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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Use of Any Type of Postmenopausal Hormone Therapy

Most studies of postmenopausal hormone therapy and breast cancer have found a small increase in the risk of breast cancer associated with ever use (Fig. 6.10), with an overall average risk of breast cancer in ever-users compared to never-users of 1.14 (95 CI 1.09-1.49). Further examination of breast cancer risk according to the pattern of use of postmenopausal hormone therapy shows that this excess risk is largely confined to current and recent users and among these women the risk increases with increasing duration of use (Fig. 6.11). Indeed, in current users and those who ceased use less than 5 years previously, the RR of breast cancer is estimated to increase by 2.3 (95 CI 1.1 -3.6 ) for each year of use. In contrast, women who have ceased use 5 or more years previously do not appear to be at any overall increase in risk, nor does their risk increase with increasing duration of use of postmenopausal hormone therapy. This pattern of increasing breast cancer risk with increasing...

Comparison of Risks According to Type of Postmenopausal Hormone Therapy Used

Table 6.1 Relative Risk (RR) of Breast Cancer by Time Since Last Use, Duration of Use, and Type and Dose of Postmenopausal Hormone Therapy Mainly Used Table 6.1 Relative Risk (RR) of Breast Cancer by Time Since Last Use, Duration of Use, and Type and Dose of Postmenopausal Hormone Therapy Mainly Used Type and Dose of Postmenopausal Hormone Therapy Since the collaborative reanalysis, three studies have published new results on breast cancer risk according to type of postmenopausal hormone therapy used. The first, which is an extended follow-up of a large cohort within the Breast Cancer Detection Demonstration Project15 (a U.S. breast cancer screening program), with over 2000 cases of breast cancer, has shown that the risk of breast cancer is increased both in recent users of estrogen-only therapy (RR 1.2, 95 CI 1.0-1.4) and in recent users of combined therapy (RR 1.4, 95 CI 1.1-1.8). However, when the trend in breast cancer risk with increasing duration of use was estimated separately...

Menopausal Symptoms

The natural oestrogen-receptor activity of soy is popularly considered an alternative to controversial HRT for postmenopausal women (Sliva 2005). A recent analysis of 17 trials, however, found mixed results for the effects of soy isoflavone extracts on menopausal symptoms (Nelson et al 2006). Although some data seem to support the efficacy of isoflavones in reducing the incidence and severity of hot flushes, many studies have not found any difference between the isoflavone recipients and the controls. Inadequate data exist to evaluate the effect of isoflavones on bone mass and vaginal dryness (Greenwood et al 2000).

Menopause and Obesity in Women

There are relatively few data on changes in adiposity and fat distribution associated with menopause in women. This is an important issue because of the relationships that have been noted between obesity and cardiovascular disease (5), and obesity and certain cancers (56,57) in postmenopausal women. As noted above, body weight reaches its maximum in women very near the time of menopause, and there is an increase in relative adiposity for any given weight or BMI. While some studies find that the increase in weight accompanying menopause is more related to age than menopause itself (58,59), others have noted specific menopause-related increases in BMI, overall adiposity, central adiposity and intra-abdominal adiposity (60-64). A recently published longitudinal study that followed 35 women aged 44-48 for 6 years (65) found that those women who experienced menopause during the period of follow-up lost significantly more FFM ( 3 vs. 0.5 kg), and had greater increases in fat mass (FM 2.5...

Postmenopausal Dyspareunia

Attempts to lessen the pain through the use of water-based lubricants and topical estradiol cream had not been successful, and she did not wish to try systemic hormone replacement therapy for fear of developing breast cancer. A detailed sexual history revealed that Brenda had suffered from intermittent pain during intercourse for at least 15 years but had never complained about it, and that Alexander had always had difficulties with ejaculatory control. Over the past 4 years, Brenda reported difficulty getting sexually aroused, diminished lubrication, postcoital bleeding, and less interest in sex. Their current sexual frequency was less than once every 3 months, a frustrating situation for Alexander, who had hoped that their youngest child leaving home in the previous year would result in more frequent sexual activity. In the previous 5 years, the couple had also experienced significant life stressors including the sudden death of Brenda's mother and major financial problems....

Managing Menopausal Symptoms

This chapter deals with menopause-associated symptoms including hot flashes, night sweats, sleep disturbances, and vaginal symptoms. Other symptoms that accompany the perimenopause transition but are related to other life events or aging, including sexual dysfunction and mood disturbances, are discussed. The options for managing these changes include menopause hormone therapy, both systemic and local, as well as complementary therapies and nonhormonal therapies for each of the symptoms.

Hormone Replacement Therapy

It is well established that women who use hormone replacement therapy (HRT) are at a slightly increased risk of breast cancer and that risk increases with duration of use (by 2-3 per year of use), but decreases when use is ceased (38). Rebbeck et al. have reported that use of HRT in mutation carriers who had undergone a bilateral prophylactic oophorectomy (BPO) did not significantly alter the reduction in breast cancer risk associated with BPO. These data suggest that short-term HRT does not negate the protective effect of BPO on subsequent breast cancer risk in BRCA1 orBRCA2 mutation carriers. In addition, theNarod-led collaboration have reported that HRT use by carriers does not appear to adversely influence their risk of ovarian cancer (OR 0.93 95 CI 0.56-1.56) (39). Despite these encouraging results, additional research on the use of HRT and its role in breast cancer risk among women with BRCA1 or BRCA2 mutations is warranted.

Age at Menopause

Early menarche and late menopause increase the number of ovulatory cycles during which a woman is exposed to high levels of estrogen. It has been estimated that women who experience natural menopause (as defined by cessation of periods) before the age of 45 have only one-half the breast cancer risk of those whose menopause occurs after the age of 55.23 Artificial menopause, by either bilateral oophorectomy or pelvic irradiation, also markedly reduces breast cancer risk. The effect appears to be slightly greater than that of natural menopause, probably because surgical removal of the ovaries causes an abrupt cessation of hormone production, whereas some hormone production continues for a few months or years after a natural menopause.

Menopause

The climacteric or menopause, the cessation of menstruation, occurs by age 50 in most women and marks the end of the childbearing years. Some women manage to give birth during their fifties and even sixties, but for most, the period of fertility ends sometime during the fifth decade. Associated with menopause is a sharp drop in the production of estrogen The degree of vasocongestion of the breasts, clitoris, and vagina is also affected, and vaginal lubrication is reduced with menopause. The decreased acidity of vaginal secretions also increases the likelihood of infection. These changes in the vagina may result in pain and discomfort during sexual intercourse and an aching, burning sensation afterward. A minority of meno-pausal women experience these symptoms to any great degree, and they can, of course, be treated (Corby & Solnick, 1980). For example, vaginal irritation can be treated with a water-based lubricant such as K-Y, and by enhancing lubrication by means of estrogen...

The menopause

Epidemiological studies do not demonstrate any increase in major psychiatric morbidity in women of menopausal age. However, mild to moderate depression or anxiety may develop at this time of life perhaps secondary to hormone changes, perhaps reactive to physical symptoms, or perhaps reflecting life changes such as children leaving home, death of parents, and awareness of ageing. Again, a variety of treatments has been used (http www.clinicalevidence. especially hormone replacement therapy (HRT) progesterone alone is 'beneficial', but oestrogen alone or in combination with progesterone causes 'improved menopausal symptoms but increased risk of breast cancer, endometrial cancer, stroke, and venous throm-boembolism after long term use', and there is a 'trade-off between benefits and harms'. Antidepressants are of 'unknown effectiveness'.

Contemporary Endocrinology

Menopause Endocrinology and Management, edited by David B. Seiferand Etienne-Emile Baulieu, Michael Schumacher, and Paul Robel, 1999 15. Autoimmune Endocrinopathies, edited by Robert Volp , 1999 14. Hormone Resistance Syndromes, edited by J. Larry Jameson, 1999 13. Hormone Replacement Therapy, edited by A. Wayne Meikle, 1999 12. Insulin Resistance The Metabolic Syndrome X, edited by Gerald M. Reaven and Ami Laws, 1999

Telomerase And T Cells

Our data on estrogen effects in T cells in vitro are reminiscent of an earlier study in which we documented the reversal of some of the age-related T cell changes in postmenopausal women treated with hormone replacement therapy (Porter et al., 2001). In another set of preliminary experiments with small molecule activators of telomerase, we have shown a significant enhancement of telomerase activity in T cells from both healthy and HIV-infected persons (Fauce et al., manuscript in preparation). Thus, therapeutic approaches that are based on telomerase modulation would seem to be promising candidates for clinical interventions in the elderly that are aimed at reversing or retarding the process of replicative senescence in T cells. The major question to be addressed is whether the process of replicative senescence, characterized so extensively in cell culture, has any relationship to events within the immune system during normal human aging. As will be described below, this certainly...

