Natural Menopause Relief Secrets

Women's Midlife Revolution Summit

The Women's Midlife Revolution Summit is an online event that presents a wonderful opportunity for women to learn, bond and share in the privacy of their homes. The interviews of the day will be online viewable for 24 hours for absolutely FREE, starting at 10:00 am. And every day for eleven days, there will be another set of experts videos releasedfor 24 hours for FREE viewing. This will be 11 days packed with knowledge, experience, inspiration, and wisdom as Arnold interviews 22 female professionals, releasing two new interviews per day over this 11-day period. Female nutritionists, doctors, herbalists, holistic therapists, authors, life coaches, entrepreneurs, hormone experts, and physical trainers have all been gathered to lend credence to the joy of seasoned womanhood. Registration is free. You will be required to fill a registration form. After filling the form you will receive an email to click on a link to confirm your participation. Then 3 days before the event starts, you will receive the Playbook for this event, which you can download.You can join the talks easily on your PC, Tablet, Laptop or Cellphone. It is time to shed light on the myths and lies women are told about aging and let women reclaim their power. More here...

Womens Midlife Revolution Summit Summary

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Bone Density in Premenopausal Women

Hansen (9) evaluated 249 healthy premenopausal women whose average age was 39 years, measuring BMD at the distal forearm using SPA and at the PA spine and proximal femur using DXA (Hologic QDR-1000). In this study, no decline in BMD was seen at any site after age 30 and peak BMD appeared to be reached prior to age 30. Two other large cross-sectional studies have suggested that BMD in the proximal femur does decline in women prior to menopause. Rodin et al. (10) found a significant premenopausal decline in femoral neck BMD in a study of225 women who ranged in age from 18 to 52. Similarly, Bonnick et al. (11) found a decline in proximal femoral BMD after the age of 30 in a study of 237 premenopausal women ages 20 to 45. In this latter study, no increase in BMD in the spine or proximal femur was seen in any age group, suggesting that peak BMD in both regions was achieved prior to the age of 20. There was no significant change in spine BMD, again suggesting that spine BMD does not change....

Dissimilar BMDs Between Skeletal Sites at Peak and Prior to Menopause

Two hundred thirty-seven premenopausal women between the ages of 20 and 45 were evaluated with DXA (Lunar DPX) measurements of the PA spine and proximal femur to determine if differences exist in z-scores for the spine and proximal femur (11). The reference population for the calculation of the mean BMD and the SD were the 20- to 29-year-old women of the study population. Twenty to 24 of the 20 to 29-year-old women had differences in z-scores of more than1 between the lumbar spine and any of the three sites in the proximal femur (neck, Ward's, trochanter). In the 30- to 45-year-old women, however, this percentage increased to 32 to 46 . In the younger age group, the percentage of women having higher z-scores in the spine or higher z-scores in the proximal femur was roughly equally split. In the older age group, however, there was clearly a shift in percentages favoring a higher z-score in the spine. This appeared to be due to the earlier onset of bone loss from the proximal femur in...

Bone Density in Perimenopausal Women

Changes in spine BMD in pre-, peri- and postmenopausal women were evaluated in a longitudinal study by Pouilles et al. (13). The subjects were 230 Caucasian women ranging in age from 45 to 66 years. Menopausal status was determined by menstrual history and estradiol and LH levels. Based on these determinants, 71 women ages 45-51 were premenopausal throughout the study, 42 women ages 47-57 experienced menopause during the study and were considered perimenopausal, and 117 women were postmenopausal throughout the study. BMD in the PA spine was assessed using DPA. The women were followed for an average of 27 months. Bone loss in the premenopausal women averaged 0.8 per year. In the perimenopausal women, bone loss was 2.3 per year. In the postmenopausal women, bone loss was again 0.5 per year. The authors noted that approximately half the bone loss observed in the first 10 years after menopause was seen in the first 3 years after menopause. There was no difference in the rates of bone loss...

Dissimilar Spine and Femoral BMDs in Perimenopausal Women

Eighty-five Caucasian women between the ages of 45 to 60 who were within 6 months to 3 years past menopause underwent spine and proximal femur bone density testing using DXA (Lunar DPX) (15). These values were compared with reference values (mean and SD) from a group of 30 healthy women between the ages of 40 to 45. Thirty-nine women had both spine and femoral neck z-scores that were better than -1. Seventeen women had both spine and femoral neck z-scores that were both poorer than -1. Out of the 85 women, 22 (26 ) had dissimilar spine and femoral neck z-scores. Eight had spine z-scores that were better than -1 but femoral neck z-scores that were poorer than -1. Fourteen had femoral neck z-scores that were better than -1 but spine z-scores that were poorer than -1. In a similar study, Lai et al. (16) evaluated 88 Caucasian women, ages 44 to 59, who were within 5 years past menopause. BMD measurements of the lumbar spine and proximal femur were made using DXA (Hologic QDR-1000). The...

Estrogen Deficiency Postmenopausal

Ninety-three healthy women who had experienced a natural menopause 6 to 60 months earlier were followed prospectively for two consecutive 22-month periods (38). BMD was measured in the spine and proximal femur using DXA (Lunar DPX). The average decline in BMD in the spine was 1.46 per year (+2.6 to -6.9 ) in the first period and 1.28 per year (+2.8 to -5.3 ) in the second period. In the proximal femur, the average decline in the first period was 1.41 per year (+4.8 to -6.8 ) and 1.35 per year (+1.8 to -7.0 ) in the second. Individual rates of bone loss were not stable over time. Only 20-30 of women retained their initial classification as fast, intermediate, or slow losers during both observation periods. Of 24 women classified as fast losers during the first observation period, 5 remained fast, 12 became intermediate, and 5 became slow losers during the second period. The mean rate of loss in the fast loser group initially was -3.9 . Women who were originally classified as slow...

Hormonal Changes In Menopause

Menopause is defined as cessation of menstruation and fewer remaining follicles causing infertility, generally at around 50 years of age. Perimenopause, the period of time leading into the menopause in women, is often characterized by irregularity in length of the menstrual cycle. Perimenopause is marked by dramatic changes in the hypothalamic-pituitary-ovarian axis. An early finding is a rise in circulating FSH levels unaccompanied by a rise in LH. It has been suggested that there is a decreased secretion of ovarian inhibin along with the decreasing follicular pool, which may be the primary cause of the rise in FSH. The resultant ovarian changes include short follicular phases with early ovulation, and ovarian insufficiency characterized by lower levels of estrogen and progesterone secreted for shorter periods of time compared with the luteal phase of younger women. The major significant endocrine event in women in the early perimenopausal phase is a fall in the circulating levels of...

North American Menopause Society Recommendations

The North American Menopause Society (NAMS) published a comprehensive review of postmenopausal osteoporosis in the journal Menopause in 2002 (14). Included in the review were recommendations for bone density testing in the specific context of osteoporosis prevention and management. NAMS noted that measurement of BMD is the preferred method for diagnosing osteoporosis and that DXA is the technological standard for measuring BMD. NAMS stated that the total hip was the preferred region of interest to evaluate, particularly when measuring bone density in women over 60 because of the increased likelihood of degenerative calcification in the spine that would affect spine measurements.3 Nevertheless, spine measurements were described as useful in early postmenopausal women because of the faster rate of bone loss at that site compared to the rate seen at the proximal femur. Citing a report from the International Osteoporosis Foundation (IOF) published in 2000 (15), NAMS stated that they...

Premenopausal Women

There are little preclinical and clinical data on the utility of fulvestrant in premenopausal women, and fulvestrant does not have an indication for this group. A phase II, second-line trial is investigating the 500 mg IM dose of fulvestrant in premeno-pausal women with hormone receptor-positive ABC who have not been exposed to endocrine therapy. Up to three courses of chemotherapy for metastatic disease are allowed (69). A phase II neoadjuvant study comparing 750 mg IM fulvestrant (single dose) versus 20 mg tamoxifen daily for two weeks prior to surgery will assess tumor marker changes in premenopausal women (10).

Medical guidelines for the prevention and management of postmenopausal osteoporosis

For risk assessment in perimenopausal or postmenopausal women who have risk factors for fractures and are willing to consider available interventions. 8. In younger postmenopausal women who have risk factors. (From Osteoporosis Task Force. American Association of Clinical Endocrinologists 2001 medical guidelines for clinical practice for the prevention and management of postmenopausal osteoporosis. Endocr Pract 2001 7 293-312.)

Postmenopausal hormone replacement therapy HRT

HRT refers to the use of oestrogen treatment in order to reverse or prevent problems due to the loss of ovarian hormone secretion after the menopause, All types of HRT (oestrogen with or without progestogen) are effective in reducing the hot flushes experienced by more than 50 of postmenopausal women. The benefit is most during the first year of treatment when 80 of women report a reduced likelihood of flushes, and becomes less as the frequency of flushing diminishes, even in the placebo treated groups in trials. The other major value from HRT is the relief of vaginal dryness. Vaginal administration is the most effective route for treatment of dyspareunia and related symptoms. ment Study (HERS)6 daily therapy with conjugated oestrogen and progestin did not reduce the incidence of coronary events during four years of follow-up. The trial was too small to be informative about hip fractures but there was no difference in overall fracture rate between the groups. More recently, the...

