Endogenous sex hormones and metabolic syndrome in aging men.

BACKGROUND: Sex hormone levels in men change during aging. These changes may be associated with insulin sensitivity and the metabolic syndrome. METHODS: We studied the association between endogenous sex hormones and characteristics of the metabolic syndrome in 400 independently living men between 40 and 80 yr of age in a cross-sectional study. Serum concentrations of lipids, glucose, insulin, total testosterone (TT), SHBG, estradiol (E2), and dehydroepiandrosterone sulfate (DHEA-S) were measured. Bioavailable testosterone (BT) was calculated using TT and SHBG. Body height, weight, waist-hip circumference, blood pressure, and physical activity were assessed. Smoking and alcohol consumption was estimated from self-report. The metabolic syndrome was defined according to the National Cholesterol Education Program definition, and insulin sensitivity was calculated by use of the quantitative insulin sensitivity check index. RESULTS: Multiple logistic regression analyses showed an inverse relationship according to 1 sd increase for circulating TT [odds ratio (OR) = 0.43; 95% confidence interval (CI), 0.32-0.59], BT (OR = 0.62; 95% CI, 0.46-0.83), SHBG (OR = 0.46; 95% CI, 0.33-0.64), and DHEA-S (OR = 0.76; 95% CI, 0.56-1.02) with the metabolic syndrome. Each sd increase in E2 levels was not significantly associated with the metabolic syndrome (OR = 1.16; 95% CI, 0.92-1.45). Linear regression analyses showed that higher TT, BT, and SHBG levels were related to higher insulin sensitivity; beta-coefficients (95% CI) were 0.011 (0.008-0.015), 0.005 (0.001-0.009), and 0.013 (0.010-0.017), respectively, whereas no effects were found for DHEA-S and E2. Estimates were adjusted for age, smoking, alcohol consumption, and physical activity score. Further adjustment for insulin levels and body composition measurements attenuated the estimates, and the associations were similar in the group free of cardiovascular disease and diabetes. CONCLUSIONS: Higher testosterone and SHBG levels in aging males are independently associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, independent of insulin levels and body composition measurements, suggesting that these hormones may protect against the development of metabolic syndrome.

Are cause of subfertility and in vitro fertilization treatment risk factors for an earlier start of menopause?

OBJECTIVE: To study whether women diagnosed with unexplained subfertility reach the menopause transition and natural menopause earlier than women with tubal subfertility, in an in vitro fertilization (IVF)-treated population, and to examine the influence of the number of IVF cycles on the occurrence of an early menopause transition and natural menopause. DESIGN: This retrospective cohort study included 12 IVF clinics in the Netherlands. A nationwide retrospective cohort study was conducted among women whose first IVF cycle was stimulated with gonadotrophins in the Netherlands between 1983 and 1995 (n = 7,842). Most of the women were in their late 30s at the end of the follow-up period (range 24-55 y). The main outcome measures were the relative risk (RR) of having reached natural menopause and the risks (RR) of having entered the menopause transition or natural menopause according to the cause of subfertility and the number of IVF cycles. RESULTS: Women with unexplained subfertility did not have an increased risk of entering the menopause transition or natural menopause (adjusted RR = 0.5; 95% CI, 0.2-1.5; and RR = 0.8; 95% CI, 0.6-1.1). After a 5-year follow-up period, we found no increased risk for entering the menopause transition or natural menopause among women who had undergone six or more IVF cycles when compared with women who had undergone only one IVF cycle (adjusted RR = 0.4; 95% CI, 0.1-1.7; and RR = 0.9; 95% CI, 0.6-1.6). CONCLUSIONS: Underlying causes of unexplained subfertility do not predispose women to an early start of menopause. Although the number of IVF cycles was not associated with early menopause, longer follow-up is needed.

Endogenous sex hormones in men aged 40-80 years.