Evolution Of Current Treatment Approaches

The successful introduction of sildenafil contributed to the search for pharmacological treatments for female sexual disorders. Initially, many companies did clinical trials in women with substances that had proven successful in treating erection problems. In general, these trials were unsuccessful. The one exception is a clitoral vacuum erection device, which has FDA approval (16,17). Another approach is the study of androgens to stimulate desire in women. Off-label use of androgen preparations increased significantly after the work by Gelfand and Sherwin (18,19) demonstrated that supraphysiological levels of testosterone increased libido in postmenopausal women (20). The use of androgen preparations to treat desire problems in women is currently undergoing clinical trials. As Rosen (21) pointed out, many large pharmaceutical trials of female sexual dysfunction are unfortunately hindered by various methodological problems, such as the lack of use of physiological outcome measures and...

Inflammation on Pap smear

(HGSIL) or invasive cancer therefore, persistent inflammation is an indication for colposcopy. 6. Atrophy with inflammation is common in post-menopausal women or in those with estrogen-deficiency states. Atrophy should be treated with vaginal estrogen for 4-6 weeks, then repeat Pap smear.

Christopher I Li Introduction

In addition, there are different histologic types of BC. The two most common are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), which account for approximately 80 and 5-15 ofall BCs, respectively (2, 3). In this chapter a summary of the pathologic, clinical, and epidemiologic characteristics of ILC, in contrast to IDC recent work investigating associations between hormone replacement therapy (HRT) use and risks of ILC compared to IDC and the accumulated evidence supporting the role of progesterone (P) in the etiology of BC in general, and ILC in particular are presented.

Management of glandular cell abnormalities

When a Pap smear is performed during menstruation, endometrial cells may be present. However, endometrial cells on a Pap smear performed during the second half of the menstrual cycle or in a post-menopausal patient may indicate the presence of polyps, hyperplasia, or endometrial adenocarcinoma. An endometrial biopsy should be considered in these women.

The Relationship Between HRT and Risk of Lobular Carcinoma

As a result ofthe observations described above, attention has been paid to potential risk factors that may be more strongly related to ILC risk than to IDC risk. In particular, there is a growing interest in the relationship between combined E and P HRT (CHRT) and ILC risk. Two main observations have driven this research. First, CHRT use in the USA increased over the same time period that ILC rates increased and IDC rates remained constant. From 1982-1992 the number E and P prescriptions increased 2.3-fold and 4.9-fold, respectively (24). Among controls from a recent USA multi-center case-control study of postmenopausal women spanning 1994-1998, 45 were current HRT users (25). Second, CHRT use has been shown to be associated with an elevated BC risk in numerous studies, and more recently in the Women's Health Initiative (WHI), a randomized controlled trial. The pooled analysis conducted by the Collaborative Group on Hormonal Factors in Breast Cancer of 51 observational studies found...

Henri Rochefort Majida Esslimani Sahla and Dany Chalbos Introduction

The assumed role of progesterone and progestins on mammary glands and human breast carcinogenesis has varied between laboratories and countries and is still controversial. Progestins inhibit estrogen (E) action in cell lines and provide protection against the mitogenic effect of Es in endometrium, which is why they are required to overcome the mitogenic activity of E in hormone replacement therapy (HRT) of non-hysterectomised postmenopausal women. The effect of progestins on mammary carcinogenesis is much less clear since molecular and cellular studies diverge according to laboratories (1-2), and it was even proposed that progestins protect against breast cancer (BC) (3). The results of a large randomised NIH clinical trial in USA (4) involving post-menopausal women treated with medroxyprogesterone acetate (MPA) and the E conjugate, Premarin, vs placebo indicate that this association increases the risk of BC by 30 , as previously shown in several observational studies also attained...

History of venous thromboembolism

Oral contraceptives and hormone replacement therapy Compared with oral contraceptives, there have been fewer studies on the relationship between the use of post-menopausal hormone replacement therapy and VTE. The doses of oestrogen used for post-menopausal replacement are much lower than those used for contraception, and the route of administration is sometimes different (transdermal vs. oral). Yet, several studies have shown a 2- to 4-fold increased risk of thrombosis associated with hormone replacement therapy.56,57 Perhaps the lower risk associated with the low oestrogen dose of hormone replacement therapy is neutralised by the higher baseline risk of post-menopausal women due to their older age, in comparison with women of child-bearing age who use oral contraceptives. The high-risk (Table 4) category includes patients with the most severe forms of thrombophilia, including anti-thrombin deficiency, homozygous protein C or protein S deficiency, homozygous factor V Leiden,...

Identifying Psychosocial Barriers to Success

There are a variety of bio-psychosocial obstacles to be recovered that contribute to treatment complexity. All of these variables impact compliance and sex lives substantially, in addition to the role of organic etiology (20). There are multiple sources of patient and partner psychological resistance, which may converge to sabotage treatment (i) What is the mental status of both the patient and the partner and how will this impact treatment, regardless of the approach utilized What is the nature and degree of patient and partner psychopathology (such as depression) What are the attitudinal distortions causing unrealistic expectations, as well as endpoint performance anxiety (ii) What is the nature of patient and partner readiness for treatment When and how should treatment begin, and be introduced into the couple's sex life What is his approach to treatment seeking What should be the pacing of intimacy resumption The average man with ED waits 2-3 years, before seeking...

The Clinical Significance of FAS

Moreover, FAS staining in BC was generally greater in pre-menopausal patients than after menopause. These results indicated that progestins also induced FAS expression in vivo, in both malignant and non malignant mammary gland cells, and suggested that FAS is a marker of responsiveness to progestins. Based on the dominant paradigm concerning progestins in BC in France, we initially proposed that FAS is a differentiation marker First, in normal mammary glands, FAS is known to be mostly active during lactation to produce milk lipids (30). Secondly, we observed high accumulation of lipid droplets in R5020-treated T47D cells with

Age Gender Ethnicity and Geography

Whereas a malignant glioma can occur at any age, the average age of onset for glioblastoma is 62 yr (2). In general, gliomas affect males 40 more frequently than females (6). According to a recent study, this greater incidence of glioblastoma in males becomes evident around the age of menarche, is greatest around the age of menopause, and then decreases, suggesting a possible protective effect provided by female hormones (7), though such a protective effect is merely speculation.

Breast Cancer Susceptibility And Other Risk Factors

An important and largely unresolved question is the relationship between genetic and lifestyle risk factors for breast cancer. The combined analysis by the Collaborative Group examined the effect of several important risk factors on the familial risk of breast cancer, including parity, age at first full-term pregnancy, and ages at menarche and menopause. In each case, they found that the relative risks conferred by these risk factors were similar in women with and without a family history (1). These results imply that such risk factors can be assumed to multiply the familial risks of breast cancer (an assumption made in the Tyrer et al. and Gail models). It also suggests that such risk factors are largely independent of genotype. Whether this is true for specific susceptibility genes, in particular BRCA1 and BRCA2, is less clear however. Several studies have examined the effects of these risk factors in BRCA1 2 carriers but many of the results are contradictory, perhaps reflecting...

Treatment of acute DVT

Trauma, or major medical illness) from which they have fully recovered. Their risk of recurrence when anti-coagulants are discontinued at 3 months is estimated to be less than 5 in the next year and somewhat lesser in subsequent years. These patients should be encouraged to have prophylactic anti-coagulants if exposed to a high-risk state and, in general, should be encouraged to seek alternatives to oestrogens for contraception or post-menopausal use. Moderate-risk patients are those without inherited or acquired thrombophilia who had a thromboembolic event in association with a minor risk factor, such as, oestrogen use or long distance travel. Their risk of recurrent thrombosis after 6 months of anti-coagulants is likely to be less than 10 in the year after stopping anti-coagulants, provided that the precipitating risk factor is avoided they should be treated with anti-coagulants for 6 months. If, however, the precipitating factor cannot be avoided (e.g., oestrogens) they should be...

Protection of the Patient

In normal pelvic films, gonadal protection may obscure the region of interest in women. The female fertile phase ends with menopause, which makes gonadal protection less important. The law states that men need protection where appropriate. G. E.'s old chief used to put it this way Every man up to the age of 60 gets gonadal protection. Older men get it if they request it but they get a piece of sweet chocolate with it.

Natural Models Of Alzheimerlike Pathology

Rhesus monkeys are Old World monkeys with a maximum life span of approximately 40 years they reach puberty at 3-4 years of age, and females go through menopause at approximately 25 years of age (Walker, 1995). Age-related cognitive decline is well-documented in rhesus monkeys, but a dementia-like state has not been reported. Rhesus monkeys develop senile plaques with age, usually in their early-mid 20's (Walker and Cork, 1999). These lesions are cytologically and biochemically similar to human plaques, except that the abnormal neurites that surround the core are devoid of tau filaments. Indeed, although primates can manifest tau abnormalities in brain, fully formed neurofibrillary tangles have not yet been detected in any nonhuman primate, including the apes. Squirrel monkeys. In addition to widely varying phenotypes and lifespans, nonhuman primates show species-specific patterns of age-associated lesion development in brain. Squirrel monkeys are small, New World...

