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Magnetic resonance imaging of overall and regional body fat, estrogen metabolism, and ovulation of athletes compared to controls
Abstract
The association of menstrual dysfunction of athletes with changes in body composition has been controversial, because most estimations of body fatness have been indirect. Using magnetic resonance imaging, we quantified the sc and internal fat over a specific volume from the fifth thoracic vertebra to femoral fat in the upper thigh and at 4 other anatomical landmarks of 17 athletes (13 oarswomen and 4 runners) compared to that in 11 nonathletic controls. The magnetic resonance imaging data were also analyzed for the athletes and controls in relation to ovulatory status, which was determined by assay of urinary pregnanediol glucuronide, and in relation to the extent of 2-hydroxylation of estradiol to a nonpotent metabolite, 2-hydroxyestrone, which was evaluated by radiometric analysis. We found that 1) the relative and absolute body fat values of the athletes were significantly less (P < 0.05) than those of the controls overall and at each of the six regional sites, although the body weights of the rowers were significantly heavier than those of the controls, and the runners did not differ from the controls; 2) the ratio of sc fat to internal fat was 80%:20% among both athletes and controls, even though the athletes had significantly less fat; 3) the extent of estradiol 2-hydroxylation was significantly (P = 0.005) inversely related to total fat as a percentage of the total volume and to sc fat as a percentage of the total volume (P = 0.004) overall and at each of the regional fat depots; 4) athletes with menstrual disorders had significantly decreased sc and internal fat overall and at all regional sites compared to controls; and 5) a subgroup of ovulatory rowers had an apparent increase or lack of decrease in internal fat at the level of vertebrae lumbar 4, sacral 1, and sacral 4, compared to controls, whereas their sc fat was decreased at these sites compared to that in controls. Changes in regional fat deposits of both sc and internal fat may be involved in the menstrual dysfunction of the athletes in addition to their decreased overall fatness. The body weight and body mass index of well trained athletes can be a misleading index of body composition.
... The competitive female athlete has about 50% less body fat than the non-competitor, who is very much under the 10 th percentile of secondary amenorrhea (the 22% body fatline). This change in body fat can occur with no discernible change in total body weight, because fat is converted to lean muscle mass [59]. Looking analytically at the critical weight hypothesis, it argues that there is no cause and effect relationship between body fat and menstrual function, but only a correlation [60,61]. ...
... The conversion of estradiol to catechol estrogens rapidly yield 2-hydroxy estrone and 4-hydroxy estrone, which are relatively inactive metabolites which are further metabolized to 2- methoxy estrogen and 4-methoxy estrogen by methylation.These products and this pathway is increased by physical exercise [71,72] . The extent of 2- hydroxylation correlates inversely with body fat, increasing with decreasing adiposity [59,73]. This could be a mechanism which interferes with the negative feedback and local roles of estradiol in pituitary-ovarian interactions. ...
Hypothalamic Amenorrhea is one of the most common causes of amenorrhea in women of reproductive age, accounting for almost 50%cases of secondary amenorrhea, while the genetic causes account for a lower percentage of cases of HA presenting as primary amenorrhea. HA is a heterogeneous condition with main characteristics being reduced pulsatile GnRH secretion which is evidenced as reduced circulating LH levels along with decreased frequency and amplitude of LH plasticity. It has been observed in 10% of female athletes. Besides that, affected patients may have more than one etiological factor like low body weight, excessive exercise as well as stress. Other important causes such as heterozygous mutations in genes associated with GnRH migration or GnRH secretion maybe responsible for congenital GnRH deficiency whose presentation is also as HA. Thus pulsatile s/c administration remains the treatment of choice in women desiring pregnancy. Priming with LH followed by FSH initiation may be effective in ovulation induction as well. But since infusion pumps requiring GnRH administration intermittently are not available in all countries Kp54/kp10 offers a better alternative once its efficacy and full therapeutic window has been accurately worked out,besides being very effective in Kp/GPR54 mutations as well as neurokin deficiency as it acts downstream of Kp. Emphasis on weight increase and correcting anetiological factors remains the mainstay in patients presenting with functional HA as secondary amenorrhea and factors which will increase intake as well as reduce energy expenditure will go a long way in correcting the GnRH and thus LH pulsatility. Only if these patients require immediate fertility is hormonal therapy indicated along with ovulation induction.