OBJECTIVE: To determine the relationship between aging, life-style factors and health-related factors and endogenous sex hormone levels. DESIGN: Cross-sectional study of 400 independently living men between 40 and 80 Years of age. METHODS: After exclusion of subjects who were not physically or mentally able to visit the study center, 400 men were randomly selected from a population-based sample. Total testosterone (TT), bioavailable testosterone (BT) (i.e. not bound to sex hormone-binding globulin (SHBG)), SHBG, estradiol (E(2)) and dehydroepiandrosterone-sulfate (DHEA-S) were investigated for their relationship with age, body mass index (BMI), waist circumference, smoking, physical activity and general health status. Multivariate models using ANCOVA analyses were used to examine the contribution of life-style factors to sex hormone variability. RESULTS: TT, BT and DHEA-S decreased with age; 0.2, 0.7 and 1.2%/Year respectively. SHBG showed an increase with age of 1.1%/Year. No changes with age were found for E(2). General health status modified the association of TT and SHBG with age (P interaction 0.10 and 0.002 respectively). Increased BMI and waist circumference were associated with decreased TT, BT, SHBG and DHEA-S and increased E(2) (all P<0.01). Current smoking, lower alcohol intake and a higher physical activity score were associated with higher TT and SHBG levels. CONCLUSION: This study showed the important determinants of sex hormones were age, BMI, waist circumference, smoking, general health status and physical activity. Furthermore, it can be concluded that general health status modified the effect between sex hormones and age. For future observational studies it should be taken into account that the above-mentioned determinants may alter the association between sex hormones and diseases and related conditions.

Caloric restriction reduces age at menopause: the effect of the 1944-1945 Dutch famine.

OBJECTIVE: To assess the effect of caloric restriction, as endured during the 1944-1945 Dutch famine, on the age at which natural menopause occurs and to identify specific vulnerable age periods in which caloric restriction has the largest effect. DESIGN: This was a population-based cohort study conducted in Utrecht, the Netherlands. Between 1983 and 1986, 9,471 women aged 40 to 73 years at the time of interview were classified regarding their exposure to the famine. Age at natural menopause was obtained from all available data, retrospectively as well as prospectively. We estimated differences in mean age at natural menopause between famine exposure categories (not, moderately, and severely exposed), with adjustment for smoking, parity, socioeconomic status, body mass index, age at menarche, and year of birth. RESULTS: Women experienced natural menopause on average 0.36 years earlier (95% CI: -0.60, -0.11) when severely exposed to the famine and 0.06 years earlier (95% CI: -0.22, 0.09) when moderately exposed compared with the unexposed women. This effect was particularly pronounced in those severely exposed from 2 to 6 years of age: -1.83 years (95% CI: -3.03, -0.63). CONCLUSIONS: Our findings suggest that caloric restriction decreases age at natural menopause. Early childhood seems to be a particularly sensitive age period for this effect.

A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause.

OBJECTIVE: To investigate whether women with a low number of retrieved oocytes at the first in vitro fertilization (IVF) attempt have an increased risk of early menopause. DESIGN: Nested case-control study. SETTING: Twelve IVF clinics in the Netherlands. PATIENT(S): Women participating in a nationwide Dutch cohort study (OMEGA) of ovarian stimulation for IVF and subsequent gynecologic diseases (n = 26,428). Each patient who experienced natural menopause at or before 46 years (n = 38) was individually matched to five controls (n = 190) who had not yet entered menopause at the age the patient became postmenopausal. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relative risk of reaching natural menopause at an early age ( three oocytes). Women who were stimulated with gonadotropins during IVF treatment but did not undergo an IVF puncture because of an anticipated poor response (canceled IVF cycle) had a relative risk of 8.3 (95% confidence interval: 2.9-23.9). CONCLUSION: These results suggest that women with a low number of retrieved oocytes at the first IVF treatment are more likely to become postmenopausal at an early age than women with a higher number of retrieved oocytes. Our study is the first longitudinal study to provide strong evidence for the quantitative aspect of the ovarian concept of reproductive aging.

