cycles the age-adjusted odds ratio was 0.84 (95% CI: 0.75-0.99) per 100 menstrual cycles increase. CONCLUSIONS: Later age at menopause and increasing lifetime cumulative number of menstrual cycles decreased the risk on frontal T-axis changes. This supports the view that estrogens may protect against ventricular repolarization disturbances.

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Use of a Gonadotropin-releasing Hormone Agonist to Manage Perimenopausal Women With Symptomatic Uterine Myomas.

Taiwan J Obstet Gynecol. 2009 Jun; 48(2): 133-7Wang PH, Lee WL, Cheng MH, Yen MS, Chao KC, Chao HTOBJECTIVE: To determine the acceptability and effectiveness of a gonadotropin-releasing hormone (GnRH) agonist for the treatment of perimenopausal women with symptomatic uterine myomas. MATERIALS AND METHODS: The participants included 43 women with symptomatic myomas who wished to retain their uteri. All the women were older than 45 years old, agreed to use the GnRH agonist for menopause induction, and were without any underlying malignancy. They were treated with six courses of GnRH agonist between 2004 and 2005. The definition of re-intervention included: (1) surgical intervention, such as hysterectomy, myomectomy or laparoscopic uterine vessel occlusion, or (2) modification of GnRH agonist use. Modification of GnRH agonist use included either failure to complete a 6-month GnRH agonist treatment course, or re-use of GnRH agonist with/without interruption of continuity. Failure was defined as women who underwent surgical intervention or failed to complete the 6-month GnRH agonist treatment. Evaluations were performed every 6 months, for up to 2 years. RESULTS: Re-intervention rates were 14.0% (n = 6), 23.3% (n = 10) and 32.6% (n = 14), and failure rates were 7.0% (n = 3), 11.6% (n = 5) and 16.3% (n = 7), at the end of the 6-, 12- and 24-month follow-up periods, respectively. Three patients failed to complete the 6-month GnRH agonist treatment, and four received surgical interventions. CONCLUSION: More than 80% of women in this study benefited from the use of GnRH agonist to produce menopause, suggesting that this can be an alternative choice for managing perimenopausal women with symptomatic uterine myomas.

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What Can We Learn from Design Faults in the Women's Health Initiative Randomized Clinical Trial?

Bull NYU Hosp Jt Dis. 2009; 67(2): 226-9Design faults resulted in the inability of the Women's Health Initiative (WHI) randomized clinical trial to test the level of cardioprotection conferred by timely hormone treatment of women seeking help for menopausal complaints. Adopting a design constructed around the avoidance of symptomatic subjects and recruitment of older subjects who were more likely to manifest cardiovascular events during the life of the WHI resulted in recruitment of older, sicker subjects than are normally treated for complaints around the time of menopause. The lack of cardioprotection in subjects that began treatment a decade or more after menopause diluted ardioprotection in subjects starting treatment close to the menopausal transition. As a result, despite having the largest number of subjects ever, there were not enough women in the WHI who were comparable to those in the observational trials that showed cardioprotection. This led the WHI to report that there was no cardioprotection in the trial, a position that has been qualifed after further analysis. Misapprehension of the initial WHI conclusions by the media, professionals, and regulatory agencies led to a major shift away from menopausal hormone treatment. This remains problematic since the evidence continues to favor cardioprotection and other benefts that are denied under present regulations and guidelines. Regulatory agencies and professional organizations need to better understand the faws in the WHI design and results in order to properly consider its results and the sustainability of their earlier conclusions and recommendations. Additionally, new trials are needed to test the validity of menopausal hormone-related cardioprotection.

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Ovarian status in healthy postmenopausal women: follow-up 12 months after transvaginal ultrasound.