Keywords: Hypothalamic amenorrhea; Anorexia nervosa; Bulimia nervosa; Exercise; Stress; GnRH mutations; Idiopathic hypogonadotropic hypogonadism;Pulsatile GnRH therapy;Kisspeptin 54; Estrogen supplementation; Weight control
... However, muscles are heavy (80% water, compared to 5–10% fat) and the BMI of an athlete can be misleading as to per cent fat. A study of young athletes, compared to controls, using MRI (magnetic resonance imaging) for direct measurements of fat showed athletes had 30–40% less fat at the same weight as controls (Frisch et al, 1993). When we used the equations of Cohn et al (1980) and Ellis et al (1974), to determine per cent body fat, we found that former athletes had significantly less body fat. ...
A growing body of evidence indicates that physical activity is protective against breast cancer. In 1996-97, we conducted a 15-year follow-up of 5398 college alumnae comprised of former college athletes with their non-athletic classmates. Participants completed a detailed mailed questionnaire on their health history from 1981-82 to the present. Excluding women who had died and non-deliverable questionnaires, 84.7% (n = 3940) of the participants in our earlier study responded to the questionnaire; the response rate for former athletes was 86.6% (n = 1945), for non-athletes, 83.0% (n = 1995). Results confirmed our earlier findings. Based on self-reports, former college athletes had a significantly lower risk of breast cancer than the non-athletes. The OR for the 15-year incidence of breast cancer is 0.605 with 95% confidence interval (CI) (0.438-0.835); the 15-year incident breast cancers were 64 among the athletes and 111 among the non-athletes. Among women under 45 the protective effect of physical activity on the risk of breast cancer is considerably greater; odds ratio (OR) = 0.164, 95% CI (0.042-0.636). Athletic activity during the college and pre-college years is protective against breast cancer throughout the life span, and more markedly among women under 45. These results confirm our earlier findings and the findings of other investigators.
... Although the biological basis of this phenomenon remains obscure, it is consistent with the known positive effect of body mass on bone density, (35,36) and the negative effects of total body fat on 2-hydroxylation of estrogens. (37,38 ) Therefore, the many factors that modulate the synthesis of these metabolites could selectively influence estrogen target tissues such as bone. Concordant conclusions emerge from studies in postmenopausal osteoporosis, a consequence of estrogen deficiency . ...
Because lifelong exposure to estrogen is a strong determinant of bone mass, we asked whether metabolic conversion of estrogen to either inactive or active metabolites would reflect postmenopausal bone mineral density (BMD) and rate of bone loss. Biochemical markers of inactive estrogen metabolites, urinary 2-hydroxyestrogen (2OHE1) and 2-methoxyestrogen (2MeOE1), and active metabolites, urinary 16alpha-hydroxyestrone (16alphaOHE1), estradiol (E2), and estriol (E3), were determined in 71 untreated, healthy postmenopausal women (age, 47-59 years) followed prospectively for 1 year. Urinary 2MeOE1 was correlated negatively with baseline vertebral (anteroposterior [AP] projection, r = -0.23 andp < 0.05; lateral view, r = -0.27 and p < 0.05) and proximal femur bone density measured by dual-energy X-ray absorptiometry (DXA; total, r = -0.38 and p < 0.01; neck, r = -0.28 and p = 0.02; trochanter, r = -0.44 and p < 0.01). BMDs of women in the lowest quartile of urinary 2MeOE1 (< 15 ng/g) were significantly higher than those in the highest quartile at all skeletal sites (p < 0.05). Likewise, women in the lowest quartile of urinary 2OHE1/16alphaOHE1 ratio (< 1.6) did not experience bone loss after 1 year, in contrast to women in the higher quartiles. We propose that the rate of inactivation of estrogens through 2-hydroxylation may contribute to postmenopausal osteoporosis.
Human papillomavirus (HPV) induced cervical cancer is becoming a major cause of mortality in women. The present research aimed to identify the natural inhibitors of HPV-18 E1 protein (1R9W) from Himalayan herbs with lesser toxicity and higher potency. In this study, one hundred nineteen phytoconstituents of twenty important traditional medicinal plants of Northwest Himalayas were selected for molecular docking with the target protein 1R9W of HPV-18 E1 Molecular docking was performed by AutoDock vina software. ADME/T screening of the bioactive phytoconstituents was done by SwissADME, admetSAR, and Protox II. A couple of best protein-ligand complexes were selected for 100 ns MD simulation. Molecular docking results revealed that among all the selected phytoconstituents only thirty-five phytoconstituents showed the binding affinity similar or more than the standard anti-cancer drugs viz. imiquimod (-6.1 kJ/mol) and podofilox (-6.9 kJ/mol). Among all the selected thirty-five phytoconstituents, eriodictyol-7-glucuronide, stigmasterol, clicoemodin and thalirugidine showed the best interactions with a docking score of -9.1, -8.7, -8.4, and -8.4 kJ/mol. Based on the ADME screening, only two phytoconstituents namely stigmasterol and clicoemodin selected as the best inhibitor of HPV protein. MD simulation study also revealed that stigmasterol and clicoemodin were stable inside the binding pocket of 1R9W, Stigmasterol and clicoemodin can be used as a potential investigational drug to cure HPV infections.