Association of 16aHydroxylated Estrogens with Breast Cancer Risk

Mation of 16a-hydroxylated estrogen metabolites might be associated with increased risk of developing breast cancer. Their initial studies showed that 2- and 16-hydroxylation of estradiol was minimally affected by age and did not differ between premenopausal and post-menopausal women.129 However, when these enzymatic activities were compared between breast cancer patients (n 33) and matched controls (n 10), 16-hydroxylation was associated with increased risk of breast cancer, whereas the competing 2-hydroxylation pathway was either neutral or associated with decreased risk.135 The investigators suggested that the breast cancer patients had an increased extent of 16a-hydroxylation prior to the onset of the disease, unless the increase was a consequence of the cancer itself. In a subsequent study, using a murine mammary tumor model, Bradlow and associates136 reported a close correlation between the extent of tumor incidence and 16a-hydroxylation, but not 2-hydroxylation, of estra-diol....

BS2 Intermediate Course of the Disease

The process usually burns out with more or less fibrous sequelae, but the ending of the inflammatory process is unpredictable. Frequently menopause brings relief in women, but the association is not constant, and the end may come after or before the menopause. For men it is similarly unpredictable.

Estrogen Receptor and Normal Cell Cycle in Breast Tissue

PR mediates the mitogenic effect ofprogesterone which further stimulates proliferation (4). This latter effect has now been demonstrated epidemiologically in that hormone replacement therapy (HRT) after menopause has only a mild effect on BC risk if it involves estrogen only (7), whereas the addition of progestins adds significantly to the likelihood of later BC development in the post-menopausal woman (8-10) Most ofthe studies of expression in normal ducts and lobules, as well as in-situ neoplasia, are immunohistochemical studies focused on the ERa, although the potential cross reactivity for the much more recently discovered is not currently clear (11). Normal terminal duct-lobular units express ERa approximately 90 ofthe time, and in perhaps a third ofthese the expression is quite limited and only seen in a minority of cells. During the childbearing years (12), the number of positive cells varies with the menstrual cycle and is much higher during the follicular phase....

The Nature of Subsequent Invasive Carcinoma

Although not widely accepted or utilized in clinical decision making, it is quite evident that there are some important associations between hormonal manipulation and the nature of the subsequently developing invasive BC (34). Simply, many BCs, particularly in the post-menopausal age range (35), are of low grade, low

Tyrercuzick International Breast Cancer Intervention Study

The personal risk factors incorporated into the IBIS model are the ages at menarche, first childbirth and menopause, parity, height, and body mass index, and two diagnoses associated with increased risk, namely atypical hyperplasia and lobular carcinoma in situ. Both these diagnoses are known to be associated with at least a fourfold increase in risk in the general population (35,36). Some risk factors have not yet been included. These are the administration of exogenous hormones such as the oral contraceptive pill and hormone replacement therapy and the presence of ductal carcinoma in situ.

Estrogen Progesterone and Androgen Receptors

Reproductive and homeostatic systems, respectively. The sex steroid receptors ER, PR, and AR direct transcription of genes involved in sexual development, differentiation, and specification (Tables 3.4, 3.5). As a result of their growth-promoting activities in these processes, these receptors are pharmacologically targeted in a number of neoplastic reproductive tissues. Receptors ERa and ERjS are predominantly expressed in reproductive tissues, as well as in vasculature, cardiac muscle, and bone. Their activity is subject to estradiol availability, which is regulated by hormonal cascades generated from the ovary and other steroidogenic tissues. Confirmation of the role of ERs in the regulation of the reproductive tract was achieved by targeted deletion of ERa and ERjS alleles in transgenic mice, which develop normally but are infertile or suffer ovarian dysfunction, respectively.296,297 In addition to reproductive maintenance, specialized roles for ERs include regulation of bone...

Iron Intake And Iron Absorption

The amount of iron that needs to be obtained through the diet varies according to age and gender. Males need to absorb about 1 mg day, premenopausal females about 0.2 to 2.0 mg day, and children approximately 0.5 mg day.2 For perspective, if an adult male eats a 2500-calorie diet, he will ingest about 15 mg of iron ofwhich only 10 will be absorbed, giving him 1.5 mg day of iron that can be used for red cell production or stored in the reticuloendothelial system (RES).3 Iron in the diet is available as heme iron through meats or as nonheme nonmeat iron. For a listing of sources, see

What is Your Diagnosis

Osteoporosis If the normal continuous formation and breakdown of the bone derails in such a fashion that the cancellous bone loses its density and stability to a greater degree than normal for that age, fractures may occur spontaneously or after minor trauma. Such a degree of demoralization of bone is termed osteoporosis. Bone density is the highest around 35 years of age. After that it declines steadily estrogen-depleted postmenopausal women are at a greater risk than men. The consequences of osteoporosis pathological fractures and vertebral height loss due to progressive collapse lead to the typical loss of body height and stature (the famous infamous little old lady). Another major complication is, of course, the femoral neck fracture. Standard radiographs of the thoracic and lumbar spine show the osteoporosis best. The density of the vertebral bodies is decreased the vertebral end plates therefore appear enhanced. If the vertebral end plates fracture, the typical fish vertebra...

Clinical evaluation of premenstrual syndrome

The differential diagnosis includes hypothyroidism, anemia, perimenopause, drug and alcohol abuse, and affective disorders. Common alternative diagnoses in patients complaining of PMS include affective or personality disorder, menopausal symptoms, eating disorder, and alcohol or other substance abuse. A medical condition such as diabetes or hypothyroidism, is the cause of the symptoms in 8.4 , and 10.6 have symptoms related to oral contraceptive (OC) use.

William R Miller Introduction

There is compelling evidence that estrogens (Es) both increase risk of developing breast cancer (BC) and maintain the growth and progression of established tumors (1). Recently, drugs have been developed which specifically and potently block E biosynthesis (aromatase inhibitors). These agents now occupy a central role in the treatment of postmenopausal patients with BC, and are being considered as preventative agents in women at high risk ofthe disease. The success ofthese drugs is founded on (A) The peripheral production of Es in postmenopausal women. (B) The key role of aromatase in the pathway of E synthesis. (C) The unique endocrinology of postmenopausal BCs. (D) The evolution of different types of aromatase inhibitors. (E) The mechanisms whereby Es initiate and promote BC. Therefore, the objectives of this chapter are to review (i) the pivotal role of aromatase in maintaining E within the breast and its tumors, and agents which have been developed as inhibitors of this enzyme,...

Sites of Estrogen Production

The major sites ofE production differ in pre- and postmenopausal women. Before the menopause, the ovary is mainly responsible for circulating levels of E. However, peripheral synthesis of E is of greater importance in postmenopausal women when ovarian E biosynthesis ceases. The postmenopausal ovary along with the adrenal cortex produces substantial amounts of androgen (2,3) that can be used as substrate for synthesis of E at peripheral sites such as fat (4), skin (5), muscle (6), liver (7), and BC (8), all of which possess aromatase activity.

Endocrinology of Aromatase Inhibitors

These effects on peripheral aromatization translate into decreased levels of Es in the circulation. Thus, daily anastrozole (1 mg), letrozole (2.5 mg), and exemestane (25 mg) reduce circulating E in postmenopausal women to levels often below the detection amount ofcurrent assays (21,28). Additionally, differences in potency between inhibitors that are apparent on whole body aromatase can also be detected at the level of circulating Es. Thus, exemestane will reduce E levels in patients relapsing on the first-generation inhibitor aminoglutethimide (29).

Female Reproductive System Disorders

Menopausal hot flushes According to one randomised, double-blind placebo-controlled study EPO supplementation significantly reduces the maximum number of night-time flushes, although other symptoms failed to respond. The study used a dose of four capsules daily (each containing 500 mg EPO and 10 mg vitamin E) over 6 months (Chenoy et al 1994). A position statement of the North American Menopause Society (2004) concluded that evidence was lacking to warrant the use of EPO in the treatment of vasomotor symptoms of menopause.

Differences Between SERMs and Aromatase Inhibitors

SERMs and aromatase inhibitors are often thought of as being equivalent however differences in mechanism of action may lead to variations in biological and clinical effects. For example, aromatase inhibitors reduce endogenously synthesized Es in contrast, SERMs generally do not inhibit synthesis, and E levels remained unaltered (60), or, in the case of pre-menopausal women, may increase (61, 62). This difference may be important because metabolites ofnatural Es can have influences independent of ER (63). Although aromatase inhibitors reduce levels of Es synthesized endogenously, they will not diminish the activity of exogenous Es and adrenal androgens that interact with the ER (64-66). In contrast, SERMs will interfere with ER signaling irrespective of ligand. However, as the third generation aromatase inhibitors appear more effective than tamoxifen (67-71), it is unlikely that exogenous Es are responsible for the induction and growth of most BCs (64).

