Natural Menopause Relief Secrets

Holistic Hormone Balance

Every woman experiences hormonal imbalance at one point in life. The Holistic Hormone Balance is an essential guide that provides women with the information that they need to know on how to balance their hormones and reduce stress levels, fatigue, excessive weight gain, skin problems and increase desire in intimacy. In addition to that, the book provides women with steps to follow to identify any symptoms of hormonal imbalance and how to create an original and personalized treatment plan that works best for their body. A combination of natural hormone treatment has also been provided in the guide, making it easier for women to choose their best plan, that works best for them. Hormonal imbalance affects the female body and most of the time; they take the issue lightly, thinking that other people have more significant problems than theirs. Imbalance affects moods and creates discomfort in women. The frustration comes from the fact that they cannot do anything to change their situation, and always remain suffering in silence. The Holistic Hormone Balance book works towards helping women with hormone imbalance feel amazing again, by identifying the root cause of their problem and treating the symptoms when they occur. Continue reading...

Holistic Hormone Balance Summary


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The author presents a well detailed summery of the major headings. As a professional in this field, I must say that the points shared in this manual are precise.

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Perimenopausal transition

Perimenopause is defined as the two to eight years preceding menopause and the one year after the last menstrual period. It is characterized by a normal ovulatory cycle interspersed with anovulatory cycles. Menses become irregular, and heavy breakthrough bleeding can occur. Some women complain of hot flashes and vaginal dryness. C. Irregular bleeding and menopausal symptoms during this perimenopausal transition may be treated by estrogen-progestin replacement therapy. However, some women still require contraception. In this case, menopausal symptoms may be effectively treated with a low-dose oral contraceptive if the woman does not smoke and has no other contraindications to oral contraceptive therapy. D. The oral contraceptive can be continued until the onset of menopause, determined by a high serum FSH concentration after six days off the pill. Estrogen replacement therapy can be started at this point. II. Menopause occurs at a mean age of 51 years in normal women. Menopause...

Treatment of menopausal symptoms with estrogen

Data from the WHI and the HERS trials has determined that continuous estrogen-progestin therapy increases the risk of breast cancer, coronary heart disease, stroke, and venous thromboembolism over an average follow-up of 5.2 years. As a result, the primary indication for estrogen therapy is for control of menopausal symptoms, such as hot flashes. 2. Estrogen therapy remains the gold standard for relief of menopausal symptoms, and is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous venous thromboembolic event or stroke, or those at high risk for these complications. Estrogen therapy should be used for shortest duration possible (eg, 6 months to 5 years). 5. Low-dose oral contraceptives. A low-estrogen oral contraceptive (20 g of ethinyl estradiol) remains an appropriate treatment for perimenopausal women who seek relief of menopausal symptoms. Most of these women are between the ages of 40 and 50 years and...

Hormone replacement therapy HRT gonadatropinreleasing hormone GnRH agonists estrogen

Epidemiological studies showing an increased prevalence of AD in postmenopausal females focused interest on the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in AD. Additionally, females with high levels of endogenous estrogen were less prone to develop AD.42 The possibility that estrogen might serve as an AD preventive led to several preclinical studies examining its protective effects against amyloid toxicity and on cognitive performance. HRTwas found not only to be ineffective in preventing AD in postmenopausal women over the age of 65 years in the National Institute of Health-sponsored Women's Health Initiative Memory Study, but increased the risk of dementia. Despite this finding, regulation of the HPG axis is still thought to be key in the development of AD, since AD patients show a twofold increase in gonadotropins, specifically luteinizing hormone in AD patients. Luteinizing hormone is thought to cause reactivation of the cell cycle in neurons leading to cell...