Purpose
Polycystic ovary syndrome (PCOS) is an increasingly prevalent disorder in adolescent girls, commonly presenting with hirsutism/oligomenorrhea, commonly treated with an oral contraceptive (OC), and commonly followed by oligoanovulatory subfertility. We tested whether an intervention targeting the reduction of hepato-visceral adiposity is followed by a higher ovulation rate than OC treatment.
Methods
This randomized, open-label, single-center, pilot proof-of-concept study (12 months on treatment, then 12 months off) was performed in adolescent girls with hirsutism and oligomenorrhea (PCOS by National Institutes of Health; no sexual activity; N = 36; mean age 16 years, body mass index 23.5 kg/m²; 94% study completion). Compared treatments were OC (ethinylestradiol–levonorgestrel) versus low-dose combination of spironolactone 50 mg/d, pioglitazone 7.5 mg/d, and metformin 850 mg/d (SPIOMET). Primary outcome was post-treatment ovulation rate inferred from menstrual diaries and salivary progesterone (12 + 12 weeks). Secondary outcomes included body composition (dual X-ray absorptiometry), abdominal fat (magnetic resonance imaging), insulinemia (oral glucose tolerance test), and androgenemia (liquid chromatography – tandem mass spectrometry).
Results
SPIOMET was followed by a 2.5-fold higher ovulation rate than OC (p ≤ .001) and by a 6-fold higher normovulatory fraction (71% vs. 12%; p ≤ .001); oligoanovulation risk after SPIOMET was 65% lower (95% confidence interval, 40%–89%) than after OC. Higher post-treatment ovulation rates related to more on-treatment loss of hepatic fat (r² = .27; p < .005). Visceral fat and insulinemia normalized only with SPIOMET; androgenemia normalized faster with OC but rebounded more thereafter. Body weight, lean mass, and abdominal subcutaneous fat mass remained stable in both groups.
Conclusions
Early SPIOMET treatment for PCOS normalized post-treatment ovulation rates more than OC. Focusing PCOS treatment on early reduction of hepato-visceral fat may prevent part of later oligoanovulatory subfertility.
Dr. Garza-Flores and his colleagues have presented evidence of systematic differences in the pharmacokinetic profiles of depo medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) between Mexican and Thai women. Comparing these data with similar studies conducted in other regions (cited in the same paper), it appears that the pharmacokinetic parameter displaying the greatest variability between populations is the Cmax, the maximum concentration observed; it is the mean Cmax observed with DMPA among Thai women that is the most dramatic outlier.
In a total of 94 cows the mean back fat thickness (BFT) on Day 275 of pregnancy and 2 to 3 days after calving (peripartal) as well as between Days 42 and 44 post partum (postpuerperal) has been examined sonographically. Based on their BFT levels all examined cows have been divided into three groups: overconditioned, optimal conditioned and underconditioned cows. Cows which were peripartal overconditioned had more often ovarian cysts (p < 0.05) and were culled more frequently (p < 0.1) because of infertility than peripartal cows which were optimal or underconditioned. Nevertheless, the interval from calving to conception of peripartal cows being in different physical conditions was not significantly different. Postpuerperal cows which were overconditioned had more often ovarian cysts (p < 0.05) and were more frequently (p < 0.05) slaughtered because of infertility than postpuerperal cows which were optimal or underconditioned. Postpuerperal cows which were over- or underconditioned had a significantly longer interval from calving to conception than cows which were optimal conditioned 6 weeks after calving. The correlation coefficient between peripartal and postpuerperal BFT was 0.82 (p < 0.05). The decrease of BFT between the peripartal and postpuerperal timepoint had no significant influence on the frequency of ovarian cysts, he interval from calving to conception and the infertility caused culling rate.
This acclaimed text has been fully revised and updated, now incorporating issues including aging of the reproductive system, and updates on the chapters on conception and Gamete Transport and Fertilization, and Pregnancy. Human Reproductive Biology, 3rd edition emphasizes the biological and biomedical aspects of human reproduction, explains advances in reproductive science and discusses the choices and concerns of today. Generously illustrated in full color, the text provides current information about human reproductive anatomy and physiology. The ideal book for courses on human reproductive biology - includes chapter introductions, sidebars on related topics of interest, chapter summaries and suggestions for further reading.