Specific interventions

Coronary heart disease (CHD) includes history of myocardial infarction, unstable angina, stable angina, coronary artery procedures, or evidence of clinically significant myocardial ischemia. CHD risk equivalents include clinical manifestations of non-coronary forms of atherosclerotic disease, diabetes, and > 2 risk factors with 10-year risk for hard CHD > 20 . Risk factors (RF) include age (male > 45 years, female > 55 years or premature menopause without hormone replacement), positive family history for premature CHD (in first-degree relatives < 55 years and first-degree female relatives < 65 years), cigarette smoking, hypertension (blood pressure > 140 90 mmHg or taking antihypertension drugs), HDL < 40 mg dl (1.0 mmol l). If HDL cholesterol is over > 60 mg dl (1.6 mmol l), subtract one risk factor from the total (adapted from Dub 2000 and Schambelan 2002). Coronary heart disease (CHD) includes history of myocardial infarction, unstable angina, stable angina,...

Aromatase Inhibitors and Prevention of Breast Cancer

0.007. compared with an expected 85 cases with no treatment,) (79). Aromatase inhibitors also have not been successful in premenopausal women (80-82) because of the high levels of aromatase activity in the premenopausal ovary and compensatory feedback loops (13). However, the new aromatase inhibitors may be sufficiently powerful to produce effective blockade, but they are not yet used routinely in premenopausal women Pilot chemoprevention studies which target high risk women, using third generation aromatase inhibitors are being planned or underway. One study has identified a small cohort of women with either DCIS or benign breast disease who were treated for 3 months with letrozole, the primary objective being to measure surrogate biomarkers of BC risk, and bone and lipid metabolism (83). The WISE trial aims to recruit women at risk on account of high circulating Es and randomize to either letrozole (1 year) or placebo. The National Institute of Canada is conducting double blind,...

Regulatory Status

The German E Commission has approved St. John's wort for internal consumption for psychogenic disturbances, depressive states, sleep disorders, and anxiety and nervous excitement, particularly that associated with menopause. Oily Hypericum preparations are approved for stomach and gastrointestinal complaints, including diarrhea. Oily Hypericum preparations are also approved by the Commission E for external use for the treatment of incised and contused wounds, muscle aches, and first degree burns (96).

Terminology and Definitions

The term andropause indicates a particular type of hypogonadism that is related to aging in men and is said to consist of the following diminished sexual desire and erectile function, decrease in intellectual activity, fatigue, depression, decrease in lean body mass, skin alterations, decrease in body hair, decrease in bone mineral density resulting in osteoporosis, and increase in visceral fat and obesity (24). The word andropause is an attempt to draw a parallel in men to the experience of menopause in women. Whereas menopause occurs abruptly, andropause is said to occur quite slowly. As well, menopause is associated with the irreversible end of reproductive life, whereas in men spermatogenesis and fertility continue into old age. In the opinion of some observers, trying to equate the two is rather questionable (23). The existence of andropause is a subject of controversy partly because of great difficulty distinguishing this syndrome from age-related confounding variables such as...

Anthropometric Factors

The data on breast cancer risk and height have been relatively consistent in demonstrating an increase in risk with increased adult height. A pooled analysis of seven prospective cohort studies of height and breast cancer risk reported relative risks for breast cancer, after adjusting for other risk factors, of 1.02 per 5 cm of height among premenopausal women 95 confidence interval (CI) 0.96-1.10 and 1.07 among postmenopausal women (95 CI 1.03-1.12).29 The relationship between greater height and risk of breast cancer is hypothesized to be due to the influence of growth hormone, insulin-like growth factor-I (IGF-I),30 or possibly in utero influences on ductal stem cells.31 The relationship between weight and breast cancer risk is dependent on age. In premenopausal women, high body weight does not increase the risk of breast cancer. Pooled results have shown an inverse association between risk of breast cancer in premenopausal women and body weight.29 Compared to women weighing less...

The Insulin Like Growth Factor Family

Epidemiological studies have begun to investigate the role of circulating IGFs and IGFBPs, as well as polymorphisms in the genes that encode them, in the etiology of breast cancer. Most studies have focused on the association with serum of plasma levels of IGF-I, IGFBP-3, or their ratio, which is a proposed proxy for biologically active IGF-I. Hankinson et al.65 found a markedly increased risk of premenopausal breast cancer relative risk (RR) 7.28, 95 CI 2.40-22.0 for women with the highest levels of plasma IGF-I but no association among post-menopausal women. Risk of breast cancer was also elevated among premenopausal women with a high ratio of IGF-I to IGFBP-3 (RR 2.46, 95 CI 0.97-6.24) compared to those with a low ratio. Studying this pathway presents important challenges to understanding the role of IGFs in carcinogenesis. In this complex family, risk of cancer could be mediated through any of the members, the IGFs, the receptors, or the binding proteins, or through interactions...

Dietary Fat and Fiber

Many case-control studies of fat consumption and breast cancer have found only small differences between cases and controls, generally no larger than the differences in total caloric consumption. However, Howe and colleagues68 combined 12 large case-control studies representing populations with a wide range of dietary habits and underlying rates of breast cancer to study the diet-breast cancer relationship. They found that the breast cancer risk of post-menopausal women was positively associated with both total fat intake (RR 1.46 for 100 g day, p 0.0002) and saturated fat intake (RR 1.57 for highest quintile of intake, p < 0.0001). Nonetheless, cohort studies that have examined total fat, saturated fat, or vegetable fat69-72 have found little or no difference in breast cancer risk over a wide range of fat intakes.73 There have been several attempts to demonstrate a reduction in serum estrogen levels following dietary interventions that reduce fat or increase fiber intake.75 A...

What conditions are often missed

Menopausal symptoms can also be overlooked as we focus on a particular symptom. Some important pitfalls are given in Table 15.3 . Lead poisoning Malnutrition (unsuspected) Menopause syndrome Migraine (atypical variants) Paget's disease Pregnancy (early) Seizure disorders Tourette's syndrome Urinary infection

Gillian K Reeves Emily Banks Timothy Ja

The importance of endogenous hormones in the etiology of breast cancer is evident from the strong relationships between breast cancer risk and certain aspects of a woman's reproductive history, such as age at menarche, age at first birth, and age at menopause.1 More recently, the risk of developing breast cancer among post-menopausal women has also been shown to increase substantially with increasing levels of circulating estradiol,2 thus providing more direct evidence for the role of hormones in the development of the disease. The relationship between endogenous hormones and breast cancer risk leads naturally to the question of whether exogenous hormones, such as oral contraceptives and postmenopausal hormone therapy, might also have an effect on breast cancer risk. Over 60 epidemiological studies worldwide have examined breast cancer risk in relation to either hormonal contraceptive use or post-menopausal hormone therapy. There have been collaborative reanalyses of data on breast...

The Maiden Must Be Kissed Into A Woman

Most pharmacological treatments that are currently being developed for women with sexual arousal disorder are aimed at remedying a vasculogenic deficit. In a study we did in the late 1990s we compared pre- and postmenopausal women with and without sexual arousal disorder, diagnosed according to strict DSM-IV criteria (1). Women with any somatic or mental comorbidity were excluded. This study investigated whether pre- and postmenopausal women with sexual arousal disorder were less genitally responsive to visual sexual stimuli than pre- and postmenopausal women without sexual problems. From the findings of this study we concluded that in such women, sexual arousal disorder is unrelated to organic etiology. In other words, we are convinced, from this and other studies to be reviewed, that in women without any somatic or mental comorbidity, impaired genital responsiveness is not a valid diagnostic criterion. The sexual problems of women with sexual arousal disorder are not related to...

Cardiovascular Complications

Patient characteristics associated with cardiac long-term and late effects are older age and preexisting cardiac disease. Premature menopause from cancer Chemotherapy, particularly alkylating agents like cyclophosphamide, can induce infertility and, in women, premature menopause, with its attendant problems of hot flashes, mood swings, vaginal dryness, and urinary incontinence. Cyclophosphamide is commonly used in breast cancer, but management of the menopausal symptoms is complicated by the fact that hormone replacement therapy is considered contraindi-cated in patients with a history of breast cancer. Consequently, other treatments must be used for hot flashes, such as antidepressants.52 This example illustrates the importance of both recognizing the symptoms related to ovarian failure in a cancer patient in which it would be otherwise unexpected, and having knowledge of the oncologic considerations of the therapies being chosen. Bone health can be impaired in many ways. Premature...

Fertility Enhancing Drugs

Women who undergo treatment for infertility can be exposed to a variety of hormonally active drugs, including clomiphene citrate, human menopausal gonadotrophin, and gonadotrophin-releasing hormone. Studies examining the relationship between use of fertility drugs and breast cancer risk have been hampered by small numbers of women and the inability to adequately control for all important confounding factors. Bearing this in mind, their findings have been generally reassuring, showing no significant increase in the risk of breast cancer in infertile women treated with fertility drugs compared to infertile women who did not receive such treat-ment.24-27 However, a recent study reported a significant, transient excess of breast cancer in the 12 months following ovulation stimulation for in vitro fertilization compared to the general female population,25 and there remains considerable uncertainty about the effect of fertility drugs on breast cancer risk.