Alternative Therapies to Hormone Replacement Therapy

SERMs are nonsteroidal estrogenic compounds with both estrogenic agonist (on bone and lipoproteins) and estrogenic-antagonist (on breast and endometrium) effects in use for the treatment of osteoporosis. Although SERMs have shown beneficial effects on some surrogate markers of CVD it is not known whether this will translate into clinical benefit. The recent secondary analysis of the osteoporosis prevention study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, suggested that there were no significant differences between raloxifene and placebo group regarding combined CHD and CVD events. Interestingly, however, in the subset with increased cardiovascular risk, the raloxifene group had a significantly lower risk of CVD events compared with placebo (99). The Raloxifene Use for the Heart Studyis currently testing the impact of raloxifene on cardiovascular endpoints in postmenopausal women. The results of this trial will provide information on the net clinical cardiovascular...

Effects of HRT on Endothelial Function in Postmenopausal Women With Diabetes

Endothelial dysfunction is the hallmark of diabetes and is regarded as an early manifestation of atherogenesis. In postmenopausal women with diabetes, multiple pathophysiological processes may contribute to endothelial dysfunction. These are diabetes- related, as a result of hyperglycemia and obesity insulin resistance and menopause-related as a result of loss of the protective effect of estrogen, as discussed earlier. Despite the importance of the endothelium, there is limited data on the effects of HRT on endothelial dysfunction in postmenopausal women with diabetes. In a recent study comparing healthy and diabetic postmenopausal women, Lim and associates (109) found that, although cutaneous vasodilation was impaired in postmenopausal women, it was able to be improved by HRT in nondiabetic subjects, but the improvement was less apparent in the diabetic cohort. However, the use of HRT in women with diabetes was associated with lower soluble ICAM levels, suggesting an attenuation in...

Risk Factors and Cancer

Diet and obesity in adults account for 30 of all cancer deaths in the USA. Diet has been shown to play a significant role in the causation of cancer but little is known about how it plays its role as a carcinogen.15,18 Excessive fat in the diet raises the risk of colorectal and breast cancer and possibly prostate cancer. Adult obesity is associated with endometrial cancer, postmenopausal breast cancer, and cancers of the colon, rectum, and kidney.15,18 Obesity in concert with other risk factors such as low activity level, menopausal status, and predisposition to insulin resistance significantly increase the risk of cancer. While some methods of food preparation and preservation have been shown to increase the risk of various forms of cancers, certain classes of foods appear to contain protective substances against cancer including vegetables, whole grain products (fiber), and citrus fruits.12,15,18,20 Salt intake has been associated with risk of stomach cancer, but no other food...

Special circumstances

Atrophic epithelium (a normal finding in postmenopausal women) is often characterized by nuclear enlargement, which meets one of the pathologic criteria for ASC. Administration of estrogen (eg, 0.3 mg conjugated estrogen applied as vaginal cream nightly for four weeks 1 8th of the applicator ) causes atypical atrophic epithelium to mature into normal squamous epithelium.

Background and Introduction

In 1896 George Beatson1 demonstrated that removal of the ovaries from premenopausal women could cause the regression of breast cancer. By the turn of the century it was established2 that about one-third of all premenopausal women with advanced breast cancer could benefit from oophorectomy and from that time, a principal strategy for the treatment and prevention of breast cancer has been either to block or to restrict the action of estradiol in its target tissue, the breast. However, the successful clinical development of the antiestrogenic drug tamoxifen did not initially focus on the therapy for breast cancer but evolved to this application by drawing upon expertise in several unrelated disciplines. Most of the early interest in antiestrogens was focused on reproductive endocrinology but it was clear from the beginning of clinical studies that the effects of the drugs on cholesterol biosynthesis would play a pivotal role in assessing safety considerations for long-term therapy....

Gender Ethnicracial And Life Span Considerations

Because early cervical cancer is usually asymptomatic, establish a thorough history with particular attention to the presence of the risk factors and the woman's menstrual history. Establish a history of later symptoms of cervical cancer, including abnormal bleeding or spotting (between periods or after menopause) metrorrhagia (bleeding between normal menstrual periods) or menorrhagia (increased amount and duration of menstrual bleeding) dysparuenia and postcoital bleeding leukorrhea in increasing amounts and changing over time from watery to dark and foul and a history of chronic cervical infections. Determine if the patient has experienced weight gain or loss abdominal or pelvic pain, often unilateral, radiating to the buttocks and legs or other symptoms associated with neoplasms, such as fatigue.