Menopause. 2009 Jul 1; Bell RJ, Healy DL, Robertson DM, Jobling T, Oehler MK, Edwards A, Shekleton P, Oldham J, Piessens S, Teoh M, Mamers P, Taylor N, Walker FOBJECTIVE:: We have previously reported on the point prevalence of ovarian lesions detected by transvaginal ultrasound (TVU) in 515 asymptomatic women at least 5 years postmenopause. The aims of this study were to report, in the same women, on the repeatability of visualization of the ovaries (TVU) and the natural history of ovarian lesions seen at baseline but not treated surgically and to assess whether any women developed new ovarian abnormalities 12 months later. METHODS:: The study involved a cohort of 515 postmenopausal women recruited from the community, at least 5 years past their last period. They were assessed at baseline and again after 12 months with TVU and serum levels of inhibin and CA-125. RESULTS:: The right and left ovaries were seen on both occasions in 80% and 68% of women, respectively. Of the 49 women who had an ovarian lesion at baseline, did not undergo surgery at that time, and had a follow-up TVU, the lesion was unchanged 12 months later in 30 women. Four women developed a new ovarian lesion within the 12 months. None of the 14 women who underwent surgery on the basis of the ovarian appearance at baseline, or the 2 who had surgery on the basis of the ovarian appearance at follow-up, had an ovarian malignancy. CONCLUSIONS:: The use of TVU in women at least 5 years after menopause is problematic because the ovaries cannot be visualized in all women and because TVU has the potential to identify many benign lesions that would otherwise remain undetected. These are important considerations in weighing up the risks and benefits of using TVU as a screening tool.

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Lower bone mineral density of forearm in postmenopausal patients with radiographic hand osteoarthritis.

Rheumatol Int. 2009 Jul 8; Kim SK, Park SH, Choe JYThe association between clinical parameters and forearm bone mineral density (BMD) in postmenopausal females with radiographic hand OA has not been determined. We investigated the difference in forearm BMD between radiographic hand OA and non-radiographic hand OA, and also the association between clinical parameters of patients and the level of forearm BMD. A total of 180 postmenopausal patients with hand OA were enrolled in this study. We classified them into two groups according to the Kellgren-Lawrence (K-L) radiological grade, one with radiographic hand OA (K-L grade >/= 2) and the other with non-radiographic OA (K-L grade < 2) as controls. The number of nodal joints, swollen joints and tender joints were determined in the physical examination, and measures of BMD (g/cm(2)), Australian Canadian (AUSCAN) OA hand index, grip strength, pinch strength, and visual analogue scale (VAS) were also estimated. Patients with radiographic hand OA had lower distal radius BMD when compared with controls (0.35 +/- 0.06 vs. 0.40 +/- 0.05, P < 0.001). After adjusting for variables such as age, menopausal duration, number of nodal joints, and AUSCAN function index, the difference in BMD between the two groups was also significantly different (0.35 +/- 0.04 vs. 0.38 +/- 0.04, P < 0.001). For analysis of risk factors for forearm BMD in hand OA, age and K-L OA grade in total hand OA are considered risk factors, whereas age and menopause duration contribute to the forearm BMD in radiographic hand OA patients (P < 0.001, P = 0.002, respectively). The development of osteoporosis at the distal radius in radiographic hand OA is associated with older age (OR = 1.216, P = 0.002), lower BMI (OR = 0.777, P = 0.004) and lower stiffness in the AUSCAN OA index (OR = 0.505, P = 0.003). This study shows that the BMD levels of the distal radius in patients with radiographic hand OA are significantly lower when compared to those of controls. Forearm BMD levels are positively associated with age and K-L radiological grade in total hand OA, whereas age and menopausal duration are closely related with radiographic hand OA. The presence of osteoporosis in the distal radius in radiographic hand OA may be influenced by age, BMI, and stiffness on the AUSCAN index.

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Vaginal symptoms in postmenopausal women: self-reported severity, natural history, and risk factors.