The fourth edition of Human Reproductive Biology emphasizes the biological and biomedical aspects of human reproduction, explains advances in reproductive science and discusses the choices and concerns of today. Generously illustrated in full color, the text provides current information about human reproductive anatomy and physiology. This expansive text covers the full range of topics in human reproduction, from the biology of male and female systems to conception, pregnancy, labor and birth. It goes on to cover issues in fertility and its control, population growth and family planning, induced abortion and sexually transmitted diseases. This is the ideal book for courses on human reproductive biology, with chapter introductions, sidebars on related topics, chapter summaries and suggestions for further reading.
IntroductionBody composition and sports performanceBody composition and healthAssessment of body compositionRecommendations for future research
Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.
We report the glucose and insulin response to a 300-min glucose tolerance test among 17 women athletes as compared with 11 normal, nonatheletic controls. Also reported is the relationship of the insulin area under the curve as a function of percentages of total fat (TF), subcutaneous fat, and internal fat of total volume (TV) quantified by magnetic resonance imaging overall and at six regional sites. Athletes had a more sensitive insulin response to the glucose tolerance test as compared with controls. The insulin area under the curve of athletes and controls was significantly (p = 0.05) related to their overall TF/TV%; athletes had significantly less TF/TV% compared with the controls.
Excess upper-body (android) fat is considered an health hazard. Exercise training is known to have the potential to modify body composition and to induce a preferential loss of abdominal fat. We studied and compared the composition of whole body and major body regions using dual-energy X-ray absorptiometry (DEXA) in 21 exercising (3-4 hours of intense physical activity/day) and 21 sedentary eumenorrhoic women of similar ages, body mass index (BMI), waist-to-hip ratio (WHR) and age of menarche. In a small number of women in each group (6 out of 21), the ACTH and cortisol response to CRH test and the 24-h urinary cortisol excretion was evaluated. Exercising women had 10% higher total and leg lean mass (p<0.05), and 38% lower total fat mass (p<0.01) than sedentary women. Furthermore, the proportion of android fat was 22% lower in exercising than sedentary women (p<0.01), while the proportion of lower-body (gynoid fat) was unchanged. BMI and WHR were not different between the two groups, while the android/gynoid fat ratios were 16% lower in exercising than in sedentary women (p<0.01). In the exercising women, ACTH and cortisol plasma levels, as well as the 24-h urinary cortisol excretion, were significantly (p<0.01) higher than in the sedentary women studied. In these subjects, a direct relationship between the peak delta percentage increases of ACTH and cortisol after the CRH test and the proportion of android fat was found (r=0.60, p<0.05 and r=0.69, p<0.02, respectively). These results demonstrate that in women who practise intense exercise there are significant differences in body fat distribution in comparison to sedentary women, with a marked less amount of android fat, and suggest that this difference may be related to a reduced response of the pituitary-adrenal axis to CRH.
Breast cancer tissue is an endocrine organ and particularly the estrogen biosynthetic properties of this tissue have been well studied. The concentration of estradiol in breast cancer tissue from postmenopausal patients is considerably higher than that in the circulation and appears to depend largely on local production. Androgenic precursor steroids are abundantly present, but estrogen storage pools like fatty acid derivatives appear to be less important than initially thought. New, potent and highly specific aromatase inhibitors effectively inhibit peripheral conversion of androgens to estrogens (Cancer Res. 53: 4563, 1993) as well as intratumour aromatase, median aromatase activity being 89% lower in the tissue from patients pretreated with aromatase inhibitor 7 days prior to surgery (P < 0.001). Also the intratissue concentrations of estrogens were decreased (64% and 80% reduction, respectively for estrone and estradiol; P = 0.001 and <0.05; Cancer Res. 57: 2109, 1997). These results illustrate that intratissue estrogen biosynthesis is effectively inhibited by the new generation of aromatase inhibitors. The pathophysiological consequences of this finding are currently under study.
Bone loss prior to menopause may contribute to later risk of fracture due to osteoporosis. Women may be able to optimize premenopausal bone mass and/or prevent losses. Heredity, and possibly age at menarche (retrospectively determined), are unmodifiable risk factors and attention should therefore be directed to more amenable factors. Amenorrhea, low body weight, disordered eating, and smoking are modifiable risk factors. Vitamin D is not a factor for premenopausal women who receive incidental sun exposure and consume fortified foods, but supplementation should be considered for others, especially during the winter months. Protective factors include a higher body weight (especially due to increased muscularity), calcium supplementation, and purposeful load-bearing exercise. Positive effects of oral contraceptives are most apparent in women with menstrual irregularities. Reproductive history (parity), lactation, moderate intakes of alcohol and caffeine, and the appropriate treatment of endometriosis have no apparent effect on premenopausal bone.