Benign Breast Disease

Rarely does breast pain represent cancer however a thorough breast exam and evaluation should be performed. Breast pain is characterized as cyclical or noncyclical with treatment as determined by the type of pain present. Cyclic pain is probably hormonal in nature, since it can be associated with elevated prolactin levels and relieved with menopause. Noncyclic mastalgia affects older women and the origin of the pain should be discriminated as chest wall or breast pain.

Current Chemoprevention

Based on a thorough review of all the available data, the FDA approved tamoxifen for the reduction of breast cancer incidence in high-risk pre- and postmenopausal women in 1998. However, the report that tamoxifen caused a small but significant increase in uterine sarcoma209 resulted in an industry request for a black box inclusion for tamoxifen from the FDA. Additionally, the IBIS-1 study noted an unacceptable increase in deaths from tamoxifen treated patients who inadvertently had surgery during the study acceptability of tamoxifen as a chemopreventive.210 This led to the development of IBIS-2 using an aromatase inhibitor to prevent breast cancer. Aromatase inhibitors have fewer side effects than tamoxifen and it is known that during adjuvant treatment, they reduce the incidence of contralateral breast cancer even more than tamoxifen.211-213 Another approach is the evaluation of the SERM raloxifene as a preventive for breast cancer in high-risk postmenopausal women. The Study of...

Risk Factors and Genetics

Breast cancer risk factors are related to prolonged exposure to estrogen. This is seen in women with early menarche and late menopause, older high estrogen dose oral contraceptives, and nulliparity. The highest risk involves a personal history of breast cancer or lobular carcinoma in situ. Family history in a premenopausal first degree relative is also an important risk factor.

System Reconstructive Procedures

The primary cause of cystoceles and rectoceles is a weakened vaginal wall. Factors that contribute to this loss of pelvic muscle tone are repeated pregnancies, especially those spaced close together, congenital weaknesses, and unrepaired childbirth lacerations. Obesity, advanced age, chronic cough, constipation, forceps deliveries, and occupations that involve much standing and lifting are also contributing factors. Lack of estrogen after menopause frequently aggravates the condition.

Raloxifene and Breast Cancer Prevention

Figure 7 Study design for the Continuing Outcomes Relevant to Evista (CORE) trial. CORE is a multicenter, double-blind, placebo-controlled clinical trial. It is a follow-up to the MORE trial and its purpose is to evaluate the long-term efficacy of raloxifene in reducing the incidence of invasive breast cancer in postmenopausal women with osteoporosis who were previously treated with raloxifene for up to 4 years in the MORE trial. All MORE investigation sites were invited to participate in the CORE trial. From those investigators choosing to participate, all women in the MORE trial (n 7705 participants) were invited to participate in the CORE trial after their completion or discontinuation from the MORE trial, and 4011 of those women chose to participate. Of the 2500 MORE trial participants who chose not to enroll in the CORE trial, 1217 women were still participating in the MORE trial as of January 1, 1999. The remaining 1283 women had completed their participation in the MORE trial...

Raloxifene and Lipids

Estrogen increases HDL cholesterol levels and decreases LDL cholesterol levels in humans39,171 as well in animal models of atherosclerosis, partly because of estrogen receptor-mediated upregulation of the hepatic LDL receptor.172 In ovariectomized rats, raloxifene treatment has been shown to reduce serum total cholesterol concentrations,97,173 and this reduction correlates with the extent of raloxifene binding to the estrogen receptor.97,173 These results are not surprising for a 'nonsteroidal antiestrogen,' as the original observations for clomiphene analogs and tamoxifen show (see 8.08 Tamoxifen). Raloxifene may also have cardioprotective effects because of its antioxidant properties. This is important since oxidative modifications of LDL have been implicated in atherogenesisis.174 Raloxifene also appears to have a favorable effect on lipid parameters in postmenopausal women. In the published European trial,78 treatment with raloxifene in a dosage of 30, 60, or 150 mg day_ 1...