Menopause

Menopause is the permanent cessation of the menstrual periods that occurs around age 50 in most women. As a woman moves into her late 40s, her body's estrogen production slows down, and she gradually stops ovulating. Symptoms of the menopause include hot flashes, headaches, fatigue, vaginal irritation, mood swings, and depression. These symptoms can range from mild to severe about one in five women seek medical attention for symptoms of the menopause. A major concern at the menopause is the loss of bone mineral (mainly calcium) from the skeleton due to the loss of estrogens.21 Up to 20 of the bone mineral density can be lost at menopause, which can sharply increase risk of osteoporosis and bone fractures. The loss of estrogen at menopause also causes LDL cholesterol levels in the blood to rise and levels of HDLcho-

Diet Menopause

Women going through menopause should increase intake of rich food sources of calcium, magnesium, and vitamins D and K to maintain integrity of the skeleton.23,24 In addition, high amounts of phosphorus (found in red meat, processed foods, and cola drinks) should also be avoided too much phosphorus in the diet accelerates loss of minerals from bones. Reducing sodium, caffeine, and protein intake can also help maintain body stores of calcium. To keep levels of blood fats in the healthy range, the saturated fat content of the diet should be reduced (by eating less meat, eggs, and whole-fat milk products).

Preferred Form and Dosage Schedule

Villareal DT, Civitelli R, Chines A, et al. Subclinical vitamin D deficiency in postmenopausal women with low vertebral bone mass. J Clin Endocrinol Metab. 1991 72 628. 8. Dawson-Hughes B, et al. Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Intern Med. 1991 115 505.

Caveats and Qualifications

Are more likely to suffer from inflammatory pain that is often more intense and longer lasting than that in men (159-161). While there are a number of mechanisms that may contribute to this difference, evidence from both clinical and preclinical studies suggests that gonadal hormones, in particular estrogen, may be a critical factor. Its mechanisms of action are complex, as estrogen has been shown to influence structures relevant to nociception throughout the body. Timing, with respect to estrogen cycling or the sustained application of estrogen (as in the case of hormone replacement therapy), site of action, and dependent measures of nociception all appear to be important factors when assessing the impact of estrogen on specific aspects of nociceptive processing (120).

Alcoholic drinks and mortality

The benefit is largely a reduction of deaths due to cardio- and cerebrovascular disease for regular drinkers of 1-2 units d for men over 40 years and postmenopausal women. Consumption over 2 units d does not provide any major additional health benefit. The mechanism may be an improvement in lipoprotein (HDL LDL) profiles and perhaps a reduction in platelet aggregation.

Estimated Time To Complete

Radiographic Absorptiometry

The utility of modern-day RA in predicting hip fracture risk was suggested by an analysis of data acquired during the first National Health and Nutrition Examination Survey (NHANES I, 1971-1975). During this survey, 1559 hand radiographs of Caucasian women were obtained with the older technique of photodensitometry using the Texas Woman's University wedge (27). During a median follow-up of 14 years that extended through 1987, 51 hip fractures occurred. Based on radiographic photodensi-tometry of the second phalanx of the small finger of the left hand, the risk for hip fracture per SD decline in bone density increased 1.66-fold. These films were then re-analyzed using RA with some compensation for the differences in technique. This re-analysis yielded an increase in the risk for hip fracture per SD decline in RA bone density of 1.81fold. Huang and colleagues (28) evaluated the utility of RA in the prediction of vertebral fractures. They followed 560 postmenopausal women, average age...

Osteocalcin in Cell Proliferation and Differentiation

Other hormones, such as thyroid hormones, that regulate the differentiation of osteoblasts also seem to function through the mediation of osteocalcin. Triiodothy-ronine (T3) has been found to inhibit the proliferation of the osteoblast-type MC3T3-E1 cells and, in parallel, induce the expression of osteocalcin mRNA and protein and alkaline phosphatase activity (Varga et al. 1997 Luegmayr et al. 1998). Oestrogen has been reported to increase cell proliferation in the early stages of in vitro culture of osteoblasts derived from mouse bone marrow. The effects of oestrogen seem to involve the osteoblast-specific transcription factor osf2 (cbfa1) (Sasaki-Iwaoka et al. 1999). Oestrogen increases the expression of osteocalcin, alkaline phosphatase, osteopontin, and transforming growth factor (TGF)p-1 as well as collagen type 1. Furthermore, exposure to oestrogen also increased the formation of bone nodules. Anti-oestrogens (Qu et al. 1998) blocked all these effects. Post-menopausal breast...

Epidemiology and Pathogenesis

The peak in HPV prevalence among women younger than 30 years of age is followed by a decline in prevalence until age 45-50 and then a second peak in the peri- or postmenopausal years (Trottier and Franco 2006). Although the reason for this second, menopausal peak is not clear, it could be attributed to mechanisms, such as reactivation of latent infections acquired earlier in life due to a gradual loss of type-specific immunity or to acquisition of new infections due to sexual contacts with new partners later in life.

The Role of Sex Hormones

The relationship between steroid hormones and cancer production introduces serious concerns regarding hormone replacement therapy, particularly for women, to minimize bone loss in the elderly. Hormone replacement therapy can alleviate some of the symptoms of osteoporosis in men and women, but it may do so at the risk of developing cancer. Similar concerns exist in the sporting world, where steroids are used to enhance performance. While such treatments seem to be effective, the athlete who uses hormone supplements will likely pay a heavy price for it in later life by developing prostate, breast, or uterine cancer.

Epidemiologic Risk Factors

In addition to age over 50 and Caucasian race, an increased number of ovulatory cycles appears to increase risk for ovarian cancer, reflected in an association with early menarche, late menopause, and nulliparity (Berek and Bast 2006). Conversely, factors that decrease the number of ovulatory cycles, including repeated pregnancies, prolonged breast feeding and use of oral contraceptives, decrease the risk of ovarian cancer. A protective effect from tubal ligation suggests that exogenous carcinogens might gain access to the ovary from the uterus through the fallopian tube. However, evidence for viral or strong chemical carcinogens has not been obtained, with the possible exceptions of the use of talc products in all histotypes and of cigarette smoking in mucinous cancers, but not in the more common serous histotype (Berek and Bast 2006). Approximately 10 of ovarian cancers are familial and are associated with mutations in BRCA1, BRCA2 or, less frequently, with the mismatch repair...

Aging and the Incidence of Cancer

The increased incidence of cancer in those age 50 and older is also coincidental with the onset of sexual senescence in both men and women. It is quite possible that the hormonal changes that occur during this period contribute to our increased susceptibility to cancer. Age-related hormonal changes are primarily concerned with a shift in the ratio of estrogen to testosterone (ET ratio) in both men and women. Young women have a high estrogen testosterone ratio (a lot of estrogen, very little testosterone), whereas young men have a low estrogen testosterone ratio (a lot of testosterone, very little estrogen). Estrogen levels drop dramatically in women after menopause, and men show a similar decline in the level of testosterone at a corresponding age. As a consequence, men and women approach a similar ET ratio between the ages of 50 and 80, which is thought to influence the rate at which genetic instability occurs. In addition, many scientists believe the shift in the ET ratio is largely...

Early Detection of Ovarian Cancer Rationale

Positive predictive value of 19 (Menon et al. 2005). Based on the results of this preliminary study, a large randomized trial (UKCTOCS) was undertaken. A total of 200,000 postmenopausal women have been randomized to three groups 100,000 controls are followed with conventional pelvic examination annually 50,000 undergo annual TVS and 50,000 are monitored with annual CA125 with TVS performed if the risk of ovarian cancer is sufficiently high as judged by the Skates algorithm. Women will be followed for 7 years to determine whether screening improves survival.

Osteoporosis Screening

The prevalence of low bone mineral density in the elderly is high, with osteopenia found in 37 of postmenopausal women. Primary prevention of osteoporosis begins with identification of risk factors (older age, female gender. White or Asian race, low calcium intake, smoking, excessive alcohol use, and chronic glucocorticoid use). Calcium carbonate (500 mg three times daily) and vitamin D (400-800 lU d) reduce the risk of osteoporotic fractures in both men and women. Bone mineral density testing using dual-energy x-ray absorptiometry (DEXA) of patients with multiple risk factors may uncover asymptomatic osteoporosis.

Toward a Biological Definition of Aging

Reduced production of sexual hormones by the gonads is the most obvious manifestation of endocrine senescence and may affect development and growth of hormone-dependent tumors, such as prostatic, mammary, and endometrial cancer. It is important to remember that the activity of sexual hormones is also influenced by body size and shape. With aging, abdominal deposition of fat becomes more common and is associated with increased aromatization of androgens and circulating levels of estrogens (17). In addition, abdominal obesity is associated with decreased concentrations of sexual hormone-binding proteins in the circulation (17). For this reason, obesity may favor the development of breast cancer in postmenopausal women and favor its recurrence after surgery. Obesity may also be associated with increased insulin resistance, increased circulating levels of insulin and, consequently, of growth hormone and of insulin-like growth factor 1 (IGF-1), that is, a powerful growth stimulator of...

Autoantibodies Against Oncoproteins

For example, the frequency of pi85HER-2 neu AAb js highest in women with premenopausal breast cancer because there is also highest frequency of HER-2 neu protein overexpression 7 , In conclusion, there is a further need for studies of the clinical and biological nature concerning humoral autoimmune responses to oncoproteins such as (a) the evaluation of diagnostic relevance (diagnostic sensitivity and specificity) and the prognostic significance (correlation with the stage of the disease and survival) in defined patient groups using optimized and standardized methods (b) the search for associations of antibody titers with disease progression or relapse and therapeutic effects (c) the search for possible mechanisms of AAb induction (correlation with protein overexpression, mutations or presence of oncoproteins in the circulation) and (d) the search for possible effects of AAb on tumor cells.