Theoretical Issues

Two mutually informing analytic frameworks have been central to much recent fertility research the life course and the proximate determinants frameworks. The biological nature of fertility determines the structure of each framework. In fact, both frameworks rest on very straightforward observations. The life course perspective adopts a sequential model because children tend to be born one at a time, not in lots (Namboodiri 1972 198). Moreover, because women are biologically restricted to having children only between menarche and menopause, fertility may be considered as an irreversible, time-limited sequence.

Estrogen and its Receptors

Estrogens and estrogen receptor (ER) have been implicated in the pathogenesis and progression of ovarian cancer based on epidemiological and experimental observations (41-43). Even though estrogens plus progestins taken as an oral contraceptive during the premenopausal period in women are protective, when used in postmenopausal years as hormone replacement therapy, estrogens may increase the risk of ovarian cancer (7). Although no difference in risk was observed in women who had used estrogens continuously supplemented by progestins, an elevated risk of epithelial ovarian cancer in women who had used estrogen, either unopposed or combined with sequential progestins, was observed in an epidemiological study (41).

Estrogen replacement therapy

Postmenopausal women without contraindications should consider ERT. Contraindications include a family or individual history of breast cancer estrogen dependent neoplasia undiagnosed genital bleeding or a history of or active thromboembolic disorder. 2. ERT should be initiated at the onset of menopause. Conjugated estrogens, at a dose of 0.625 mg per day, result in increases in bone density of 5 .

Activation And Regulation Of Sexual Response Processing of Sexual Information

A surprising finding from our studies was the ease with which healthy women become genitally aroused in response to erotic film stimuli. When watching an erotic film depicting explicit sexual activity, most women respond with increased vaginal vasocongestion. This increase occurs within seconds after the onset of the stimulus, which suggests a relatively automatized response mechanism for which conscious cognitive processes are not necessary. Even when these explicit sexual stimuli are negatively evaluated, or induce little or no feelings of sexual arousal, genital responses are elicited. Genital arousal intensity was found to covary consistently with stimulus explicitness, defined as the extent to which sexual organs and sexual behaviors are exposed (66). This automatized response occurs not only in young women without sexual problems, but also in women with a testosterone deficiency (67), in postmenopausal women (68,69), and in women with sexual arousal disorder (42). Such responses...

Materials and Methods

A validated food frequency questionnaire (24), which included questions on reproductive, medical, and anthropometric factors. In the cross-sectional study, self-reported information was used to classify women's menopausal status and hormone use (HRT). The majority of subjects (n 208) donated an overnight urine specimen, while those ofthe cross-sectional study (n 97) only a spot urine sample.

Colin D Clyne Evan R Simpson

Recent models of estrogen insufficiency have challenged traditional concepts of estrogen ac-tion.1-3 Studies of humans with natural mutations in the genes that encode the estrogen re-ceptor4 or cytochrome P-450 aromatase5 and of estrogen receptor and aromatase knockout mouse models6-11 have revealed hitherto unexpected roles for estrogen in both males and females. For example, the critical role of estrogen in the spermatogenic process12 suggests that this hormone might more appropriately be termed an androgen in this context.13 Additionally, in postmenopausal women (as in men), estrogen no longer functions as a circulating endocrine hormone rather, it is produced in a variety of ex-tragonadal sites (e.g., adipose tissue or bone), where it acts locally as a paracrine, autocrine, or intracrine factor.2,3,14 This has great significance for our understanding of the biology of estrogen-dependent diseases such as breast cancer.

Synthesis Of Estrogens

Estrogens are synthesized from C19 precursors produced by the ovary (in premenopausal women), the adrenal cortex (in postmenopausal women and men), or the testis (in men). The first step in the pathway, common to the synthesis of all steroid hormones, is cleavage of the choles terol side chain to yield pregnenolone (Fig. 8-1).15 This reaction is catalyzed by the cholesterol side chain cleavage enzyme (P450scc) and requires 22-hydroxylase, 20a-hydroxylase, and 20 22 lyase activities,16 all of which occur at a single active site.17 The C21 steroids pregnenolone and progesterone are then converted to the C19 androgens dehydroepiandrosterone and an-drostenedione by 17a-hydroxylase (P450c17). These are two-step reactions that require 17a-hydroxylase and c17,20-lyase activities, both of which are characteristic of P450c17.18 The final step in estrogen synthesis is catalyzed by P450 aromatase (P450arom), which converts an-drostenedione and testosterone to estrone and 17j6-estradiol,...

Aging General Characteristics

Aging in the rhesus monkey has many similarities to human aging. The incidence of cancer, type 2 diabetes, and other diseases increase in the rhesus monkey similar to humans. In addition, diseases and clinical conditions, such as osteoporosis, that occur in aging women also occur in the rhesus female. Changes that occur during aging fall into two categories those associated with declining physiological function and those contributing to a disease state (Hadley et al., 2005). Obvious signs of aging in nonhuman primates and humans include loss of posture due to muscle loss (sarcopenia). Recent evidence has directed new attention to the important role of immune system function as a central element in a possible range of health-related issues and disease states that emerge as the individual ages (Nikolich-Zugish and Messaoudi, 2005). In addition, visual and auditory systems undergo an age-related decline, similar to humans (Torre and Fowler, 2000 Roth et al., 2004). Similarly, there is...

Frequency Of Infertility

Comprises artificial insemination, in vitro maturation (IVM) of oocytes, in vitro fertilization (IVF), embryo culture and embryo transfer. For presumptively infertile women aged up to about 37, the outcome of clinical IVF (in this general context meaning IVF together with embryo culture and transfer) is good, with an average of about 32 of treatment cycles in the United States resulting in a live birth (Wright et al., 2003). But for women approaching 40 or over, the efficiency of IVF drops sharply, to only about 5 after the age of 42 (Wright et al., 2003). Similarly, the incidence of natural conceptions falls progressively towards the age of 40, prior to overt menopause. The reasons for this precipitous drop in fertility are not well understood, but a decline in the ability of the uterus to support pregnancy does not seem to be a primary factor, in view of the number of births to women over 40 carrying a surrogate embryo made with oocytes from younger women. The quality of oocytes and...

Inhibition Of Aromatase

Inhibition of estrogen action is generally the first-line adjuvant therapy for patients with metastatic estrogen receptor (ER)-positive breast cancers. Recent trials have demonstrated superiority of aromatase inhibitors such as anas-trozole over traditional estrogen receptor antagonists in this setting,66 and there is therefore much interest in the development of more effective aromatase inhibitors, both as treatment and as preventive agents.67 Estrogen receptor antagonists and aromatase enzyme inhibitors inhibit estrogen action in a global fashion, particularly in bone tissue and this inhibition may cause osteoporosis.68 Although this might be of less consequence in advanced postmenopausal breast cancer, the effects of estrogen deprivation in bone of young postmenopausal women could be significant. In addition, other sequelae of estrogen deprivation with anti-estrogen therapy for breast cancer such as hepatic steato-sis69-71 and cognitive impairment,72,73 have been described. For...

Clinical Investigations

In patients with suspected ovarian neoplasia, a risk-malignancy index is calculated. This is a means of assessing the likelihood that an ovarian mass is malignant and takes into account the menopausal status (pre or post menopausal) of the patient, the ultrasound findings and the serum CA-125 measurement.

Oestrogenprogesterone receptor expression

Most postmenopausal patients receive the anti-oestrogen tamoxifen but positive oestrogen receptor (ER) status in premenopausal patients is important so that consideration can be given to hormonal treatment. Progesterone receptor expression is a prognostic marker and may also indicate hormone responsiveness.

Hellevi Peltoketo Veli Isomaa Debashis Ghosh Pirkko Vihko

Estrogen and steroid metabolism in the target or surrounding cells therefore determine the availability of estrogens in breast tissue. The ovary is the single primary source of estradiol (E2) in the circulation of premenopausal women, but circulating estrone (E1) and androgens originating from the adrenal gland are also converted to E2 in peripheral tissues such as adipose tissue and muscles, including smooth muscle cells of the vena cava.15-18 Breast adipose and epithelial cells also contain enzymes needed for the production in situ of E2 from circulating precursors,7,16 which may further enhance estrogen action in the tissue. After menopause, in particular, estrogen biosynthesis in peripheral tissues has a major role in estrogen action.19 Finally, nutriment may contain compounds with estrogenic and or antiestrogenic effects.20

Nonneoplastic Conditions

Endometriosis the ovary is the most common site of endometriosis, which is defined as the presence of endometrial tissue, usually both glands and stroma, outside the uterus. Most common in the reproductive age group, but occasionally encountered in postmenopausal women, the symptoms are protean and varied. Patients may present with a palpable abdominal mass, abdominal or pelvic pain, dysmenorrhoea, dyspareunia, irregular uterine bleeding or infertility. Stromal hyperplasia this is relatively common in the perimenopausal or early postmenopausal age group. Both ovaries are enlarged, often only mildly so, by a nodular stromal proliferation. Usually the nodules are yellow to white in colour and they may be confluent. Histology confirms a nodular proliferation of stromal cells with scant cytoplasm. There may be androgenic or oestro-genic manifestations and, on occasions, associated endometrial hyperplasia or adenocarcinoma.