Physicians commonly recommend estrogen replacement as treatment for exercise-associated amenorrhoea. While the evidence shows that the basis of the amenorrhoea is estrogen deficiency, it is not clear that it is the only factor in the development of lowered bone density found in oligo-amenorrhoeic female athletes. Nutritional factors, significant in the development of the reproductive dysfunction, could also contribute to bone loss. No randomised, controlled studies of estrogen replacement in athletes have been published. However, one nonrandomised study of a small group of athletes does suggest that there are significant gains in bone density to be made by the initiation of estrogen therapy. More research is clearly needed.
Physical activity has been associated with reduced breast cancer risk, potentially via hormonal pathways, and high urinary excretion of 2-hydroxyestrone (2-OH E(1)) relative to 16alpha-hydroxyestrone (16alpha-OH E(1)) also has been associated with reduced breast cancer risk. Studies suggest that body composition and exercise can influence estrogen metabolism. We determined the effects of a 12-month moderate intensity aerobic exercise intervention on urinary 2-OH E(1), 16alpha-OH E(1), and their ratio in overweight and obese, previously sedentary, postmenopausal women, ages 50-75 years. Women were randomized to a 12-month exercise intervention (n = 87) or stretching control group (n = 86); 170 completed the study. Urinary 2- and 16alpha-OH E(1) were measured in spot urines collected at baseline, 3, and 12 months. Body composition was measured at baseline and 12 months. Differences between exercisers and controls for excretion of estrogen metabolites were determined using general estimating equations. Further analyses assessed change in estrogen metabolites and their ratio by subgroups of change in body composition. Overall, there were no significant effects of the exercise intervention on 2-OH E(1), 16alpha-OH E(1), or their ratio (P > 0.05). There appeared to be an effect of change in intra-abdominal fat and adherence to the exercise intervention on change in the estrogen metabolites or their ratio. However, this did not reflect a potentially desirable change in estrogen metabolites associated with the exercise intervention. Thus, this 12-month moderate intensity exercise intervention did not significantly alter urinary excretion of 2-OH E(1), 16alpha-OH E(1), or their ratio in this population of women.
For this investigation 50 Brown Swiss cows from 21 different farms were used. Twenty-five peripartal overconditioned cows (back fat thickness > 38 mm) were compared with 25 peripartal not overconditioned animals (back fat thickness < 38 mm). On days 20, 30 and 40 post partum the ovaries were examined sonographically and 10, 15, 20, 30 and 40 days after calving plasma concentrations of progesterone and 17-beta estradiol were determined. In peripartal overconditioned animals 12 ovarian cysts were found while only one cyst was present in not overconditioned cows (P < 0.05). At first examination all ovarian cysts were classified by ultrasound as follicle theca cysts (progesterone < 0.5 ng/ml plasma). Follow examinations resulted in 3 cysts which persisted as theca cysts while 8 cysts became luteinized and 2 cysts completely regressed. There was no indication of increased plasma progesterone and/or estradiol concentrations in overconditioned cows with higher fat deposit before of ovarian cysts had occurred.
Disruptions in hypothalamic-gonadal and other endocrine axes due to energy deficits are associated with low levels of the adipocyte-secreted hormone leptin and may result in hypothalamic amenorrhea. We hypothesized that exogenous recombinant leptin replacement would improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea.
Eight women with hypothalamic amenorrhea due to strenuous exercise or low weight were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to three months. Six control subjects with hypothalamic amenorrhea received no treatment and were studied for a mean (+/-SD) of 8.5+/-8.1 months.
Luteinizing hormone (LH) pulsatility, body weight, ovarian variables, and hormone levels did not change significantly over time in the controls and during a one-month control period before recombinant leptin therapy in the treated subjects. In contrast, recombinant leptin treatment increased mean LH levels and LH pulse frequency after two weeks and increased maximal follicular diameter, the number of dominant follicles, ovarian volume, and estradiol levels over a period of three months. Three patients had an ovulatory menstrual cycle (P<0.05 for the comparison with an expected rate of spontaneous ovulation of 10 percent); two others had preovulatory follicular development and withdrawal bleeding during treatment (P<0.05). Recombinant leptin significantly increased levels of free triiodothyronine, free thyroxine, insulin-like growth factor 1, insulin-like growth factor-binding protein 3, bone alkaline phosphatase, and osteocalcin but not cortisol, corticotropin, or urinary N-telopeptide.
Leptin administration for the relative leptin deficiency in women with hypothalamic amenorrhea appears to improve reproductive, thyroid, and growth hormone axes and markers of bone formation, suggesting that leptin, a peripheral signal reflecting the adequacy of energy stores, is required for normal reproductive and neuroendocrine function.