Menopause. 2009 Jul 1; Huang AJ, Moore EE, Boyko EJ, Scholes D, Lin F, Vittinghoff E, Fihn SDOBJECTIVE:: This study aimed to examine factors other than estrogen deficiency influencing the development and persistence of vaginal dryness, itching, and painful sexual intercourse after menopause. METHODS:: We analyzed data from a 2-year, population-based cohort of 1,017 postmenopausal women aged 55 to 75 years. Vaginal symptoms were assessed by interviewer-administered questionnaire, and vaginal swabs were performed to assess vaginal pH and microbial flora at baseline, 12 months, and 24 months. Generalized estimating equations were used to identify characteristics associated with symptoms. RESULTS:: Half of the women (n = 471) reported problematic vaginal dryness, a third (n = 316) reported itching, and 40% of sexually active women (n = 166) reported painful intercourse at baseline. Of women not taking estrogen, half of those reporting baseline symptoms were symptomatic after 24 months. Vaginal dryness was associated with younger age (odds ratio [OR], 0.81; 95% CI, 0.69-0.94, per 5-y increase), nonwhite race (ie, African American, Hispanic, Asian or Pacific Islander, or American Indian [OR, 1.53; 95% CI, 1.04-2.27]), diabetes (OR, 1.51; 95% CI, 1.07-2.12), lower 36-item Short-Form Health Survey physical functioning scores (OR, 0.90; 95% CI, 0.85-0.97, per 10-point increase), lower body mass index (OR, 0.81; 95% CI, 0.71-0.93, per 5 kg/m increase), recent sexual activity (OR, 1.14; 95% CI, 1.08-1.21), and vaginal colonization with enterococci (OR, 1.25; 95% CI, 1.04-1.51). Vaginal itching was also associated with lower physical functioning scores (OR, 0.86; 95% CI, 0.80-0.92, per 10-point increase). Risk factors for painful intercourse included younger age (OR, 0.72; 95% CI, 0.56-0.93, per 5-y increase), diabetes (OR, 3.48; 95% CI, 1.93-6.27), lower body mass index (OR, 0.76; 95% CI, 0.61-0.95, per 5 kg/m increase), and higher vaginal pH (OR, 1.10; 95% CI, 1.00-1.21, per 0.5 units). CONCLUSIONS:: Vaginal symptoms affect a large proportion of postmenopausal women, particularly those with diabetes and those with lower body mass index, but may resolve for up to half of women without estrogen therapy.

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Effects of alendronate treatment on serum levels of osteoprotegerin and total receptor activator of nuclear factor kappaB in women with postmenopausal osteoporosis.

Menopause. 2009 Jul 1; Reyes-García R, Muñoz-Torres M, García DF, Mezquita-Raya P, García Salcedo JA, de Dios Luna JOBJECTIVE:: Bisphosphonates are potent inhibitors of bone resorption that are used as effective therapeutic agents for the management of osteoporosis and other bone diseases. The osteoprotegerin (OPG)-receptor activator of nuclear factor kappaB (RANKL) system plays an important role in the regulation of bone metabolism and vascular biology. The effects of bisphosphonate treatment in OPG-RANKL system have not been fully elucidated. The aims of the study were to evaluate the effects of alendronate treatment (70 mg once/wk) on serum concentrations of OPG, total RANKL, and biochemical markers of bone turnover in untreated women with postmenopausal osteoporosis and to determine the correlation between changes in bone mineral density and changes in serum OPG, total RANKL, and bone turnover markers. METHODS:: The study was a single group pretest/posttest design including a total number of 46 participants. Serum OPG and total RANKL serum levels were determined before and after 3, 6, and 12 months of treatment with alendronate. We also measured serum carboxyterminal cross-linked telopeptide of type I collagen, osteocalcin, and bone-specific alkaline phosphatase. The main outcome measures are the changes in OPG and total RANKL serum levels after alendronate treatment. RESULTS:: Serum OPG changes were not significant at 3 and 6 months (-1.6% and -1%), but at 12 months, there was a significant reduction of 6.5% (P < 0.01). Total RANKL serum levels increased during treatment: 23% at 3 months, 25% at 6 months, and 52% at 12 months (P < 0.001 for all comparisons). Basal levels of OPG, total RANKL, and bone turnover markers were not correlated, and we did not find correlations between changes in these parameters after treatment. CONCLUSIONS:: We conclude that the determination of total RANKL integrates the free RANKL and the fraction bound to OPG. The apparent decrease in the serum levels of OPG might reflect an increase in OPG binding to RANKL, which results in a beneficial effect on bone.