Neoplastic Conditions

Malignant tumours primary malignant ovarian neoplasms are of surface epithelial, germ cell or sex cord-stromal type. Surface epithelial tumours are most common and these are serous, mucinous, endometrioid, clear cell, transitional or undifferentiated carcinomas in type. Borderline neoplasms (tumours of low malignant potential) also occur and these may be one of any of the morphological subtypes described, most commonly serous or mucinous. These are neoplasms with malignant nuclear characteristics but in which there is no evidence of stromal invasion. Ovarian surface epithelial adenocarcinomas are most common in middle-aged and elderly women, in nulliparous women and those with an early menarche and late menopause. The oral contraceptive pill is protective. It has been suggested than women who are exposed to ovulation-inducing drugs are at increased risk of the development of ovarian carcinoma. Women with BRCA1 or BRCA2 gene mutations are at increased risk of the development of both...

Scoring system Quick score

Individual cancers can show heterogeneity of ER receptor expression and in some respects the Histo and Quick Scores can take this into account. Carcinoma in situ (low to intermediate-grade), infiltrating lobular carcinoma, low-grade invasive ductal carcinoma and post-menopausal cancers tend to be ER positive, while high-grade in-situ and invasive ductal lesions and a significant number of premenopausal carcinomas (grade-related) are ER negative. In practice with improved immunocytochemistry the vast majority of breast cancers are either strongly positive or completely negative for ER and assessable at a glance. Quantifying PR expression can be less clear-cut.

Effects of sex steroid hormones on behavior over the lifespan

Most of the data reviewed in this chapter concern effects of sex steroid hormones on adult behavior, resulting either from organizational effects of early hormonal exposure during the fetal or neonatal periods or from activational effects of sex steroid hormones in adulthood. However, sex steroid hormone levels change dramatically both in children as they mature and enter puberty, and in women when the activity of the reproductive axis declines at menopause thus, one would expect to see accompanying changes in behaviors modulated by sex steroid hormones at these times. One would also predict that sexually dimorphic areas of the brain that are dependent on adult levels of sex steroid hormones for maintenance of the dimorphism would change in morphology over puberty and menopause. Although we know a good deal about the development of sex-related behaviors at puberty (Baum, 1979), surprisingly few studies have examined pubertal or menopausal changes in other behaviors that appear to be...

Lymphovascular Supply

Clinical features related to uterine pathology are most commonly those of abnormal uterine bleeding. In premenopausal patients this may take the form of menorrhagia (heavy periods), dysmenorrhoea (painful periods) or a variety of other forms of abnormal uterine bleeding. In postmenopausal patients, the most common symptomatology is postmenopausal bleeding. This should always be taken seriously and uterine malignancy excluded. Other symptomatologies related to uterine pathology include a palpable abdominal or pelvic mass, pain within the pelvis or abdomen (often deep seated), a feeling of fullness within the abdomen and uterine prolapse. Uterine pathology may also be associated with symptoms such as constipation, urinary frequency or infertility.

Colorectal cancer epidemiology

Figure 17.1a demonstrates that colorectal cancer is more common in males than in females and in both sexes the incidence rate increases with advancing age. This difference in sex incidence may partly be explained by evidence from a number of case-control and cohort studies which demonstrated an association between hormone replacement therapy (HRT) and colorectal cancer, with the majority of these suggesting a protective effect (Giacosa et al., 1999). Accumulating evidence implicates obesity as a risk factor for colorectal cancer (Giacosa et al., 1999), and a positive association may exist between colorectal cancer and diabetes (La Vecchia et al., 1997). Not surprisingly, smoking has also been suggested as a significant risk factor (Giovannucci, 2001). Many studies have elucidated precise dietary and other variables responsible for the observed

Influence of Age and Sex on Metal Toxicity

Adult women before menopause lose iron with menstrual blood, and there is a high prevalence of low iron stores in this population group. Because it is known (cf Chapter 23) that persons with low iron stores have an increased gastrointestinal uptake of cadmium, women often accumulate more cadmium than men. Higher blood cadmium values have been reported among women than men in many epidemiological studies.

Concentration Of Estrogens And Their Sulfates In Normal And Pathological Breast

Estrogen sulfotransferase activity is very high in both physiological and pathophysiological conditions. It is well established that EXS is quantitatively the most important form of circulating estrogen during the cycle (Honjo et al., 1987 Nunez et al., 1977) as well as in postmenopausal women (Noel et al., 1981 Roberts et al., 1980). Different studies agree that the plasma levels of unconjugated estrone and estradiol are similar in normal women and in breast cancer patients (for a review, see Pasqualini and Chetrite, 1996), although Thomas et al. (1997) reported a strong positive relationship between breast cancer susceptibility and increased serum estradiol concentration. However, the concentration of E1S is significantly higher in the follicular phase of premenopausal breast cancer patients than in normal women (Pasqualini et al., 1996). In breast cancer tissues, most authors agree that the concentrations of unconjugated estrogens are found at high levels (Bonney et al., 1983...

Management of the Unaffected Carrier

Alternative methods of imaging are being assessed in the high-risk population in the hope that they may provide an alternative to mam-mography. Mammography may be less effective in the younger population because breast tissue in premenopausal women is more dense. In addition, there is some concern that the radiation dose associated with mammography may cause tumor progression in gene carriers. The value of magnetic resonance imaging in screening for breast cancer is being evaluated in a U.K. study of known BRCA1 2 carriers or women at 50 genetic risk.23 Ovarian screening is more controversial because it has not been proven to be of benefit. It is currently offered on the basis of local availability, although the UKCGG has recommended that it should be offered only as part of a clinical trial.21 When it is available, women are screened annually by transvaginal ultrasonogra-phy from the age of 35, usually together with measurement of serum CA125 antigen. In a pilot study of 21,935...

Agerelated Changes in Hormones and Their Receptors in Animal Models of Female Reproductive Senescence

Traditionally, the onset and progression of menopause in humans has been attributed to ovarian follicular decline. Because the follicles are the primary source of circulating estrogens, these age-related changes lead to a number of symptoms such as hot flashes, mood swings, irritability, and depression, as well as increased risk of osteoporosis, cardiovascular disease, and age-associated diseases. Recent research indicates that along with the ovarian changes at menopause, the hypothalamic and pituitary levels of the reproductive axis also undergo significant changes during reproductive aging. Indeed, current research suggests a neural, as well as hormonal, mechanism involved in the menopausal process. A number of animal models are available to study these processes, most commonly the nonhuman primates and rodents, and to a lesser extent, avian systems. Here, we will discuss Old and New World monkey models, rats, mice (wild type, transgenic, and genetically modified), and birds as...

Clinical evaluation

Ninety percent of patients with endometrial cancer have abnormal vaginal bleeding, usually presenting as menometrorrhagia in a perimenopausal woman or menstrual-like bleeding in a woman past menopause. Perimenopausal women relate a history of intermenstrual bleeding, excessive bleeding lasting longer than seven days or an interval of less than 21 days between menses. Heavy, prolonged bleeding in patients known to be at risk for anovulatory cycles should prompt histologic evaluation of the endometrium. The size, contour, mobility and position of the uterus should be noted. B. Patients who report abnormal vaginal bleeding and have risk factors for endometrial cancer should have histologic evaluation of the endometrium. Premenopausal patients with amenorrhea for more than six to 12 months should be offered endometrial sampling, especially if they have risk factors associated with excessive estrogen exposure. Postmenopausal women with vaginal bleeding who either are not on hormonal...

Role Of Mammographic Density

Mammographic sensitivity is lower in women with mammographically dense breasts.11,12 The differences in sensitivity and false-positive rate observed in women below and above age 50 parallel the decrease in mammographic density observed with increasing age between 35 and 55.14,15 Very dense mammographic patterns especially appear to change to lower-risk patterns during the perimenopausal period (age 45-55).14 There is, of course, no abrupt change in the positive predictive value of mammogram at age 50,16 but, rather, a gradual increase. This decrease in mammographic density and increase in sensitivity is most likely an effect of menopause and not age per se.17,18

BARD1BRCA1Associated RING Domain

As mutations in BRCA1 and BRCA2 account for only 30 to 40 of familial breast cancer, BARD1 was an excellent candidate as an additional breast cancer susceptibility gene based on its interaction with BRCA1, because as well as their functional similarity, both have a RING finger domain. Several studies screened high risk breast and breast ovarian cancer families without mutations in BRCA1 and BRCA2 for mutations in BARD1 . These studies did not find any evidence that BARD1 was a breast cancer susceptibility gene. Ghimenti et al. screened 40 families by single-strand conformation polymorphism and identified five mutations including 1139del21 and Cys557Ser (86). None of the mutations were associated with allelic loss of BARD1 and so did not support a role as BARD1 as a tumor suppressor associated with cancer susceptibility. In a similar manner, Ishitobi et al. screened 60 families and found several missense mutations, most of which had been previously observed and the same in-frame...