Estrogen is metabolized in the body through two mutually exclusive pathways yielding metabolites with different biological activities: the low estrogenic 2-hydroxyestrone (2-OHE1) and the highly estrogenic 16alpha-hydroxyestrone (16alpha-OHE1). The ratio of these metabolites (2/16) may be predictive of risk for developing breast cancer. Early evidence has demonstrated that exercise may alter estrogen metabolism to favor the weak estrogen, 2-OHE1.
Seventy-seven eumenorrheic females completed physical activity logs for two weeks prior to providing a luteal phase urine sample. Concentrations of 2-OHE1 and 16alpha-OHE1 were measured and the 2/16 ratio computed. Hierarchical regression, controlling for age and body mass index (BMI), was used to determine relationships between estrogen metabolites and daily physical activity.
Regression analyses indicated significant positive relationships between physical activity and 2-OHE1 and the 2/16 ratio (p < 0.05) that appears to be independent of BMI. 16alpha-OHE1 was not significantly related to physical activity.
These results indicate that physical activity may modulate estrogen metabolism to favor the weak estrogen, 2-OHE1, thus producing a higher 2/16 ratio. This alteration in estrogen metabolism may represent one of the mechanisms by which increased physical activity reduces breast cancer risk.
Physical activity is a protective factor for breast cancer. Exposure to estrogen is an important determinant of breast cancer risk and exercise reduces estrogen levels, with the level of evidence being stronger for post-menopausal women. Possible mechanisms for estrogen induced breast cancer include increased breast epithelial cell proliferation, the metabolism of estrogen to genotoxic metabolites, such as DNA-adducts, and the silencing of tumor suppressor genes (TSGs) that have been implicated in breast carcinogenesis by inducing gene promoter hypermethylation, which is potentially reversible. Animal studies suggest that physical activity decreases breast tumor growth by promoting changes in cellular proliferation and apoptosis. Human studies provide some support for exercise producing favorable changes in estrogen metabolism that may lead to reduced breast epithelial cell proliferation. No studies have been performed to determine whether exercise decreases the accumulation of estrogen metabolite DNA-adducts in breast tissue. However, research supports the hypothesis that physical activity reduces promoter hypermethylation of TSGs implicated in breast carcinogenesis by lowering circulating estrogen levels. Thus, further research is necessary to clarify the mechanisms that relate to physical activity as a negative modulator of breast cancer risk to develop meaningful guidelines for the use of physical activity in breast cancer prevention.
The prevalence (lifetime occurrence) rate of cancers of the reproductive system (uterus, ovary, cervix and vagina) and breast cancer was determined for 5,398 living alumnae, 2,622 of whom were former college athletes and 2,776 non-athletes, from data on medical and reproductive history, athletic training and diet. The former athletes had a significantly lower risk of cancer of the breast and reproductive system than did the non-athletes. The relative risk (RR), non-athletes/athletes, for cancers of the reproductive system was 2.53. 95% confidence limits (CL) (1.17, 5.47). The RR for breast cancer was 1.86, 95% CL (1.00, 3.47). The analysis controlled for potential confounding factors including age, family history of cancer, age of menarche, number of pregnancies, use of oral contraceptives, use of oestrogen in the menopausal period, smoking, and leanness. Of the college athletes, 82.4% had been on pre-college teams compared to 24.9% of the college non-athletes. We conclude that long term athletic training may lower the risk of breast cancer and cancers of the reproductive system.
The oxidative metabolism of estradiol was studied in normal men and women by a radiometric procedure that provides information on the totality of the biotransformations concerned. The release of 3H into body water from estradiol labeled with 3H in the 17 alpha, 16 alpha, and C-2 positions permits measurement of the rate and extent of 17 beta-ol oxidation and of the competing hydroxylations at C-2 and 16 alpha, which lead to products with different biologicaly properties. In both men and women the 17 beta-ol oxidation is the most rapid transformation, followed by 2-hydroxylation and finally by 16 alpha-hydroxylation. Hydroxylation at C-2 predominates by a faccto of 2-4 over 16 alpha-hydroxylation. In men a large fraction (37%) of the substrate is unmetabolized at any of the three sites and is not excreted in urine; in women the corresponding fraction is only 18%. The estradiol fraction that does undergo metabolism is hydroxylated at C-2 vs. 16 alpha to a greater extent in women than in men. These major sex differences in the metabolism of estradiol in the human may have an important influence on the expression of the biological actions of the hormone. The radiometric technique used in this study can be generally applied to study the oxidative transformations of hormones, drugs, and other exogenous chemical that can be specifically labeled at reactive sites.