Sexual Development Reproductive Patterns and Sexual Behavior

The duration of hormonal exposure appears to play a role in the susceptibility to breast cancer in women. The carcinogenic effects ofhormones were first demonstrated in animals. In 1932, Lacassagne reported the induction of mammary carcinomas in mice injected repeatedly with an ovarian extract containing estrogen. Later, he also showed that the synthetic estrogen diethyl-stilbestrol produced mammary tumors in susceptible strains of mice.76 Furthermore, ovariecto-mized mice and rats have a decreased frequency of breast cancer, whereas rodents subjected to increased levels of estrogen, progesterone, and prolactin have an increased frequency of breast cancer, although timing of exposure to individual hormones appears to be crucial.77,78 Similarly in humans, a role of hormones in the development of breast cancer has been deduced from the known risk factors associated with the disease. These factors include early age of menar-che, delayed age of first pregnancy, and delayed menopause,...

Air and Water Pollutants

Establishing the fact that about two-thirds of all human cancers have an environmental cause and thus, theoretically at least, are preventable. This has led many people to believe that the environmental agents responsible for cancer are chemicals that we inhale or ingest. However, as Hig-ginson himself has reiterated,101,102 what he meant by the environment is the total milieu in which people live, including cultural habits, diet, exposure to various infectious agents, average age of menarche, number of children a woman bears, age of menopause in short, the cultural as well as the chemical environment.

Genomic Changes Induced by Pregnancy in Breast Epithelial Cells

The collections of normal breast tissue that adhere to well-established parameters of normality are extremely difficult to obtain (J. Russo et al. 1988), mainly because the normal human breast tissue must be obtained from women with different reproductive histories. One group must represent the low-risk group composed of post-menopausal women without breast cancer who completed their first full-term pregnancy (FFTP) before age 24. The second group for comparison is postmenopausal women without breast cancer who are nulliparous. The selection of post-menopausal women must be those who are at least 1 year after their last menses if menopause occurred naturally or basal serum follicle stimulating hormone (FSH) greater than 40 ng ml if menopause was surgical and the participant is less than 60 years old. The age at menarche, day of last menstruation, number of miscarriages, year of first full-term pregnancy, number of pregnancies, and no replacement therapy or previous surgical procedures...

Fat Mass and Distribution Changes Total Adipose Tissue

Little is known about age-related changes in body fatness in elderly adults. Most studies have documented increases up to 50-60 years of age, after which body fatness appears to stabilise 13-16 . In a cross-sectional survey, Baumgartner et al. 6 suggest that body fatness (in terms of both absolute FM and percent body fat) may be relatively stable in elderly men, but may decrease with age in elderly women. In their study, the distribution of body fat, as assessed by DEXA, did not appear to change with age beyond 65 years, leading to the conclusion that the accumulation of abdominal and visceral fat with age (in both men and women) occurs primarily in middle age, while FM remains constant or increases slightly in subsequent decades. In a longitudinal observation of body composition in older adults, as determined using hydrodensitometry, Hughes et al. 17 found an overall increase in adipose tissue in an older cohort, but this increase was attenuated with advancing age in women, whereas...

Periodontal Diseases In Older Adults Etiology

Some medications that are frequently prescribed to older adults can alter the gingival tissues. Steroid-induced gingivitis has been associated with postmenopausal women on steroid therapy. Gingival overgrowth can he induced by certain medications such as cyclosporines, calcium channel blockers, and anticonvulsants (e.g., nifedipine or phenytoin) in the presence of poor oral hygiene. This gingival overgrowth further decreases a person's ability to maintain good oral hygiene.11

Influence ofAge and Gender

Several noncardiac factors may influence the circulating levels of natriuretic peptides and potentially confound the relation to indices of cardiac function. Age has been shown to be an important determinant of circulating natriuretic peptide levels (216-218). Both increased release and decreased clearance may contribute to elevated circulating levels of BNP and NT-proBNP in advanced age, but the exact mechanisms remain to be elucidated. Subclinical reduction in renal function, increased LV mass, and LV diastolic dysfunction are factors that may be essential for the observed increments in BNP and NT proBNP levels with age. Population-based studies have convincingly shown that BNP and NT-proBNP levels not only increase with age but are also significantly higher in women than in men (216-218). The association between female gender and BNP may be owing to estrogen status, because BNP levels were found to be higher in women using hormone replacement therapy (217).

Cancer and the North American Diet

The realization that fat cells have an endocrine function came as a surprise to physiologists and endocrinologists. Normally, hormone production is regulated by an area in the brain called the hypothalamus, which in turn controls the pituitary gland, the so-called master gland of the body. Stimulation of the pituitary gland by the hypothalamus leads to the production and release of pituitary hormones that regulate the activity of secondary glands and tissues throughout the body. A specific example is the control of the ovaries and the reproductive cycle. In this case, the pituitary gland releases follicle-stimulating hormone (FSH), resulting in the growth and development of ovarian follicle cells. These cells, under the influence of FSH, begin to synthesize and secrete large amounts of the hormone estrogen. The physiological role of estrogen is to stimulate the growth and development of the mammary glands for eventual lactation, and of the uterine lining, in preparation for...

Targets for Estrogen Deprivation Within the Breast

Available evidence suggests that the normal breast is highly responsive to ED and shuts down proliferative activity within lobules. In premenopausal women, this phenomenon is exemplified by a marked decline in epithelial proliferation during the ED of the follicular phase of the menstrual cycle (Fig. 2a Potten et al. 1988). The pro-liferative response of the breast declines before the menopause (Fig. 2a) and there is low proliferation in postmenopausal lobules (Fig. 2d). Low proliferative activity in postmenopausal lobules is surprising since many authors have demonstrated that the concentrations of estradiol and precursor steroids are similar in normal postmenopausal breast tissue and nipple aspirate fluid to the con centrations seen in tissue or fluid in premenopausal women (Blankenstein et al. 1992 Bonney et al. 1983 Chatterton et al. 2004 Pasqualini et al. 1996 Geisler 2003), although they are not as high as E2 concentrations found in tumours. The requirement of the normal...

Resistance to Estrogen Deprivation

Although ED at the menopause or associated with early menopause or treatment with AIs reduces the incidence of breast cancer, it is clear that only a proportion of tumours are prevented (Fig. 1). The protective effect of the menopause appears to be declining in many parts of the world, particularly in the West. Reduction is exemplified by data from the United States collected as part of the SEER programme. Figure 5a shows the age incident curves for breast cancer for the period 1973-1977 compared with those from 1993-1995 for whites, blacks and other races (Karagas et al. 2000). Irrespective of ethnic group, there was a reduction in the angle of the age incidence curve at the menopause in the latter time period, indicating an increase in the numbers of postmenopausal breast cancers. This change may, in part, be related to differences in methods of cancer detection, but increases in postmenopausal breast cancer are also seen in non-screened populations. Yasui and Potter (1999)...

Treatment Strategies to Prevent Resistance to Estrogen Deprivation

The treatment strategies to reduce the known relative resistance to the ED of the menopause include premature ovarian suppression in pre-menopausal women and the use of potent AIs in postmenopausal women. Pike et al. (1999) suggested the use of luteinising hormone-releasing hormone analogues (LHRH) to cause ED with various types of add-back hormones to prevent flushes and bone loss (low-dose estradiol and low-dose androgens) and intermittent progesterone to protect the uterus. Spicer and Pike (2000) showed that this approach was feasible and we have conducted similar studies of 2 years of the LHRH agonist, goserelin, with add-back raloxi-fene (to protect bone) is feasible. However, large randomised trials will be required in order to determine whether temporary ovarian suppression will be effective for breast cancer prevention. A number of pathways stimulate the activity of the aromatase enzyme including prostaglan-dins IL6 and TNFa. Potentially this could cause resistance to...

Lifespan Of Galactocele

Fibrocystic changes, the most common of the benign breast conditions, are described as multiple, irregular, lumpiness of the breast. It is not a disease per se but rather an exaggerated response to ovarian hormones. Fibrocystic changes are very common in premenopausal women but are rare following menopause. The clinical presentation is cyclic, painful, engorged breasts, more pronounced just before menstruation, and occasionally associated with serous or green breast discharge. Fibrocystic changes usually can be differentiated from the three-dimensional dominant mass suggestive of cancer, but occasionally FNA or core-needle biopsy must be performed to establish the diagnosis. Treatment includes decreasing caffeine ingestion and adding nonsteroidal antiinflammatory drugs, a tight-fitting bra, oral contraceptives, or oral progestin therapy. With severe cases, danazol (a weak antiestrogen and androgenic compound) or even mastectomy is considered.

Central nervous system

Adverse effects include sedation and dry mouth. Tricyclic antidepressants antagonise the antihypertensive action and increase the rebound hypertension of abrupt withdrawal. Low dose clonidine (Dixarit, 50-100 microgram d) also has a minor role in migraine prophylaxis, menopausal flushing and choreas.