How Ovarian Steroids Affect Mammographic Density

The association between ovarian steroids and mammographic density parallels what is known about the effects of ovarian steroids and breast cell proliferation.43 Breast cell proliferation is higher in pre- than postmenopausal women and higher in women in the luteal than in the follicular phase of the menstrual cycle. In short, high estrogen progesterone levels are associated with high amounts of breast cell proliferation.

Using Hormonal Strategies To Improve Mammographic Density And Sensitivity Of Screening Mammograms

It is possible that the benefit of such hormonal strategies varies substantially. It is clear that not everyone who takes a GnRHA regimen has a reduction in density,36 just as not everyone who starts EPRT has an increase.51 The biological or genetic predictors of mammographic density changes with hormonal alterations are currently unknown. Thus, in the absence of such predictive markers, the best clinical approach currently to improve the screening benefit in a young woman with dense breasts would be to simply test whether a temporary endogenous hormone reduction will result in a reduced amount of density on her mammogram. For premeno-pausal women, a reversible approach, such as a GnRHA-based regimen, ought to be attempted first. Women with a substantial reduction in mammographic density with a GnRHA-based regimen may be more likely to benefit from ta-moxifen treatment or early oophorectomy than women who do not have density reduction with such hormonal manipulation. Postmenopausal...

QOL in Long Term Survivors of Breast Cancer

Eleven of the 16 studies discussed physical domain QOL outcomes for long-term survivors.2,4,32,41,43,46-51 Generally, survivors report lower physical domain QOL than healthy controls and poorer physical functioning.4,41,43,49 Arm pain, including swelling, loss of sensation, weakness, and stiffness, are common.4,32,48,50,51 Survivors also report fatigue,2,46 with one study finding that younger survivors report the lowest levels of vitality.51 Physical problems associated with treatment induced menopause are also common.2,32 One study shows that physical functioning was predicted by age at diagnosis,48 while another found that older age in general is related to worse physical domain QOL.47 Another study found that physical health was most affected among women who were both diagnosed with lymphoma and treated with chemotherapy.2

Lacassagnes Prevention Principle A Target And An Estrogen Antagonist

Were conducted exclusively on postmenopausal women with advanced breast cancer,3,4 and not until 1977 was it suspected that tamoxifen was more effective in ER-positive breast cancer.46 Tamoxifen is currently used as a palliative therapy in the treatment of pre- and postmenopausal patients with ER-positive, advanced breast cancer. Adjuvant therapy revolutionized the treatment of breast cancer and is now used after breast surgery to destroy undetected mi-crometastases in a woman's body. The general principles derived from the use of tamoxifen as a therapy for breast cancer serve as the basis for consideration of tamoxifen as an estrogen antagonist in the prevention of breast cancer.

Biological Basis For Tamoxifen As A Breast Cancer Preventive

Tamoxifen produces partial agonist action in the rat uterus,56 but until the late 1980s there was little information about its actions in the normal human uterus. It is now clear that a variety of en-dometrial changes occur in unselected populations of women.110 The most significant finding is an increase in the stromal component, rather than endometrial hyperplasia.111,112 Laboratory data suggesting that tamoxifen has the potential to encourage the growth of preexisting disease harbored in the uterus67,68 provoked an intense investigation of the rates of endometrial cancer detection in women using adjuvant tamoxifen treatment for breast cancer. It is clear from the results of the tamoxifen prevention trial106 that ta-moxifen does not cause an excess of endometrial cancer in premenopausal women but does increase risk by three- to fourfold in post-menopausal women. This is consistent with the fact that women harbor four to five times the level of endometrial cancer than is detected...

Risk Factors For Breast Cancer

Breast cancer is clearly related to endogenous hormones, and numerous studies have linked breast cancer risk to age at menarche, menopause, and first pregnancy. Although the absolute age-specific incidence of breast cancer is higher in postmenopausal than premenopausal women,125 the absolute rate of rise of the curve is greatest up to the time of menopause, then slows to one-sixth of that seen in the pre-menopausal period. Further support for the promotional role of estrogen in breast cancer comes from observations that early menarche,126 late menopause,127 nulliparity, and late age at first birth128 all increase the risk of breast cancer development. An increased number of ovu-latory cycles is suggested to be the common mechanism of increased risk. ers have found no relationship between abortion and breast cancer.131,132 Studies of the effect of lactation on breast cancer risk have also been inconclusive,133,134 but recent studies have suggested that a long duration of lactation...

Interactions among Risk Factors

The interactions between a family history of breast cancer and other risk factors have been examined, often with conflicting results. Data from the Nurses Health Study149 show that women with known risk factors, such as age at menarche or menopause, parity, age at first birth, alcohol use, the presence of benign breast disease, and a mother or sister with breast cancer, develop disease at rates equivalent to women with a family history alone. In contrast, Anderson and Badzioch150 and Brinton et al.151 reported that hormonal factors further modulate risk in women with a family history of breast cancer, although the effect varies with the factor under study. Studies of the interaction between HRT and other known risk factors also have variable results, depending on the risk factor under study. In a meta-analysis of 16 published studies, Steinberg et al.143 found that the effect of HRT did not differ among parous and nulli-parous women and those with or without benign breast disease...

Identification of Candidates for Chemoprevention

Come from studies of white women thus, little is known about the impact of ethnic diversity. Finally, with the exception of women with predisposing genetic mutations, the majority of women with risk factors will not develop breast carcinoma. A recent study of the fraction of breast cancer cases in the United States attributable to risk factors152 found that fewer than 50 of women who develop the disease have any identifiable risk factors. Family history of breast cancer accounted for only 9 of cases, while relatively minor risk factors, such as later age at first birth and nulliparity, were seen in 29 of cases. In a similar study, Seidman et al.153 noted that only 21 of breast cancer cases in women aged 30-54 and 29 of cases in women aged 55-84 occurred in women with at least one of 10 common breast cancer risk factors. The majority of women had minor risk factors, which increase the RR of breast cancer only twofold, and most had only a single risk factor. This level of increased risk...

Royal Marsden Pilot Study

Acute toxicity was low for participants in the pilot study, and compliance remained correspondingly high 77 of women on tamoxifen and 82 of women on placebo remained on medication at 5 years.163 There was a significant increase in hot flashes (34 vs. 20 , p < 0.005), mostly in premenopausal women vaginal discharge (16 vs. 4 , p < 0.005) and menstrual irregularities (14 vs. 9 , p < 0.005). At the most recent follow-up, 320 women had discontinued tamoxifen and 176 had discontinued placebo prior to the study's completion.160 In contrast, tamoxifen exerted antiestrogenic or estrogenic effects on bone density, depending on menopausal status. In premenopausal women, early findings demonstrated a small but significant (p < 0.05) loss of bone in both the lumbar spine and hip at 3 years. In contrast, postmenopausal women had increased bone mineral density in the spine (p < 0.005)

Urogenital Infections

Probiotics are widely used to decrease the frequency of recurrent bacterial vaginosis and candidal vulvovaginitis, and have undergone clinical testing that supports this use. They are administered both orally and intravaginally. Additionally, lactobacilli play a significant role in the prevention of UTIs. One study using intravaginal administration of probiotics such as Lactobacillus GR-1 and B-54 or RC-14 strains twice weekly for 2 weeks and then monthly for 2 months demonstrated that treatment resulted in 45 less UTIs than placebo and improved the maintenance of normal flora (Reid & Burton 2002). A significant reduction in UTI rate was also reported in a randomised double-blind study involving 55 premenopausal women (Reid 2001 b). The study investigated the effectiveness of treatment for 1 year with a weekly suppository containing either 0.5 g L. rhamnosus GR-1 and L. fermentum B-54 or a Lactobacillus growth factor. Treatment resulted in the UTI rate decreasing by 73 and 79 ,...

Fertility and Aging Men An Introduction to the Male Biological Clock

The levels of sex hormones in men decline with age. The roughly 1 per year decline in testosterone levels after age 30 has been termed andropause, or ''symptomatic hypogonadism in the aging male.'' Rhoden and Morgentaler estimate that between 2 and 4 million men in the United States alone suffer from hypogonadism, but only 5 of men are getting treatment for their symptoms. or as sudden as that associated with menopause, but it can be equally significant for fertility and overall well-being. Recently, there has been a lot of interest in declining testosterone levels in men. The roughly 1 per year decline in testosterone levels after age 30 has been termed andropause and is associated with a plethora of congenital and acquired disease-syndromes (McLachlan, 2000).