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Coronary heart disease and menopause management: The swinging pendulum of HRT.

Atherosclerosis. 2009 Jun 6; Stevenson JC, Hodis HN, Pickar JH, Lobo RAThe Women's Health Initiative comprised a randomized placebo-controlled clinical trial of therapeutic and dietary interventions influencing postmenopausal women's health. One arm evaluated hormone replacement therapy and its effects on major health outcomes. Initial publication of the preliminary results suggested overall harm from hormone replacement therapy, leading to a dramatic worldwide decrease in its use, and concerns from clinicians and regulatory authorities. Subsequent publications with more detailed analyses appear to have countermanded these initial concerns. Analyses of the studies have not been adherent to those specified in the original published protocol. Nominal confidence intervals should have been used only for the primary outcome, which was coronary heart disease. Initially reported as showing a significant increase in events with hormone replacement therapy, in a subsequent analysis of the full data the increase was no longer significant. Adjusted confidence intervals showed no significant increase for breast cancer, the primary adverse outcome. A major difference in the effects of hormones between younger and older women has emerged but this important finding has been minimized. For women under age 60 years or within 10 years of menopause, the final findings for all outcomes closely resemble those from observational cohorts. The raw data must be made available for independent assessment to obtain valid conclusions which may again change clinical practice.

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Transdermal Nitroglycerin Therapy May Not Prevent Early Postmenopausal Bone Loss.

J Clin Endocrinol Metab. 2009 Jun 23; Wimalawansa SJ, Grimes JP, Wilson AC, Hoover DR, Context: Osteoporosis is common among postmenopausal women; pilot studies support the concept of nitric oxide (NO) donors reducing bone mineral density loss. Objective: Evaluate if NO donor, nitroglycerin prevents postmenopausal bone loss. Design: Three-year randomized, blinded, single-center, placebo-controlled clinical trial. Setting: Single-center study at the University of Medicine and Dentistry - Robert Wood Johnson Medical School, New Brunswick, New Jersey. Participants: 186 postmenopausal women aged 40 to 65 years, with lumbar bone mineral density (BMD) T-scores of 0 to -2.5. Intervention: Women, stratified by lumbar T-score (< -1.50 and >/= -1.50) and years since menopause (5 years), were randomized to receive, i) nitroglycerin ointment (22.5 mg as Nitrobid(R), or ii) placebo ointment receiving daily for three years. Both groups took 630 mg daily calcium plus 400 IU vitamin D supplements. Measurements: Bone mineral density (BMD) was measured at 6 months and annually by dual energy x-ray absorptiometry. Percent change in lumbar vertebrae BMD was the primary outcome. Hip BMD, total body bone mineral content and height were secondary outcomes. Results: After 36 months of therapy, changes of -2.1% in the active group (n=88) and -2.5% in the placebo group (n=82) in lumbar spine BMD were seen; p = 0.59 (95% CI -1.001, 1.975). Secondary outcomes also did not differ by intervention arm. The active group reported more headaches compared to the placebo group (57% vs. 14%, p

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Influence of gender on serum growth hormone, insulin-like growth factor-I and its binding protein-3 during aging.

Yonsei Med J. 2009 Jun 30; 50(3): 407-13Lin CM, Huang YL, Lin ZYPURPOSE: The serum concentrations of insulin-like growth factors-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and growth hormone (GH) are related to body composition, function and metabolism, and are influenced by the aging process. This study was to investigate the influence of gender on serum concentrations of IGF-I, IGFBP-3 and GH in middle and old age subjects. MATERIALS AND METHODS: Sixty healthy volunteers (male 35, female 25, 36-70 years) were divided into < or = 50 and > 50 years groups, based on gender. Women > 50 years were post-menopause. IGF-I, IGFBP-3, and GH were determined by immunoradiometric assay. RESULTS: IGF-I was shown to be negatively correlated with age (women r = -0.62, p < 0.001; men r = -0.38, p < 0.05), whereas there was no correlation between IGF-I and GH values. Women > 50 years showed a significant reduction in IGF-I values than women < or = 50 years (p < 0.01). Women > 50 years showed smaller IGF-I/IGFBP-3 molar ratios (0.177998 +/- 0.039404) than men of same age group (0.228326 +/- 0.050979, p < 0.01) and women < or = 50 years (0.247667 +/- 0.069411, p < 0.01). Age was shown to positively correlate with GH/IGF-I (r = 0.49, p < 0.05) and GH/IGFBP-3 ratios (r = 0.40, p < 0.05) in women. CONCLUSIONS: The influence of aging on serum concentrations of IGF-I is more remarkable in women than in men. Menopause causes reduction of IGF-I/IGFBP-3 molar ratio. Women have the trend of progressive hypoactivity of GH to stimulate IGF-I and IGFBP-3 secretions with age.