Organochlorine Compounds Polycyclic Aromatic Hydrocarbons and Breast Cancer

An argument has been made that since PCBs and DDTs have been banned since the 1970s, these may not have been the correct chemicals to look at or exposure of female babies in utero may be the key factor here. While there may be some truth to these assumptions since organo-chlorines do persist in the environment and can remain in the body for more than a decade. However, a case-control study based on cohorts of women who donated blood in 1974, 1989, or both and who were matched on age, race, menopausal status, and month and year of blood donation showed that even after 20 years of follow-up after exposure to relatively high concentrations of DDE or PCBs there was no association with an increased risk of breast cancer.178 One might argue that a better way to assess risk is to look at damage to the target in the body to which environmental agents might bind. This was done in a study that looked at polycyclic aromatic hydrocarbon-DNA adduct levels in blood mononuclear cells of women who...

Artifacts in PA or AP Spine Densitometry

Osteoporosis Lumbar Spine

In 1982, Krolner et al. (16) observed that osteophytes caused a statistically significant increase in the BMD in the AP spine when compared to controls without osteophytes. More recently, Rand et al. (17) evaluated a population of 144 postmenopausal women, aged 40 to 84 years, with an average age of 63.3 years, for the presence of osteophytes, scoliosis, and aortic calcification. These women were generally healthy women referred for the evaluation of BMD because of suspected postmenopausal osteoporosis. Table 2-5 lists the percentages of these women

Age And Natural History Of Cancer

Beneficial to older post-menopausal women 45. Likewise, age does not seem to reduce the benefits of adjuvant chemotherapy in patients with stage III cancer of the large bowel46. The only situations in which the natural history of cancer may suggest to forgo the use of antineoplastic treatment include smoldering AML and early stage prostate cancer in man aged 70 and older. Though smoldering acute leukemia is an obsolete term, this definition may still be helpful to encompass two conditions hypoplastic acute leukemia, that is AML with a marrow cellularity lower than 10 and AML associated with Myelodysplasia, with a percentage of blasts in the bone marrow between 20 and 30 , that does not undergo any significant change over three months. In both cases the predominant clinical picture is pancytopenia, the incidence of leukostasis is negligible, cytotoxic chemotherapy is associated with low therapeutic response and high risk of early mortality, while supportive treatment with transfusion...

Gluten Sensitive Enteropathy

In a study from Argentina, Gonzalez et al. (46) evaluated 127 consecutive postmenopausal women with osteoporosis, who had a mean age of 68. Osteoporosis was defined as at least one nontraumatic fracture and an L2-L4 and or femoral neck T-score below -2.5. Bone density was measured using a Lunar DPX. The Buenos Aires reference population was used to calculate T- and z-scores for the study populations. This reference database is reported as similar to the reference database for Caucasian women in the United States. The mean T-score for the osteoporotic population was -3.2 and -3.0 for spine and femoral neck, respectively. The prevalence of celiac disease in these osteoporotic women was compared to 747 women, with a mean age of 29, recruited for a population-based study. Screening for celiac disease was done using IgA and IgG antigliadin antibodies (AGA) in all patients. This was followed by antiendomysial antibodies (EmA) and total IgA in the patients testing positive for AGA....

Markers of inflammation

This relationship also bears out in women. In a prospective nested case-control study involving postmenopausal women enrolled in the Women's Health Study, Ridker and colleagues 21 showed hsCRP to be the most powerful predictor of cardiovascular risk compared with other inflammatory markers, baseline lipid levels, and homocysteine. Women in the highest quartile had a relative risk of 4.4 (95 CI, 2.2-8.9, P < .001) compared with those in the lowest quartile. Addition of hsCRP to cholesterol measurement increased the area under the receiver operating characteristic (ROC) curve from 0.59 to 0.66 (P < .001). Furthermore, in women who had LDL levels less than 130 mg dL (the target level recommended for primary prevention by the National Cholesterol Education Program), those who had elevated baseline CRP were still at increased risk for future events with a 3.1 relative risk in the highest quartile compared with the lowest (95 CI, 1.7-11.3, P .002) after adjustment for traditional risk...

Why Women And Men Experience Different Risk For Heart Attacks

The Food and Drug Administration (FDA) and American Heart Association suggest that women are protected from heart attacks due to lipid plaque before they reach menopause. Estrogen levels in younger women are typically a factor causing them to maintain high levels of HDL in most situations. Once menopause occurs, women experience a reduction in HDL as their estrogen levels decline. Post- menopausal women are at the same risk for coronary artery disease and heart attack as men, particularly if they have risk factors of smoking, elevated cholesterol, elevated triglycerides, family history, and or elevated blood pressure.9'10'17,18 It has only been through recent research that the effect of lowered estrogen levels in postmenopausal women with coronary artery disease has become evident. Previously risk of heart attacks was not studied in women because it was not considered a common event. Also, there currently is evidence that women do not express the same physical symptoms of a heart...

Primary Hyperparathyroidism

Among endocrine disorders inducing weight change, and theoretically weight loss, primary hyperparathyroidism (PHPT) must be mentioned. PHPT is a common endocrine disorder that predominantly affects post-menopausal women 43 . It is mostly caused by solitary adenomas of the parathyroid gland and is characterised by hypersecretion of parathyroid hormone (PTH) and consequently by hypercalcaemia. In addition to regu lating calcium concentrations, PTH exerts metabolic effects, including a stimulatory effect on lipolysis. This effect has been demonstrated both in animal and in human adipose tissue 44, 45 . However, PHPT is not commonly characterised by significant weight loss and there is contrasting evidence in the literature concerning this effect. For instance, it has been reported that PTH excess may promote weight gain by impeding cate-cholamine-induced lipolysis 46 . In a study by Grey et al., it was reported that post-menopausal women with mild untreated PHPT are markedly heavier than...

Standardization of Dxa Bmd Results for the Femoral Neck Trochanter and Wards Area

In 2001, Lu et al. (13) developed equations for an sBMD for the femoral neck, trochanter, and Ward's area based on information obtained from studies of the same 100 women whose data was previously used to create formulas for the sBMD of the spine and total femur (10,12). The authors developed site-specific standardization formulas for the hip subre-gions. They compared the utility of the subregion formulas in reducing the disparity in BMD results among the three manufacturers' devices to that of the total femur standardization formulas developed previously when both sets of formulas were applied to the hip subregions. The authors applied the formulas to bone density data from a multicenter clinical trial involving 3139 postmenopausal women. Bone density data was acquired on 51 Hologic, 17 Lunar, and 2 Norland DXA scanners. Table 5-6 shows the difference between scanners for each subregion depending on whether no calibration, the total femur, or subregion calibration was used. The...

CerbB2 as a predictive factor for response to endocrine manipulations

Tumors from more than 50 of women diagnosed with breast cancer will express the ER and or progesterone receptor (PgR). Most of hormone receptor-positive women will be offered endocrine manipulations at some point during the treatment course. The most common endocrine therapy administered to women with breast cancer is tamoxifen. Aromatase inhibitors are commonly administered as first- or second-line therapy for menopausal women with metastatic breast cancer. Based on the results from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial, the United States Food and Drug Administration recently approved the aromatase inhibitor anastrozole for adjuvant therapy for women with hormone receptor-positive breast cancer (6). Other studies support the use of the aromatase inhibitor letrozole following 5 yr of tamoxifen, or exemestane for 2-3 yr following 2-3 yr of tamoxifen for a total of 5 yr (7,8). Based on these recent reports, aromatase inhibitors are likely to have an increasing...

Studies of Hormone Therapies in Metastatic Breast Cancer

Outcomes of women with c-erb-B2-positive or -negative breast cancer were evaluated in two randomized clinical trials of tamoxifen vs letrozole. In the first study, postmenopausal women with hormone receptor-positive locally advanced breast cancer received neoadjuvant therapy with letrozole or tamoxifen. Overall, response rate was greater for patients who received letrozole compared to those who received tamoxifen (60 and 41 , respectively, p 0.004). In a post hoc analysis, the presence of c-erb-B2 (IHC) predicted for improved response to letrozole compared to tamoxifen (Table 2). Response rate to letrozole was 69 and 53 for women with c-erb-B2-positive and -negative disease (odds ratio OR for response 1.93, 95 CI 0.63-5.88, p 0.25), compared to much lower response rates to tamoxifen of 17 and 40 for women with marker-positive and -negative disease, respectively (OR 0.31, 95 CI 0.10-0.97, p 0.045). The odds ratio for response to letrozole vs tamoxifen for women whose tumors...

Cytotoxic Chemotherapy

Compromise in peri-menopausal women with breast cancer who received adjuvant treatment. At least in part, this finding might have been a consequence of chemotherapy-precipitated menopause. In any case, the study of the cognitive effects of chemotherapy, and their potential reversal is a major priority in the management of older cancer patients.

Studies of Hormone Manipulations in the Adjuvant Setting

Samples for c-erb-B2 analysis were available from only a handful of studies that compared adjuvant tamoxifen or other endocrine therapies to no treatment. The Gruppo Universitario Napoletano (GUN-1) was the first large randomized clinical trial that suggested that c-erb-B2 may be a negative predictive factor for response to tamoxifen. From 1978 to 1983, 433 women whose ER status was unknown were randomly assigned to 30 mg of tamoxifen daily for 2 yr or to no hormone therapy. Of those, 173 women were node negative and did not receive adjuvant chemotherapy, and tumors from 145 (84 ) were available for c-erb-B2 analysis by IHC. Treatment with tamoxifen was associated with worse 10-yr overall survival (OS) in women whose tumors overexpressed c-erb-B2. In contrast, women with c-erb-B2-negative disease who received tamoxifen had improved OS (Table 2) (28). In a recent update of this report, c-erb-B2 was one of eight markers that were retrospectively assayed in tissues from 83 of the...