Young female ballet dancers attending professional schools or dancing in companies in which thinness is much admired restrict their food intake and are highly active. The unusual eating habits and levels of activity of some of these dancers have been related to lack of menstrual cycles. Amenorrhea and late menarche among girls and women with average activity levels are associated with undernutrition and weight loss in the range of 10 to 15 per cent of the normal weight for height; such weight loss apparently reduces the fat/lean ratio to less than a critical level. The authors report here on 89 young ballet dancers among whom there was a high incidence of primary amenorrhea, secondary amenorrhea, irregular cycles, and delayed menarche - an incidence correlated with excessive thinness.
The metabolism of adipocytes from severely obese patients was investigated before and after weight was reduced by jejuno-ileal by-pass. After weight reduction lipolysis and glucose incorporation into triglycerides were decreased as was the cell size. The effect of submaximal concentrations of insulin on glucose incorporation increased with weight reduction implying increased cellular insulin sensitivity.
The rate of glucose incorporation and basal lipolysis in the adipocytes correlated directly with the fasting plasma insulin level before weight reduction. After weight reduction there was a positive correlation between the decrease in glucose metabolism and the reduction in the plasma insulin level. These data support the concept that plasma insulin may be important for the long-term regulation of glucose metabolism and lipolysis in fat cells.
In other patients with normal body weight, studies on regional differences in adipocyte metabolism showed that fat cells from the subcutaneous abdominal region responded better to both noradrenaline and insulin than femoral fat cells. The differences between these sites were less pronounced during incubation with isopropylnoradrenaline, suggesting there was increased α-receptor activity in the femoral region.
Adipocytes in the abdominal subcutaneous region are thus metabolically much more active than those in the femoral region. This might explain why several blood parameters such as arterial free fatty acid and glycerol levels correlate with lipolysis of abdominal but not femoral cells and why plasma insulin and triglyceride levels correlate with abdominal but not femoral fat cell size. Also, the responsiveness of adipocytes in the abdominal region may explain why cells in this region decreased more in size than those in the femoral region during weight reduction.
Omental fat cells were 30% smaller than those in subcutaneous regions. In omental fat cells with a mean diameter of 95 mu, the basal cAMP concentration was 50% lower, but the basal rate of glycerol release was three times as rapid as in subcutaneous (epigastric) fat cells of identical size. Added at maximal effective concentration, noradrenaline increased the level of cAMP and the rate of glycerol release more markedly in the omental than in the subcutaneous adipocytes, whereas the response to isopropyl noradrenaline was similar. Before starvation the lipolytic effects of noradrenaline and isopropyl noradrenaline, respectively, were identical in the two regions of subcutaneous adipose tissue investigated (femoral and hypogastric). The findings were well related to the tissue levels of cAMP induced by the two agents. During starvation noradrenaline and isopropyl noradrenaline increased the cAMP level and the rate of lipolysis in fat cells obtained from the hypogastric region, whereas noradrenaline decreased these parameters in femoral adipocytes. Starvation was associated with a more prominent inhibitory effect of phenylephrine on basal and isopropyl-noradrenaline-induced lipolysis in femoral than in hypogastric adipose tissue. In conclusion, differences exist between different regions of adipose tissue in their lipolytic responsiveness to noradrenaline, which seems related to the balance between alpha- and beta-adrenergic receptor response.
We tested hypothalamic, pituitary and endocrine function in 19 patients with secondary amenorrhea associated with simple weight loss who did not have anorexia nervosa to evaluate the effects of weight loss on these systems. Thermoregulation at 10 degrees C and 49 degrees C was abnormal and correlated with the percentage below ideal body weight (r = 0.62, P less than 0.02, and r = 0.55, P less than 0.05, respectively). Partial diabetes insipidus was found in 27 per cent of patients with simple weight loss. They had delayed peak plasma luteinizing hormone levels after 10 microgram of luteinizing-hormone-releasing factor, which was correlated with percentage below ideal body weight (r = 0.49, P less than 0.05). Delayed peak plasma thyrotropin levels after 500 microgram of thyrotropin-releasing factor were found. No prolactin, pituitary, thyroid or adrenal abnormalities were present. These findings are qualitatively similar to results of studies in 29 patients with anorexia nervosa, but less severe and less frequently present. We conclude that hypothalamic dysfunction may be caused by weight loss per se.