Comparisons Of Longterm Effects Of Diagnosis And Treatment By Cancer Site Breast Cancer And Hodgkins Disease

We found no significant changes in marital partner status or in employment status in the breast cancer group. With regard to the SF-36 subscales, social function improved over time. We did not find differences in sexual activity or reporting of sexual problems even though by now most women were menopausal (75 due to treatment) and there were fewer children at home. There were significant decreases in the size of one's social network and emotional support. In multivariate analyses, less reduction in emotional support predicted better QOL.

Methodological issues in the hunt for human obesity genes

Obesity is defined as an excess of body fat, which can be measured directly using dual energy X-ray absorptiometry and isotopic dilution techniques. However, these are costly and their limited availability makes it difficult to perform such measurements in large numbers of subjects. In some studies fat mass has been measured indirectly using bioelectrical impedance or skin-fold thickness both of which correlate reasonably well within the normal range but less so in the very lean or the obese. The most commonly used marker of adiposity is BMI (weight in kg height in m2) which is a measure of heaviness that can be performed in large epidemiological studies and correlates reasonably well with body fat content. Body fat distribution provides an additional risk that is not given by simply the amount of body fat. Abdominal fat mass, for example, can vary significantly within a narrow range of total body fat or BMI. Furthermore, within a given BMI, men have on average twice the amount of...

Study Of Tamoxifen And Raloxifene

The STAR trial is a phase III, double blind trial that is assigning eligible postmenopausal women to either 20 milligrams daily tamoxifen or 60 milligrams daily raloxifene therapy for 5 years. Trial participants will complete a minimum of 2 additional years of follow-up after therapy is stopped. The STAR trial's primary aim is to determine if long-term raloxifene therapy is effective at preventing the occurrence of invasive breast cancer in high-risk postmenopausal women. It will additionally compare cardiovascular data, fracture data, and general toxicities for raloxifene and ta-moxifen. It is clear that the activation or suppression of various target sites is similar for ta-moxifen and raloxifene, but evaluation of the comparative benefits of the agents will provide an important new clinical database for raloxifene in postmenopausal women. Premenopausal women at risk for breast cancer are currently ineligible for the STAR trial. Although there is extensive information about the...

Pharmacological Toxicological Effects 51 Endocrine Effects

Although many products containing ginseng are marketed specifically for postmenopausal women, a recent review concluded that there is insufficient evidence that ginseng is effective for treatment of menopausal symptoms (11). In vitro, Siberian ginseng extract, but not P. ginseng extract, binds to estrogen receptors. Both extracts have affinity for progestin, glucocorticoid, and mineralocorticoid receptors (32). A recent study reported that a morning evening formulation containing ginseng and other constituents relieved menopausal symptoms, but no placebo control was included so it is difficult to tell whether the effect was caused by the formulation or a placebo effect (33). However, two studies have also suggested that administration of ginseng (or a combination of ginseng and G. biloba) has no effect on cognition (and mood). Hartley and colleagues evaluated the effects of a 6- or 12-week course of a ginkgo ginseng combination product (Gincosan ) on the mood and cognition of...

Cardiovascular Effects

In a double blind, placebo-controlled, randomised trial of red clover-derived isoflavones (43.5 mg day), with 205 women aged between 49 and 65 years, active treatment had no significant effect on total cholesterol or HDL- and LDL-cholesterol levels or triglycerides (Atkinson et al 2004b). A single-blind, randomised crossover study of 21 healthy premenopausal women (aged 18-45 years) found that tablets containing 86 mg day isoflavones for two menstrual cycles did not significantly change total cholesterol, HDL- or LDL-cholesterol or triglyceride levels (Samman et al 1999). Another study of postmenopausal women with mild to moderate hypercholesterolemia also found red clover did not significantly affect plasma lipids (Howes et al 2000). A recent double-blind, randomised parallel study found that 86 mg day purified isoflavones derived from red clover also had no effect on cholesterol homeostasis or insulin resistance in 25 premenopausal women (Blakesmith et al 2003). However, there have...

Osteoporosis Prevention

Pharmaceutical HRT is sometimes used for preventing loss of bone following menopause however, a growing number of users are concerned about the increased risk of breast cancer associated with long-term HRT. As such, phyto-oestrogens have been used as an alternative to prevent osteoporosis. Most research has focused on soy isoflavones, although there is some evidence that red clover-derived isoflavones may also be of benefit. In a recent trial by Atkinson et al, loss of lumbar spine bone mineral content and bone mineral density was significantly reduced in women taking red clover-derived isoflavones (43.5 mg day) compared to placebo in a double-blind, placebo-controlled, randomised trial in 205 women over 12 months (Atkinson et al 2004c). Bone formation markers were also significantly increased however, no improvement in hipbone mineral content or bone mineral density was noted. A double-blind study of 46 postmenopausal women investigated the effects of a red clover isoflavone...

Adverse Reactions

The oestrogenic potency of the isoflavones has been well documented. Overgrazing cattle or sheep on red clover can be detrimental to their fertility. In 'clover disease', ewes are made permanently infertile by clover consumption. In animals with clover disease, the uterine response to oestrogen is reduced, as is the surge in LH. Clover disease has not been observed with normal therapeutic doses in humans. None of the trials has reported adverse effects. An isoflavone preparation from soya bean, and red clover extracts containing genistein, daidzein, biochanin A and formononetin, did not modify the endometrial architecture in 25 postmenopausal women taking the preparation for 1 year (Aguilar et al 2002).

Epidemiological Basis For Considering Gonadotropinhormonereleasing Hormone Analogues

Of early menopause or surgical oophorectomy on breast cancer risk. Epidemiological studies clearly demonstrate that early menopause, whether natural or artificial (bilateral oophorec-tomy), substantially reduces breast cancer risk. The large case-control study of Trichopoulos et al.2 showed that artificial menopause below age 35 is associated with a breast cancer relative risk of 0.36 (a 64 reduction). Feinleib3 noted in his large cohort study that among 1278 women with artificial menopause before age 40, six had breast cancer compared to an expected incidence of 24.0, a 75 reduction. Hirayama and Wynder's4 epidemiological study found that the relative risk of breast cancer was 0.56 for women with bilateral oophorectomy for women who were oophorectomized before age 37, the relative risk was 0.41 (i.e., a 59 reduction). What is of key importance is the magnitude of the benefit and the consistency of these findings. Menopause before age 35 is associated with a 60 -75 reduction in breast...

Breast Cell Proliferation And The Estrogen Plus Progesterone Hypothesis

Breast cancers are thought to arise from the epithelial cells of the terminal duct lobular unit (TDLU). Studies of cell proliferation rates of the TDLU are therefore of substantial interest to our understanding of the factors that influence breast cancer risk. Repetitive cell proliferation is central to the risk of many common human cancers, and factors that increase cell proliferation in a tissue may result in malignant transformation by increasing the probability of converting DNA damage, however caused, into stable mu-tations.6-10 In the postmenopausal human breast, the rate of TDLU cell proliferation is low compared to the premenopausal breast.11,12 This low rate of cell proliferation is consistent with the small change in breast cancer risk seen during the postmenopausal years. The steeply rising premenopausal breast cancer rates are consistent with the measured higher breast ep ithelial cell proliferation rates and vary associated with the phase of the menstrual cycle,...

GH Administration for Age Related Osteoporosis

Only a small number of studies have evaluated the effects of GH administration on bone density in women with postmenopausal osteoporosis and elderly men. The sample sizes of these studies have typically been small and overall fail to demonstrate a positive effect of GH on bone density. Aloia et al. (49) performed a series of three studies evaluating the effectiveness of GH in the treatment of post-menopausal osteoporosis. The first of these included eight patients who received pituitary-derived human GH for up to 12 mo (49). Bone resorption increased as measured by urine hydroxyproline, and bone density of the radius decreased. A subsequent study compared 24 mo of combination treatment with GH and calcitonin to calcitonin alone in 25 post-menopausal women, and showed a deleterious effect of the addition of GH on radial bone density (50). The third study compared a regimen of alternating GH and calcitonin to calcitonin alone in 14 women over 24 mo, and showed no significant difference...

Gonadotropinhormonereleasing Hormone Analogues

Native GnRH produced by the hypothalamus controls the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary and, thence, gonadal steroid hormone production. Inhibition of GnRH action can be achieved either with recently introduced antagonists or with agonists that desensitize GnRH receptors. Potent synthetic agonists of GnRH administered to pre-menopausal women produce a transient rise in FSH LH release followed by a sustained suppression. Reduction in serum estradiol and serum progesterone to oophorectomized levels by GnRH agonists has been demonstrated in numerous reports and has led to their use in the treatment of hormone-responsive metastatic breast cancer in premenopausal women.19 The role of ovarian ablation in the adjuvant therapy of early breast cancer remains unsettled, and studies evaluating GnRH analogues continue. Adjuvant studies in hormone receptor-positive premenopausal breast cancer patients show a benefit similar to...

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