CerbB2 as a Predictive Factor for Response to Endocrine Therapies Conclusions

Given the deficiencies of most marker studies and inconsistent results from larger randomized studies, it is difficult to conclude whether c-erb-B2 is predictive of response to all or to specific hormone therapies. Based on the available data, hormone therapies should not be withheld from women simply because their tumors overexpress or amplify c-erb-B2. Hormone treatment recommendations should be based on hormone receptor status, risk of relapse, menopausal status, and comorbidities. Until further data are available, it may be reasonable to offer adjuvant anthracycline-based chemotherapy in addition to tamoxifen to women with primary breast cancer with expression of hormone receptors and overexpression amplification of c-erb-B2. Whether the addition of ovarian ablation to tamoxifen in pre- or perimenopausal women with small hormone receptor-positive c-erb-B2-positive disease will reverse possible tamoxifen resistance is simply not known. Likewise, conclusive data to support the use...

Endocrine Glands Involved In Reproduction

The pituitary gland is composed of two unique glandular tissues, the neurohy-pophysis and the adenohypophysis, which secrete a variety of hormones. The neurohypophysis or posterior pituitary stores and releases two main hormones produced in the hypothalamus, antidiuretic hormone (ADH) and oxytocin. The main function of ADH is in maintaining water balance and that of oxytocin is stimulation of uterine contractions during labor and breast milk ejection during lactation. The adenohypophysis or anterior pituitary provides a secondary level of control and stimulation of reproductive hormones through release of LH and FSH. Other pituitary hormones also may play a role in reproduction, including thyroid-stimulating hormone (TSH), growth hormone, and adrenocorticotropic hormone (ACTH). Thyroid-releasing hormone binds to plasma membrane receptors of cells in the pituitary gland to stimulate production and release of TSH, which in turn binds to receptors in cells of the thyroid gland to...

Gender Differences in Coronary Heart Disease

It is also known that smoking women reach their menopause 2-3 years earlier probably because of the proposed lowering of endogenous estrogen levels induced by smoking. A risk factor specific to women is ovarian hormone status, for example oral contraceptives, pregnancy, and menopause and hormone replacement therapy. Polycystic ovarian syndrome, gestational diabetes or hypertension, pregnancy toxicosis and birth complications are also claimed to be important hormonal cardiovascular risk factors. Menopause, including premature menopause, is associated with negative changes in several cardiovascular risk factors. Meta-analyses of observational studies, mostly conducted in the United States, showed a risk reduction of CHD events of 35-50 with hormone replacement therapy. The epidemiological evidence was supported by clinical and experimental studies reporting beneficial effects of estrogens on lipids and lipoproteins, carbohydrate metabolism, hemosta-sis, vasomotor effects, and atheroma...

CMF and Other Alkylating Agent Based Therapy

The first two controlled studies were reported more than a decade ago, and both suggested that c-erb-B2 may be a negative predictive factor for response to CMF-like regimens. Blocks were available from 306 node-negative women enrolled in U.S. Intergroup 0011. The women received cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or no systemic therapy. DFS was improved for c-erb-B2-negative women who were on the treatment group compared to control (80 vs 58 , p 0.0003). However, c-erb-B2-positive women had similar DFS regardless of the treatment assignment (78 vs 68 , p not significant) (47). In International Breast Cancer Study Group (Ludwig) Trial V, node-positive women received six cycles of CMF vs one preoperative cycle of CMF. Node-negative women received one perioperative cycle of CMF vs no therapy. Postmenopausal women also received tamoxifen. Marker analysis was performed in 60 of the clinical trial participants. In c-erb-B2-nega-tive patients, six cycles of...

Micronutrients Cramps

Boron enhances and mimics some effects of estrogen therapy in postmenopausal women. J Trace Elem Exp Med. 1992 58 237. 23. Villareal DT, et al. Subclinical vitamin D deficiency in postmenopausal women with low vertebral bone mass. J Clin Endocrinol Metab. 1991 72 628. 28. Dawson-Hughes B, et al. Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Int. Med. 1991 115 505.

Anthracycline Based Regimens

In SWOG Trial 9445 (Intergroup 0100), 1470 node-positive, ER-positive, postmenopausal women were randomly assigned to CAF combination with tamoxifen administered sequentially or concurrently (designated CAFT) vs tamoxifen alone. c-erb-B2 analysis was performed on 595 samples (41 ) using IHC. CAFT was marginally superior to tamoxifen for the entire study population however, women whose tumors overexpressed the c-erb-B2 receptor had substantial benefit form the addition of CAF to tamoxifen. Women whose tumors did not over express c-erb-B2 did not gain benefit from the addition of CAF to tamoxifen (51).

Comprehension Questions

50.1 A 28-year-old woman has been given ovulation induction agents of human menopausal gonadotropin (follicle-stimulating hormone and luteinizing hormone) and becomes pregnant. On sonography, she is noted to have a viable intrauterine pregnancy as well as a pregnancy with fetal cardiac activity in the adnexa. Which of the following is the best therapy

Test Methodology 86 Ldl Cholesterol

High HDL-C levels are seen in premenopausal women, persons who exercise regularly, and those who maintain a low but healthy weight. Insulin, estrogen, and thyroxine (T4) have an inverse relationship with total cholesterol levels. When estrogen levels are higher, as in women who menstruate, the total cholesterol level is lower, preferably 200 mg dL. The HDL-C level is also elevated in menstruating women, while the LDL-C tends to be lower.19 Test Methodology 8-8 describes the method of analysis for HDL-C.

Steroid Receptor Superfamily

The anti-estrogen, tamoxifen, is the most commonly used hormonal therapy for breast cancer and has demonstrated positive effects on the cardiovascular and skeletal systems of postmenopausal women but is associated with an increased risk of uterine cancer. Tamoxifen is described as a SERM, a selective estrogen receptor modulator with a tissue selective profile that is caused by the different distribution of the a- and j3-subtypes of the estrogen receptor (ERa and ERj3) that activate and inhibit transcription respectively (77). These selective effects have been ascribed to differential interactions with gene promotor elements and coregulatory proteins depending on whether the ERa interacts directly, or in a tethered manner with DNA (78).In uterine tissue, ta-moxifen interacts with a specific coactivator, SRC1, that is abundant in uterine tissue.

Medroxyprogesterone Acetate

Thirty women receiving injectable depot medroxyprogesterone acetate for contraception for at least 5 years were evaluated by Cundy et al. (145). BMD was measured at the PA lumbar spine and femoral neck and compared to BMD in 30 premenopausal women and 30 postmenopausal women who served as controls. Compared to the premenopausal women, the women who received depot medroxyprogesterone had BMDs that were 7.5 lower in the lumbar spine and 6.6 lower in the femoral neck. Compared to the postmenopausal women, however, women who received depot medroxyprogesterone acetate had BMDs that were 8.9 higher in the lumbar spine and 4 higher in the femoral neck.

Association ofLpPLA2 With Cardiovascular Risk

The predictive role of Lp-PLA2 was assessed within the Women's Health Study (WHS), a large cohort ofmiddle-aged normocholesterolemic women (27) representing a low-risk population for CVDs. Using a nested case-control design that included 123 cases and 123 controls, investigators found that baseline concentrations of Lp-PLA2 were significantly higher among women who subsequently developed cardiovascular events (such as MI, stroke, or death owing to CHD) compared with those who remained free of vascular disease (mean of 1.2 vs 1.05 mg L, respectively p 0.016). However, although the RR in the top quartile compared with the bottom quartile was 1.73 (95 CI 0.87-3.44), it was statistically nonsignificant and decreased further to 1.17 (95 CI 0.45-3.05) after adjustment for various risk factors. This lack of association could be attributed to existing gender differences for Lp-PLA2. Indeed, several studies (28-30) have already reported on lower levels of Lp-PLA2 in women than in men, and...

Theoretical And Practical Considerations 821 Choice of Study Population

It is also important to match the cohorts for phenotypic or environmental variables that may otherwise confound any genetic analysis for example, hormone replacement therapy (HRT) has a large impact on bone mineral density (BMD) and it would be necessary to account for this in a search for genetic factors influencing BMD using a cohort of post-menopausal women.

Mechanism Of Aromatase Inhibition

Aromatase, a cytochrome P450-dependent enzyme, converts adrenal androgens into estrogens and accounts for most of the estrogen produced in postmenopausal women. Inhibition of aromatase depletes available estrogen, thus preventing estrogen-specific stimulation of the growth of breast cancer cells. The first aromatase inhibitor (AI) that was developed, aminoglutethimide, has clinical activity against breast cancer, but its use is limited by side effects from concomitant adrenal suppression. Second-generation agents have increased specificity for aromatase with improved tolerability. The third-generation AIs, including the non-steroidal agents anastrozole and letrozole and the steroidal agent exemestane, provide potent and highly selective aromatase inhibition. The non-steroidal agents function through reversible inhibition of the aromatase enzyme, whereas the ster-oidal agent forms irreversible bonds. AIs are contraindicated in premenopausal women because the small decrease in systemic...