The extent of 2-hydroxylation of estradiol (E2), which yields a non-estrogenic metabolite (2-OHE1), increased significantly with decreasing subcutaneous fat (ScF)/total volume percent (TV%) and total fat (TF)/TV% evaluated by magnetic resonance imaging (MRI) for five athletes during low- and high-intensity training, and four controls. The increase in 2-hydroxylation with decreasing adiposity was associated with anovulation and amenorrhea among the athletes.
Osteoporosis develops in women with estrogen deficiency and amenorrhea who lose bone at an accelerated rate. It is not known to what extent bone loss differs between ovulatory women with regular menstrual cycles who are training intensely and those who are sedentary.
We measured the density of cancellous spinal bone from the 12th thoracic vertebra to the 3rd lumbar vertebra by quantitative computed tomography on two occasions one year apart in 66 premenopausal women 21 to 42 years of age. All the women had two consecutive ovulatory cycles immediately before entering the study. Twenty-one women were training for a marathon, 22 ran regularly but less intensively, and 23 had normal levels of activity. The lengths of the women's menstrual cycles and luteal phases, diet, exercise levels, and hormonal levels were also determined. We defined ovulatory disturbances as anovulatory cycles and cycles with short luteal phases.
The mean (+/- SD) spinal bone density in the 66 women decreased 3.0 +/- 4.8 mg per cubic centimeter per year (2.0 percent per year) (P less than 0.001). Amenorrhea did not develop in any woman during the year of observation (only 2.7 percent of the cycles were greater than 36 days long). Ovulatory disturbances occurred in 29 percent of all cycles, however. Bone loss was strongly associated with these disturbances (r = 0.54, 24 percent of the variance). The 13 women who had anovulatory cycles lost bone mineral at a rate of 6.4 +/- 3.8 mg per cubic centimeter per year (4.2 percent per year). The women training for a marathon had menstrual cycles similar to those of the women in the other two groups.
Decreases in spinal bone density among women with differing exercise habits correlated with asymptomatic disturbances of ovulation (without amenorrhea) and not with physical activity.
Adipocyte size, lipoprotein lipase (LPL) activity, and the lipolytic response to noradrenaline and isoproterenol were studied in three intraabdominal depots (mesenteric, omental, retroperitoneal), as well as in subcutaneous abdominal adipose tissue, in nonobese groups of middle-aged men and in premenopausal and postmenopausal women. Subcutaneous adipocytes were larger than intraabdominal adipocytes in all groups. The men had large adipocytes in all intraabdominal depots as compared with the women. The premenopausal women seemed to have low LPL activity in intraabdominal depots. Two types of responses to catecholamine-stimulated lipolysis were observed: a similar response from mesenteric and omental (portal) fat depots and from retroperitoneal and subcutaneous abdominal (nonportal) fat depots. Young women had higher lipolysis in nonportal than in portal adipose tissues. In the men the reverse characteristics were found. These dissimilarities seem to be based on differences in beta-adrenergic responsiveness. Postmenopausal women showed no differences between depots. The differences in lipolytic responsiveness between these groups might be caused by sex steroid hormones.
Adipose tissue lipolysis and lipoprotein lipase (LPL) activity were studied in biopsies from the femoral and abdominal depots in healthy women during early or late menstrual cycle, pregnancy, and the lactation period. When the differences in cell size were taken into account, basal lipolysis was similar in both regions in nonpregnant women. During lactation, however, lipolysis was significantly higher in the femoral region. The lipolytic effect of noradrenaline (10(-6) M) was significantly less in the femoral region in the nonpregnant women and during early pregnancy. However, the lipolytic response was the same in both regions in lactating women. LPL activity was higher in the femoral than in the abdominal region except during lactation when a marked decrease in the LPL activity was seen in the femoral region. The LPL activity in the abdominal region remained unchanged in all patient groups. The results imply that in both nonpregnant and pregnant women lipid assimilation is favored in the femoral depot. During lactation, however, the metabolic pattern changes; the LPL activity decreases and lipid mobilization increases in this depot. These changes are much less pronounced in the abdominal region. Thus, fat cells from different regions show a differential response during pregnancy and lactation. These results suggest that the adipose tissue in different regions may have specialized functions.
Weight loss causes loss of menstrual function (amenorrhea) and weight gain restores menstrual cycles. A minimal weight for height necessary for the onset of or the restoration of menstrual cycles in cases of primary or secondary amenorrhea due to undernutrition is indicated by an index of fatness of normal girls at menarche and at age 18 years, respectively. Amenorrheic patients of ages 16 years and over resume menstrual cycles after weight gain at a heavier weight for a particular height than is found at menarche. Girls become relatively and absolutely fatter from menarche to age 18 years. The data suggest that a minimum level of stored, easily mobilized energy is necessary for ovulation and menstrual cycles in the human female.