Menstruation during and after caloric restriction: the 1944-1945 Dutch famine.

OBJECTIVE: To investigate the relation between exposure to the 1944-45 Dutch famine and concurrent and subsequent menstrual disturbances. DESIGN: Cohort study. SETTING: Doorlopend Onderzoek Mammacarcinoom breast cancer screening project, Utrecht, the Netherlands. PATIENT(S): Between 1983 and 1986, approximately 12,500 women (born 1911-41) reported their individual famine experiences. MAIN OUTCOME MEASURE(S): Irregular menstruation during the famine; time to regular menses after menarche, and menstrual patterns in adulthood after childhood famine. RESULT(S): The famine had a direct impact on menstruation. The odds ratio (OR) of concurrent irregular menses in severely versus unexposed women was 8.85 (95% confidence interval [CI], 7.31-10.70). Women exposed to severe famine before menarche were 1.51 (95% CI, 1.15-1.98) times more likely to experience irregular menses for a prolonged time after menarche compared with the unexposed. This association was stronger in women with an early menarche. When the menstrual pattern was assessed in adulthood by menstrual diaries, a nonsignificant tendency of increased irregularity (OR, 1.13; 95% CI, 0.82-1.54) and regular but long menstrual cycles (OR, 1.41; 95% CI, 0.89-2.23) was observed in women exposed to severe famine. CONCLUSION(S): Famine relates to concurrent menstrual irregularity, and exposure in childhood seems to affect the subsequent menstrual pattern.

Validity of self-reported causes of subfertility.

The authors assessed the accuracy of cause(s) of subfertility as reported by women in a self-administered questionnaire in comparison with medical record information, in a nationwide cohort study of women receiving in vitro fertilization treatment in the Netherlands (n = 9,164) between 1983 and 1995. Validity was expressed as sensitivity and specificity, and reliability was expressed by the kappa statistic and overall agreement between self-reports and medical records for various subfertility categories. The sensitivity for subfertility attributed to tubal, male, hormonal, cervical, uterine, and idiopathic factors and for endometriosis was 84%, 78%, 65%, 40%, 46%, 59%, and 83%, respectively. The corresponding kappas were 0.79, 0.71, 0.38, 0.34, 0.13, 0.50, and 0.52, respectively. For 54% of all women who reported two or more causes of subfertility, the medical record revealed only one major factor. Conversely, for 43% of all women whose subfertility was attributed to two or more major factors in the record, only one factor was reported by the women. Older age at the time of filling out the questionnaire, low educational level, long duration of subfertility, and pre-in vitro fertilization treatment were associated with less accurate reporting. The results indicate that the validity of self-reports for tubal and male subfertility is satisfactory. For unexplained subfertility, the validity is moderate; for other causes of subfertility and when two causes of subfertility play a role, the validity is low.

Childhood exposure to the 1944-1945 Dutch famine and subsequent female reproductive function.

BACKGROUND: Childhood caloric restriction may lead to permanent changes in the hypothalamo-pituitary-gonadal axis, which could lead to impaired female reproductive ability. We assessed the effect of childhood exposure to the 1944-1945 Dutch famine on subsequent female reproductive function. METHODS: This was a population-based cohort study in Utrecht, The Netherlands. Between 1983 and 1985, 6030 women born between 1932-1941 were classified by questionnaire according to their famine exposure experiences. Dates of marriage, first and second childbirth, and information on a medical reason for having no children or fewer children than wanted were available from questionnaires, as well as ages and type of menopause. RESULTS: Severe famine exposure during childhood significantly decreased chances of first and second childbirth at any given time after marriage or first childbirth [adjusted hazard ratios (HR) 0.86, 95% confidence interval (CI) 0.76-0.96; and HR 0.87, 95% CI 0.78-0.97, respectively). Risk of a medical reason for having no or fewer children than wanted was increased in the severely exposed (odds ratio 1.88; 95% CI 1.29-2.74), as was the risk of a surgical menopause (HR 1.53; 95% CI 1.27-1.84). CONCLUSIONS: Our findings support the presence of longstanding modest effects of childhood famine exposure on reproductive function in women.

Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment.

BACKGROUND: Our aim was to examine whether women who had a low number of retrieved oocytes at their first IVF attempt reach the menopausal transition and/or the natural menopause earlier than women of similar ages with a high number of retrieved oocytes. METHODS: We conducted a retrospective cohort study among women in The Netherlands who received IVF treatment between 1983 and 1995. For the present study, we selected all cohort members who had a regular menstrual cycle at the time of the first visit to the gynaecologist (n = 4601). After a median follow-up of 5.5 years, 3871 (84%) women still had a regular menstrual cycle pattern, 547 (12%) women had entered the menopausal transition (i.e. no menses for 3-11 months, use of HRT or irregular menstrual cycles) and 27 (1%) women had reached natural menopause. We examined whether the quantity and the quality of the retrieved oocytes were related to an early menopausal transition and early menopause. The live birth rate per embryo transfer was used as indicative of the quality of the oocytes. RESULTS: The age-adjusted odds ratio (OR) for having entered the menopausal transition/natural menopause for women with a poor response (0-3 oocytes) at their first IVF attempt was 3.1 [95% confidence interval (CI) 2.4-3.8] compared with women with a normal response (>3 oocytes). Women who were stimulated with gonadotrophins during IVF treatment but did not undergo an IVF puncture because of an anticipated poor response (cancelled IVF cycle) had an age-adjusted OR of 3.2 (95% CI 2.3-4.3). There was no significant difference in the odds of reaching the menopausal transition/natural menopause, after adjustment for age and the number or retrieved oocytes, between women who did and did not have a live birth following their first embryo transfer (OR = 1.3; 95% CI 0.95-1.7). CONCLUSIONS: These results indicate that a low remaining quantity of oocytes, as reflected by a low number of retrieved oocytes at first IVF treatment, is an important predictor of the risk of an early menopausal transition/natural menopause. The quality of the oocytes did not affect the risk of an early menopausal transition/natural menopause once the number of retrieved oocytes had been taken into account. Our findings support the concept that the number of remaining follicles in the ovaries is one of the main aspects of reproductive ageing.

The number of retrieved oocytes does not decrease during consecutive gonadotrophin-stimulated IVF cycles.

BACKGROUND: Our aim was to study whether there is a decreasing trend in the number of retrieved oocytes in women who had all undergone at least seven consecutive IVF cycles. METHODS: A nationwide retrospective cohort study was conducted among women whose first IVF cycle was stimulated with gonadotrophins in The Netherlands between 1983 and 1995. Among these eligible women, we identified all women who had received at least seven consecutive IVF cycles (n = 330). Poisson regression analysis was used to assess the trend in the number of retrieved oocytes over the first six IVF cycles. RESULTS: The unadjusted results showed a slight but non-significant decrease in the number of retrieved oocytes over six IVF cycles. The change in cycle 6 compared with cycle 1 was -0.06 oocytes (5.8% decrease) (P = 0.21). When adjusting for the number of ampoules and the stimulation protocol (fertility drug used combined with use of GnRH agonists), there was a considerable and highly significant decrease from cycle 1 to cycle 6 [change in cycle 6 compared with cycle 1: -0.19 oocytes (17.4% decrease), (P < 0.0001)]. However, when adjusting for age of the women, this decrease almost completely disappeared [change in cycle 6 compared with cycle 1: -0.05 oocytes (5% decrease), (P = 0.50)]. CONCLUSION: The results suggest that there is no decrease in the number of retrieved oocytes over subsequent cycles when simultaneously accounting for the increasing age of the women, differences in the number of ampoules of gonadotrophins used, type of stimulation protocol and year of IVF treatment.