Guidelines from the European Foundation for Osteoporosis and Bone Disease

In contrast to the 1996 AACE guidelines, the EFFO guidelines do not direct the physician to perform a baseline measurement at the hip regardless of the reason for the measurement. The EFFO guidelines, like the ISCD guidelines, noted that the site of the measurement should be determined by the intent of the measurement. Although the EFFO observed that the hip may be less affected by changes of osteoarthrosis in the elderly and was the preferred site for a site-specific hip fracture risk assessment, they also observed that changes in BMD from therapeutic interventions were more likely to be documented in the spine. The EFFO also noted that the hip, wrist, or spine sites could be used for global fracture risk assessments in women around the time of menopause. Although the EFFO recommended scanning only one site initially, they acknowledged a. Premature menopause (< 45 years) The EFFO guidelines noted that the interval between BMD measurements for the detection of bone loss over time...

Initial Hormonal Therapy

Two studies have compared upfront AI therapy with standard tamoxifen therapy. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) study was a randomized, double-blind trial designed to compare tamoxifen with anastrozole as initial adjuvant hormonal treatment in 6214 postmenopausal women. An additional combination therapy arm containing 3152 patients was un-blinded at the time of the first interim analysis because of the lack of benefit as compared with the control tamoxifen arm. In the overall study population, 84 of the subjects were HR-positive, and 64 had tumors that were 2 cm or less. At a median follow-up of The Breast International Group 1-98 (BIG 1-98) study randomized 8010 postmenopausal women who had undergone resection of HR-positive tumors to one of four regimens five years of tamoxifen, five years of letrozole, initial use of tamox-ifen with a switch to letrozole after two years, and initial use of letrozole with a switch to tamoxifen after two years. As with ATAC,...

Sequential Hormonal Therapy

Four reported studies have evaluated the benefit of a crossover to AI therapy after two to five years of tamoxifen. The Intergroup Exemestane Study (IES) randomized 4742 postmenopausal women who were disease-free after two to three years of tamoxifen to either exemestane or continued treatment with tamoxifen, for a total of five years. At a median follow-up of 30.6 months, a significant improvement in DFS was noted in the exemestane group (hazard ratio, 0.68 95 CI, 0.56-0.82 P < 0.001), including a decrease in the risk of distant relapse (22). At 56 months median follow-up, an intention-to-treat analysis as well as an analysis restricted to estrogen receptor (ER)-positive or unknown patients showed sustained improvement in DFS in the exemestane group (intention-to-treat analysis hazard ratio, 0.76 95 CI, 0.66-0.88 P 0.0001 ER-positive unknown group hazard ratio, 0.75 95 CI, 0.65-0.87 P 0.0001). In addition, the analysis restricted to the patients with positive or unknown ER status...

Other Methods Of Contraception

Copper intrauterine devices are widely used and highly effective (> 99 at one year ) for 5 and some for 10 years. They are especially useful in the over-40s in whom oral contraceptives may become progressively contraindicated and for whom one IUD will last into the menopause. The IUD prevents implantation of the fertilised ovum, and has an additional antifertilisation effect enhanced by the toxic effect of copper ions on the gametes.

Gonadal Toxicity Following Malignancy Treatment

Unlike male germ cells, female germ cells proliferate only during prenatal life after birth, these progressively decrease in number due to apoptosis, and ovulation. Germ cells inside the female gonad do not proliferate, whereas the somatic cells do. Radiation and chemotherapy induce oocytes to undergo apoptosis, which reduces the number of germ cells,18 resulting in estrogen insufficiency. Therefore, when follicles are destroyed by cytotoxic therapy, the frequency of menses decreases and amenorrhea commonly occurs. Irreversible ovarian failure and menopause occur if the number of follicles falls below that is required for menstrual cyclicity.

Guide To Further Reading

352 306-311 Cooper C, Eastell R1993 Bone gain and loss in premenopausal women. British Medical Journal 306 1357-1358 Delmas P D, Meunier P J 1997 The management of Paget's disease of bone. New England Journal of Medicine 336 558-566. Editorial 1962 Arctic offal. British Medical Journal 1 855 Eastell R 1998 Treatment of postmenopausal Manolagas S C et al 1995 Bone marrow, cytokines, and bone remodeling. New England Journal of Medicine 332 305-311 Manson J E, Martin K A 2001 Postmenopausal Hormone-Replacement Therapy. New England Journal of Medicine 345 34-40 Meydani M 1995 Vitamin E. Lancet 345 170-175 Relston S H 1992 Medical management of hypercalcaemia. British Journal of Clinical Pharmacology 34 11-20 Seeman E 2002 Pathogenesis of bone fragility in

Scientific Evaluation and Clinical Applications

The prominence of the Bupleurum species cannot be overstated. Across China and Japan, it serves as a main or supplementary ingredient in over two thirds of traditional medications. For over 2000 years, it has been used to treat fevers, intestinal maladies, malaria, and countless other afflictions. Modern research indicates that it may possess anti-tumor qualities, and researchers continue to report its impact on a wide range of ailments, from hepatitis and epilepsy, to irregularity and menopause, as well as psychosis and schizophrenia.

Neoadjuvant Biologic Data

In a partially blind, randomized, multi-center study, postmenopausal women with breast cancer (n 200) scheduled for curative-intent surgery were pretreated with fulvestrant (50, 125, or 250 mg IM once), tamoxifen (20 mg per os (PO) daily), or matching tamoxifen placebo for 14 to 21 days prior to surgery. In comparison of ful-vestrant with placebo, ER, PgR, and Ki67LI (Ki67 proliferation associated antigen labeling index, a measure of cell proliferation) were significantly decreased in the surgical specimen when compared with the diagnostic biopsy (14). Compared with tamoxifen, fulvestrant produced greater reductions in ER at all doses but was statistically significant only for the 250 mg dose. Tamoxifen decreased Ki67LI to a similar degree as fulvestrant and increased PgR (14). The reduction in the cell turnover index (a composite measure of apoptosis and proliferation) was significantly greater in surgically removed tumors pretreated with fulvestrant instead of tamoxifen (26).

Clinical Evidence Early Clinical Data

Phase II data of fulvestrant demonstrated a 36 partial response (PR) rate and a 31 stable disease (SD) rate for postmenopausal women with tamoxifen-resistant advanced breast cancer (ABC) (27). In this open-label, dose escalation study (n 19), 15 patients received 250 mg of fulvestrant for the entire treatment period. The median duration of response (DOR) was 25 months (23,27). Responses were seen regardless of whether tamoxifen was utilized as adjuvant therapy or as treatment for ABC.

Clinical Trials in the Second Line Post Tamoxifen Setting

By the time fulvestrant was ready for phase III testing, the third generation aromatase inhibitors (AIs) were regarded as the standard second-line treatment for tamoxifen-resistant breast cancer in postmenopausal women (28-34). Therefore, anastrozole was the comparative agent. Both trials were large, multi-center, parallel group trials of postmenopausal women, with locally advanced or metastatic breast cancer, who failed prior endocrine therapy (adjuvant or first-line for advanced disease). All patients had either documented prior response to endocrine therapy or positive ER and or PgR. The trials were powered to show superiority of fulvestrant over anastrozole, and patients were followed until death (24,25). At a median follow-up of 27.0 months (range 0-66.9 months), there was no difference between fulvestrant and anastrozole for the combined median overall survival 27.4 and 27.7 months, respectively (HR, 0.98 95 CI, 0.84-1.15 P 0.809) (35). Because the upper CI was < 1.25,...

Clinical Data in the First Line Endocrine Nave Setting

Second-line fulvestrant is as effective as anastrozole, and first-line anastrozole possesses benefits over tamoxifen for postmenopausal women (24,25,38-40). Therefore, researchers hypothesized that first-line fulvestrant may also have benefits over tamoxifen. Trial 0025 was a multi-center, double-blind, double-placebo randomized trial (n 587) that compared monthly fulvestrant 250 mg IM with daily tamoxifen 20 mg PO as first-line therapy for postmenopausal women with ABC (40). Although patients known to be ER and PgR negative were excluded, confirmed receptor positivity was not required. Patients had not received prior endocrine or cytotoxic chemotherapy for ABC and had not received adjuvant endocrine therapy within the prior 12 months. Only 22 of patients in the fulvestrant arm and 24.8 of patients in the tamoxifen arm had received adjuvant tamoxifen (40). The primary endpoint was TTP. A prospectively planned subset analysis of the women with known ER and or PgR positive tumors (78.9...

Practical Examples of Immunostaining in Bone Sections

We have successfully used the aforementioned procedures to immuno-localize estrogen receptors (ERs) in cryosections of human neonatal bone (2) and transforming growth factor-p (TGF-P) in sections from wax-embedded samples of adult human iliac crest bone (3). The former study investigated the differential protein expression of ERa and ERp in developing human rib (Fig. 2). Intense ER expression was observed in osteoblasts and osteocytes in cortical bone. In contrast, ER-p was seen to be most highly expressed in osteoblasts and osteocytes in cancellous bone. The latter study provided quantitative data on the expression of TGF-p, TGF-p receptors, platelet-derived growth factor (PDGF), and osteoclast activity in wax-embedded sections of adult human iliac crest bone samples. Bone sections from women treated with long-term highdose estradiol were compared to those from women who had received no hormone replacement therapy. The results demonstrated that high-dose estrogen treatment is...