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Association of Polymorphism of Estrogen Receptor-alpha Gene with Circulating Levels of Adiponectin in Postmenopausal Women with Type 2 Diabetes.

J Atheroscler Thromb. 2009 Jun 25; Yoshihara R, Utsunomiya K, Gojo A, Ishizawa S, Kanazawa Y, Matoba K, Taniguchi K, Yokota T, Kurata H, Yokoyama JI, Urashima M, Tajima NAim: Menopause is a risk factor for cardiovascular disease (CVD) in women because of the reduction in endogenous estrogen. Recently, single nucleotide polymorphisms (SNPs) of the estrogen receptor alpha (ESR-1) gene (c.454-397T>C) associated with the prognosis of myocardial infarction in postmenopausal women were identified; however, the mechanism by which genetic variation of ESR-1 contributes to the pathogenesis of CVD is unknown. Circulating levels of adipokines and inflammatory cytokines predict CVD risk; hence, this study aimed to investigate whether ESR-1 genotypes (c.454-397T>C) might influence circulating levels of adipokines and inflammatory cytokines in postmenopausal women with type 2 diabetes.Methods: Sixty-three postmenopausal women with type 2 diabetes were recruited. Serum levels of adiponectin, resistin, interleukin-6 (IL-6), and high-sensitive C-reactive protein (hs-CRP) were determined.Results: The genotype of ESR-1 was closely associated with serum adiponectin, which was decreased in subjects with the T allele and was lowest in those with the T/T genotype. Multiple logistic regression analysis revealed independent contribution of the homozygote for the T allele to low serum levels of adiponectin.Conclusion: The T allele of the c.454-397T>C SNP of ESR-1 is associated with low serum levels of adiponectin, which may lead to a high risk of CVD in postmenopausal women.

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Life after a diagnosis with endometriosis - a 15 years follow-up study.

Acta Obstet Gynecol Scand. 2009 Jun 30; 1-6Fagervold B, Jenssen M, Hummelshoj L, Moen MHObjective. Previous studies have elucidated the negative impact of endometriosis on life, but the patient selection may have contributed to a skewed picture. The aim of this study was to investigate longitudinally the consequences of the disease in women diagnosed with endometriosis 15 years ago. Design. Retrospective descriptive. Setting. Trondheim 2007. Sample. One hundred thirty women diagnosed with endometriosis at St. Olav's Hospital in Trondheim between 1991 and 1993. Methods. Questionnaires. Response rate of 60%. Main outcome measures. Consequences of living with endometriosis. Results. Of the women, 19.2% never experienced pelvic pain and 21.8% did not have any further visits to the gynecological department after being diagnosed. Almost 70% had received pharmaceutical treatment and positive effect on pain was reported by 41% for NSAIDs and oral contraceptives, and by 62% for progestins and GnRH-analogues. Satisfactory effect on pain after surgical interventions at the time of diagnosis was reported by 60.9%, and by 89.9% after later surgeries. Of the infertile patients, 75.6% succeeded in delivering one or more biological children. Half of the women reported that endometriosis had some negative impact on their lives. After menopause, 96.9% were free from pain. Conclusion. This study confirms that endometriosis is a condition that often has considerable impact on a woman's life. However, the study also found that endometriosis does not always cause pain, that treatment in many cases is effective, that infertility may be overcome, and that almost all postmenopausal women were free from endometriosis-associated pain.