Comparing the performance of selfassessment questionnaires

Several studies (19-22) have compared the performance characteristics of the various indices. Cadarette and colleagues (19) compared the performance of the ORAI index to that of SCORE, ABONE, the 1998 NOF guidelines22 and the body weight criterion in a population of 2365 postmenopausal women age 45 and older who were participating in the CaMos study. These women were otherwise healthy women who had not taken HRT or any other bone-sparing agent or who had taken HRT for 5 years or more. The average age was 66.4 years and the average weight was 152 lb (69 kg). Bone density was measured at the femoral neck and T-scores were calculated using the manufacturer's reference data for Canadian women in which the mean and SD were 0.857 g cm2 and 0.125 g cm2, respectively.23 To compare the performance of the 1998 NOF guidelines to the risk indices, the authors converted the NOF guidelines to an index scoring system in which 1 point was awarded for age 65 or older, weight less than 127 lb (57.6...

Loading Dose Combined with Higher Dose Fulvestrant

Further benefit may be obtained by combining loading dose and high dose fulvestrant. In a nonrandomized, phase II trial, postmenopausal women with hormone receptor-positive ABC are given 500 mg IM fulvestrant on day 1, day 14, and then every 28 days (46). Response and pharmacokinetic parameters are measured (46). Eligibility criteria include no endocrine therapy in the metastatic setting and relapse at least 12 months after adjuvant endocrine therapy (46).

Fulvestrant After Aromatase Inhibitors Preclinical Data

The mechanisms by which tumors become resistant to AIs are not fully characterized, but differ, at least in part, from those involved in tamoxifen resistance because AIs lack the agonist effect associated with tamoxifen. Both estrogen hypersensitivity and crosstalk between growth factor pathways may contribute to endocrine resistance. In current practice patterns, AIs are often used in the first-line setting for adjuvant treatment or for advanced ABC in postmenopausal women. Therefore, fulvestrant is often used after an AL, a scenario without phase III clinical trial data available.

Guidelines of the study group of the who for the diagnosis of osteoporosis

In an extensive report published in 1994 (3), a WHO study group composed of 16 internationally known experts in the field of osteoporosis proposed criteria for the diagnosis of osteoporosis based on a specific level of bone density. The focus of the WHO study group was the study of world populations rather than the diagnosis of osteoporosis in individuals. While endorsing the prior 1991 and 1993 Consensus Development Conferences' definition of osteoporosis, the WHO recognized that their proposed criteria did not include any assessment of microarchitectural deterioration. The WHO attempted to reconcile the prevalence of the disease that would be created depending on the level of bone density chosen with published lifetime fracture risk estimates. The study group noted that a cut-off value of 2.5 SD or more below the average value for healthy young women for bone density at the PA spine or proximal femur or for bone mineral content at the midradius would result in 30 of all...

Novel Agents In Combination With Fulvestrant Crosstalk as a Target

Several targeted agents are being combined with fulvestrant in clinical trials. A phase II, open-label Eastern Cooperative Oncology Group (ECOG 4101) trial will assess gefinitib in combination with 250 mg fulvestrant versus gefinitib in combination with anastrozole in hormone-positive postmenopausal women with ABC (10). Trial treatment may be first- or second-line. A separate phase II trial will evaluate the efficacy of trastuzumab alone, high dose fulvestrant alone, and the combination of the two agents in HER2 positive, hormone-positive postmenopausal women with ABC (10). The combination of lapatinib and loading dose fulvestrant will be assessed in a phase III, placebo-controlled trial by the Cancer and Leukemia Group B (CALGB 40302) (10). The comparator will be fulvestrant alone and eligibility criteria include postmenopausal status, hormone-positive tumors, HER2- or EGFR-positive ABC, and prior exposure to an AI (10). An additional phase II trial will investigate the utility of...

Lifetime Risk of Fracture

In 1992, Black et al. (11) proposed a method for calculating a woman's lifetime risk for hip fracture. The prediction was based on the woman's bone mass at menopause expressed as a percentile for her age, estimations of bone mass at subsequent ages and then estimating her risk for hip fracture at each age. The risk of hip fracture at each age was based on two factors the risk of fracture at a particular age derived from population-based data and the risk of fracture at a particular bone mass from prospective fracture trials. Based on a review of the literature at the time, an increase in relative risk for hip fracture of 1.65 for each SD decline in bone mass at the radius was used in the calculation of risk based on the level of bone mass. Using this method, the lifetime risk of hip fracture for a 50-year-old Caucasian woman whose midradial bone mass was at the 10th percentile was 19 . If her bone mass was at the 90th percentile, her lifetime risk of hip fracture was 11 . The gradient...

Historical Context

Cancer is a leading cause of death in Americans, second only to heart disease. While breast cancer kills the most women, many gynecological cancers are part of the overall cancer statistic. Ovarian cancer, the so-called whispering disease because of its insidious nature, is detected in one in 70 predominantly perimenopausal and postmenopausal American women and often metastasizes undetected. Risk factors include family history of ovarian and breast cancer, high dietary fat, delayed menopause, and no or late childbearing. The use of oral contraceptives appears to decrease risk. Ovarian cancer often presents itself with a cluster of three persistent and severe symptoms a swollen abdomen, a bloated feeling, and urgent urination. Other symptoms associated with the disease include gas pains, anorexia, backache, and indigestion. Unfortunately most women seek medical advice when their ovarian cancer is in the advanced stage because the symptoms might be associated with other gynecological...

Regression to the Mean and Monitoring

In an article in the Journal of the American Medical Association in 2000, Cummings et al. (9) raised the issue of whether regression to the mean (RTM) invalidated serial bone density measurements in clinical practice. The statistical concept of RTM was explained in Chapter 3. Cummings et al. used bone density data from the Fracture Intervention Trial of alendronate in postmenopausal women as well as data from the Multiple Outcomes of Raloxifene Evaluation trial in postmenopausal women. They limited their analysis to data obtained during the first 2 years of each trial in women who were compliant with the medication. They analyzed bone density data at the proximal femur in women by treatment assignment (active medication versus placebo). The average change in bone density at the end of 1 year was calculated for each treatment assignment group. The women were then divided into subgroups based on their actual change in bone density during the first

Reporting the diagnosis

Such a statement is appropriate for a postmenopausal woman. If the study has been performed in a man, the statement should be amended to reflect that the WHO Criteria were originally intended to be used in postmenopausal women only. The controversy surrounding the use of the WHO Criteria in men was discussed in Chapter 9. Until this controversy is resolved, an amended statement should be used. Such a statement might read as follows When the World Health Organization Criteria for postmenopausal women are utilized,

Recommending evaluations for secondary causes of bone loss

The Canadian Panel's recommendation to comment on the z-score when it was less than -2 and to aggressively recommend an evaluation for secondary causes of bone loss is entirely appropriate. This was not listed in the top five elements of a report requested by primary care physicians but this is all the more reason that such statements should be included in densitometry reports. Statements reminding physicians to exclude secondary causes of bone loss are always appropriate in individuals with a low bone mass, regardless of the z-score. In postmenopausal women, estrogen-deficient bone loss is a diagnosis of exclusion. It is incumbent on the physician to prove that nothing else could have caused the apparent bone loss. In men, a search for secondary causes is equally important. Densitometrists may use the z-score to determine how aggressively to recommend such an evaluation, but the recommendation should always be made in some form. Statistically, a z-score of -2 or poorer is grounds for...

Inulin and Bone Health

Osteoporosis is a condition characterized by a decrease in bone mass and density that causes the bones, especially in postmenopausal women, to become fragile and vulnerable to fracture. It is a growing global problem, which can be alleviated by dietary approaches. Calcium is a key factor in bone strength. By optimizing peak bone mass in early adulthood and by minimizing bone loss during the postmenopausal period, the risk, for example, of hip fracture can be significantly reduced. Improved calcium nutrition during development is critical and can reduce hip fracture rates later in life by around 50 (Coxam, 2005). Prebiotic inulin and fructooligosaccharides added to the daily diet of animals significantly increase calcium absorption in animals (e.g., Coudray et al., 2003 Mineo et al., 2001 Ohta et al., 1994 Remesy et al., 1993). This can increase mineralization and bone mineral density (Roberfroid et al., 2002b). In humans, a beneficial effect on calcium absorption is found in both...

Reporting serial studies

The patient underwent baseline and follow-up DXA studies of the PA lumbar spine on 2 5 02 and 2 10 03, respectively. A Lunar Prodigy, software version 6.7, was used for both studies. At baseline, the L2-L4 BMD was 0.945 g cm2. At follow-up, the L2-L4 BMD was 0.987 g cm2. This represents an absolute change from baseline of 0.042 g cm2 or 4.44 . The precision of L2-L4 PA lumbar spine BMD testing at this facility is 0.011 g cm2 in postmenopausal women with an average L2-L4 BMD of 0.904 g cm2. Therefore, the statistical confidence level for the change in bone density in this patient is 99 .

Determination of tissue angiogenesis as a cancer biomarker

The clinical significance of cytosolic VEGF levels was first tested by Gasparini et al. in two studies published in 1997. The first study (32) evaluated VEGF protein in 260 consecutive patients with node-negative disease not treated with adjuvant therapy, median follow-up of 72 mo. In both univariate and multivariate analysis for RFS and OS, VEGF retained a significant and independent prognostic value. The second study (33) was performed in the same cohort of cases, with prognostic evaluation extended also to other biological factors, such as cathepsin D, p53 protein, and TP. More recently, Gasparini et al. (34) performed a study to evaluate the clinical significance of co-determination of VEGF and TP in series of node-positive breast cancer patients treated with adjuvant therapy. Two series of patients were evaluated the first group of patients included 137 patients treated with adjuvant chemotherapy (CMF iv schedule). The second group included 164 patients who received adjuvant...

Jade W M Chow 1 Introduction

Estrogen is known to be one of the major hormonal influences in bone remodeling and bone mass. Estrogen deficiency after the menopause is one of the leading causes of osteoporosis, and currently estrogen replacement is the first line management for postmenopausal osteoporosis. The bone loss associated with estrogen deficiency is due to increased bone resorption and a relative deficiency in bone formation. Although estrogen is thought to prevent bone loss mainly by suppressing bone resorption (1,2), there is also recent evidence to suggest that estrogen may exert an anabolic effect in bone in humans (3,4). Estrogen receptors (ER) are present in osteoblasts (5), and oestradiol has been shown to increase type I collagen and alkaline phosphatase production by osteoblasts in vitro (6). Animal models have proved invaluable in the study of the role of estrogen in bone metabolism. There is a large body of evidence that the cancellous bone of the secondary spongiosa of adult female rats has...

Clinical Significance of OMLN in Patients with Breast Cancer

Investigators from the Ludwig Institute and International Breast Cancer study group have performed a definitive study of the importance of occult lymph node metastases in patients with node-negative breast cancer (87). They examined serial sections of 921 node-negative breast cancer patients by routine histological methods. Nine percent of these patients were found to have OMLN these patients had a poorer disease-free (p 0.003) and overall survival (p 0.002) after 5 yr median follow-up, compared with patients whose nodes remained negative after serial sectioning. Six-year median follow-up data give even more conclusive evidence of the prognostic significance of occult lymph node metastases. Another large-scale study was performed (88). These investigators studied the lymph nodes from 1121 patients with primary operable breast cancer, by serial macroscopic sectioning they found single OMLN in 120 patients. A significant difference in recurrence (p 0.005) and survival (p 0.04) was found...

American college of obstetricians and gynecologists guidelines for bone density measurements

All postmenopausal women 65 years of age or older. 2. Postmenopausal women under 65 years of age who have one or more risk factors. 3. All postmenopausal women who have sustained a fracture. 1. Pre- or postmenopausal women with diseases or conditions associated with an increased risk of osteoporosis.

Vertebral Morphometry and Fractures

Neck Shaft Angle Femur

In a second study, Ross et al. (35) evaluated 380 postmenopausal women with an average age of 65 who were participants in a multicenter trial of etidronate therapy for postmenopausal osteoporosis. In this study, the presence of one or two spine fractures at baseline increased the risk of future spine fractures 7.4-fold. Nevitt et al. (34) evaluated the effect of the number and location of prevalent spine fractures on future fracture risk using data from the Fracture Intervention Trial (FIT), a placebo-controlled, randomized trial of alendronate therapy in postmenopausal osteoporosis. Data from 6082 women were included in this analysis, roughly half of whom were receiving a placebo. Vertebral fractures at baseline were found in 1950 women. Four hundred sixty-two new vertebral fractures occurred in 344 women during an aver Lateral spine images, such as the image shown in Fig. 10-6, can be evaluated using Genant's semiquantitative method. Morphometric software can also be used to define...

Remaining Lifetime Fracture Probability

The fracture incidence and bone loss rate data on which the RLFP model was originally based were derived from the Kuakini Osteoporosis Study. The original implementation of RLFP was based on measurements of bone mass at the calcaneus. Bone density measurements performed at other sites had to be converted to an equivalent calcaneal measurement. Using nomograms, the physician could find the calcaneal BMC on one scale and the patient's age on a second scale (19). By connecting the two values, the physician could find the RLFP on a third scale. RLFP predictions have now been recalculated for DXA measurements of the axial and appendicular skeleton and are available on the internet at www.medsurf.com. After entering the patient's age, menopausal age, skeletal site measured, type of equipment used, and BMD, the RLFP calculation is presented as shown in Fig. 10-4. In this RLFP analysis, the RLFP was Age at Menopause 51

The Fracture Threshold

Ross et al. (22) proposed that the fracture threshold be defined as the BMC or BMD at which the risk of fracture doubled in comparison to premenopausal women. This recommendation was based on a prospective study of 1098 women who participated in the Kuakini Osteoporosis Study beginning in 1981. These women underwent BMC and BMD measurements at the proximal and distal radius and os calcis yearly with SPA and, beginning in 1984, lumbar spine BMD measurements with DPA. Four hundred eight women had spine films at baseline and were used to calculate spine fracture incidence during 4 years of follow-up. Spine fracture prevalence was calculated based on data from subjects who had fractures prior to the first bone density measurement. The authors looked at a variety of ways to define the fracture threshold and the BMC or BMD levels at the various sites that resulted. These considerations are shown in Table 10-10. They observed that the levels of BMC and BMD that corresponded to the 10th...

The osteoporosis selfassessment tool

Osta Score

Koh and colleagues (11) developed the original Osteoporosis Self-Assessment Tool for Asians (OSTA) based on a study of 860 non-Caucasian, postmenopausal women from eight Asian countries. Risk factors were captured from a self-administered questionnaire and bone density was measured by DXA in the proximal femur. Proximal femur T-scores were based on the manufacturer's reference data for Asian women. Statistical analysis was performed to determine which risk factors were independent predictors of BMD. The risk factors that were captured are listed in Table 8-9. These independent predictors were combined in a multivariable model from which risk factors were dropped one at a time until only statistically significant variables remained in the model. An index was developed from the variables in the final model to identify those women with a high probability of having a femoral neck T-score of -2.5 or less.

Rapid changes in weight over a few days suggest changes in body fluids not tissues

In the overweight patient, for example, when did the weight gain begin Was the patient heavy as an infant or a child Using milestones appropriate to the patient's age, inquire about weight at the following times birth, kindergarten, high school or college graduation, discharge from military service, marriage, after each pregnancy, menopause, and retirement. What were the patient's life circumstances during the periods of weight gain Has the patient tried to lose weight How With what results Feelings of heat and sweating also accompany menopause. Night sweats occur in tuberculosis and malignancy.

Genetic And Environmental Associations With Breast Cancer Subtypes

Patients with inherited BRCA1 mutations develop breast cancer, it is virtually always basal-like (8,17-19). The reason for this segregation has not been determined, however, sporadic basal-like breast cancers also may have decreased expression of BRCAl even though somatic BRCA1 mutations are rare (12). In addition, the basal-like subtype appears to be more common among African American women, particularly premenopausal African American women (20). Indirect evidence of an increased prevalence of the basal-like subtype of breast cancer was observed in among participants in the Women's Health Initiative, which found that African American women who develop breast cancer were more likely than white women to develop high grade ER-negative cancers. In this population-based observational study, incidence of breast cancer was evaluated among 156,570 women. Although breast cancer was less common among African American women, when cancer did develop, 32 of tumors were both high grade and...

Box 1 Unique factors in women affecting exercise test results

Physiologic issues, the chest pain unit provides an important option for the evaluation of women. Their exclusion would result in the costly use of traditional hospital beds to evaluate these patients with a low rate of CAD, especially those of pre-menopausal age, no diabetes, and absence of a smoking history. Nevertheless, understanding these limitations is important for the prudent selection of diagnostic modalities when evaluating women in a chest pain unit.

Carotenoids and the Insulin Like Growth Factor System

The identification of risk factors for various types of cancer can lead to appropriate preventive measures. The importance of the sex steroids estradiol and testosterone for the development and progression of breast and prostate cancers, respectively, is well known. Recently, a similar role has been proposed for insulin-like growth factor-I (IGF-I). Chan et al. (102) found a strong positive association between IGF-I levels and prostate cancer risk in participants of the Physicians' Health Study. An equally strong association between the level of this growth factor and breast cancer risk of premenopausal women was also reported in a case control study within the Nurses' Health Study cohort (103) and, more recently, for colorectal cancer (104). Thus, plasma IGF-I levels may be useful for

The Spectrum of Malnutrition

Nearly 30 of humanity - infants, children, adolescents, adults and older persons in the developing world - are currently suffering from one or more of the multiple forms of malnutrition. This remains a continuing travesty of the recognised fundamental human right to adequate food and nutrition, and freedom from hunger and malnutrition, particularly in a world that has both the resources and knowledge to end this catastrophe. The tragic consequences of malnutrition include death, disability, stunted mental and physical growth and as a result, retarded national socioeconomic development. Some 49 of the 10.7 million deaths each year among children aged under 5 in the developing world are associated with malnutrition. Iron-deficiency anaemia affects 2 billion people, especially women and children. Iodine deficiency is the greatest single preventable cause of brain damage and mental retardation worldwide 740 million are affected. PEM affects 150 million children aged under 5. Intrauterine...

Musculoskeletal Symptoms

The pathogenesis of this postchemotherapy syndrome remains unclear. Various suggestions have included a steroid withdrawal effect or a chemotherapy induced menopause 7 , However, not all patients received corticosteroids in their chemotherapy regimen and some patients were postmenopausal or male making the latter hypothesis unlikely. One common factor to all the cases so far appears to be the use of cyclophosphamide and its place in combination chemotherapy regimens 8 . However, intravenous cyclophosphamide, often in high doses is used in the treatment of severe connective tissue diseases and this syndrome of arthralgia and myalgia has not been observed. Admittedly, it would be difficult to distinguish arthralgia from cyclophosphamide and that from the underlying connective tissue disease in these patients.

From PMS To PPD

From PMS To PPD

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