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Progesterone and ovulation across stages of the transition to menopause.

Menopause. 2009 Jun 29; O'Connor KA, Ferrell R, Brindle E, Trumble B, Shofer J, Holman DJ, Weinstein MOBJECTIVE:: Detailed characterization of progesterone and ovulation across the menopausal transition provides insight into conception risk and mechanisms of reproductive aging. METHODS:: Participants (n = 108, aged 25-58 y) collected daily urine specimens for 6-month intervals in each of 5 consecutive years. Specimens were assayed for pregnanediol glucuronide (PDG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrone glucuronide (E1G). Reproductive stage was determined using cycle length variance. A hierarchical algorithm was used to identify ovulation. Linear mixed-effects models estimated (1) the frequency and day of ovulation by age and stage; (2) differences in FSH, LH, and E1G levels between ovulatory (O) and anovulatory (AO) cycles; and (3) total PDG levels and PDG levels in O cycles by age and stage. RESULTS:: The probability of AO cycles increased across the perimenopause (P < 0.0001); reproductive stage was a stronger predictor than age of the probability of anovulation. Most cycles in late perimenopause were AO (>60%), but one quarter of cycles longer than 60 days were O. Average day of ovulation was later in the late perimenopause (mean [SD] cycle day, 27 [25] d) compared with the premenopause. FSH and LH levels were higher and E1G levels were lower in AO than O cycles (P < 0.0001 for each). Total PDG decreased in the late perimenopause, but 95th percentile PDG in O cycles declined steadily across the transition. CONCLUSIONS:: Exposure to the risk of conception in women experiencing cycles long enough to classify them as late perimenopausal is far from negligible. Reproductive stage is more informative than age about PDG levels and the likelihood of anovulation.

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Thyroid hormones affect recovery from depression during antidepressant treatment.

Psychiatry Clin Neurosci. 2009 Jun; 63(3): 305-13Pae CU, Mandelli L, Han C, Ham BJ, Masand PS, Patkar AA, Steffens DC, De Ronchi D, Serretti AAIMS: The aim of the present study was to evaluate whether thyroid hormonal changes during menopause may affect the development and the course of major depressive disorder. METHODS: Thirty-nine female patients (n = 17 in pre-menopause; n = 22 in post-menopause) with major depressive disorder based on Diagnostic Statistical Manual of Mental Disorders (4th edition) criteria and who were euthyroid and not on hormonal replacement therapy, participated in a prospective, 6-week, open-label naturalistic study. The Hamilton Depression Rating Scale-17 item, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression scale and the Cognitive Failure Questionnaire were administered at baseline, week 1, week 3, and week 6. Levels of thyroid stimulating hormone, total thyroxine and total triiodothyronine were collected at baseline visit. RESULTS: In the whole sample, particularly in pre-menopausal women, levels of thyroid stimulating hormone-potential markers of subclinical hypothyroidism were correlated with those of less severe but more resistant depressive form. Conversely, total thyroxine levels were correlated with a more severe depression, but high levels of this hormone favored the response to antidepressants. Overall, a diagnosis of subclinical hypothyroidism was associated with a poor response to antidepressant treatment. Finally, total triiodothyronine levels were associated with better cognitive functioning, though they did not influence improvement occurring with recovery. CONCLUSIONS: Our study suggests that thyroid hormones may have an impact on severity and efficacy of antidepressant treatment. However, our result should be considered with caution and merely as a suggestion due to some methodological limitations. Hence further studies are required to better ascertain the role of thyroid hormones in depression after menopause.

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HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.

Hepatology. 2009 Mar 19; 50(1): 94-101Gurrin LC, Bertalli NA, Dalton GW, Osborne NJ, Constantine CC, McLaren CE, English DR, Gertig DM, Delatycki MB, Nicoll AJ, Southey MC, Hopper JL, Giles GG, Anderson GJ, Olynyk JK, Powell LW, Allen KJ, The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02) except for females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 mug/L for compound heterozygotes and from 35 to 64 mug/L for wild-types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease. Conclusion: For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare. (HEPATOLOGY 2009;50:94-101.).

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