Estrogen and Apolipoproteins E and J in the Periphery

A considerable amount of data exists on estrogenic control of the blood-lipid profile and apoE levels. Estrogen replacement therapy (ERT) after natural or surgically induced menopause prevents elevations of total cholesterol and LDL-cholesterol, while maintaining high density lipoprotein (HDL)-cholesterol.6-10 Although ERT initially increases production of both HDL11 and LDL-cholesterol, ERT also increases the clearance of LDL6,12 and VLDL.13 One mechanism of faster clearance of postprandial lipids is an increase in hepatic LDL-receptor activity.14 However, HDL clearance does not appear to be affected by estrogen.6 Thus ERT shifts blood cholesterol and lipoproteins to a less atherogenic profile with a lower LDL HDL ratio. The risk of cardiovascular disease is correlated with earlier age of menopause, with the greatest risk if menopause occurs before 39 years the risk of cardiovascular disease is reduced by 2 for each year that menopause is delayed.15

Peroxisome Proliferator Activated Receptory Key Regulator of Adipogenesis and Insulin Sensitivity

PPAR-y was first identified as a part of a transcriptional complex essential for the differentiation of adipocytes, a cell type in which PPAR-y is highly expressed and critically involved (6). Homozygous PPAR-y-deficient animals die at about day 10 in utero as a result of various abnormalities including cardiac malformations and absent white fat (7-9). PPAR-y is also involved in lipid metabolism, with target genes such as human menopausal gonadotropin coenzyme A synthetase and apolipoprotein (apo)-A-I (10,11). Chemical screening and subsequent studies led to the serendipitous discovery that thiazolidinediones (TZDs) were insulin sensitizers that lower glucose by binding to PPAR-y. Used clinically as antidiabetic agents, the TZD class includes pioglitazone (Actos) and rosiglitazone (formerly BRL49653, now Avandia) (12,13). Troglitazone (ReZulin) was withdrawn from the market because of idiosyncratic liver failure. Naturally occurring PPAR-y ligands have been proposed, although with...

Estrogen AD and Possible Mechanisms of Estrogen Induced Neuroprotection

Long-term use of ERT have the lowest risk.2 Gender differences were suggested as a possible explanation for the higher incidence of the familial AD in women that is also linked to the apoE-associated risk factor.5 In addition, Phillips and Sherwin32 showed that exogenous E2 maintains short-term memory in surgically-induced menopausal young women. Several levels of evidence demonstrated multiple sites of estrogen actions in the brain. The specific mechanism s by which estrogen reduces dementia are unclear, and they might be combined in order to be beneficial in improvement of clinical symptoms. Estrogen and several other estrogenic steroids which are contained in Premarin (the most common ERT drug) were also indicated as potential neurotrophins that increased survival and growth of hippocam-pal and cortical neurons in vitro.33 Direct actions of E2 and other estrogenic steroids on neurons occurred rapidly, suggesting involvement of membrane receptor(s) that mediate estrogen-induced...

Musculoskeletal System

The development of osteoporosis in middle-age men is uncommon except in male alcoholics, where decreased bone mass has been documented (Turner, 2000). In women, improvement in bone mass has been shown with moderate alcohol use, especially in postmenopausal women (Laitinen et al., 1993).

Of the National Osteoporosis Foundation

Measurement of BMD is recommended for all women 65 years and older regardless of risk factors. BMD should also be measured in all women under the age of 65 years who have one or more risk factors for osteoporosis (in addition to menopause). The hip is the recommended site of measurement.

Zero population growth

Thus, Hill and Hurtado imply that a long-standing feature of human biology may have been not just the Malthusian possibility, but actual rapid increase, and a saw-tooth population history. They suggest that this may influence our ability to assess accurately the significant selective forces responsible for our biology and behaviour 'Perhaps trade-offs were not detected, and menopause not favored by kin selection, because the Ache were in a period of resource abundance'. There must also be implications for archaeologists' ideas about invention and 'intensification' as a response to population pressure.

Grandmothering age at maturity interbirth intervals and fecundity

In CM, aM is approximately invariant because longer life spans favour more advanced age at maturity. More time to accrue the benefits of increased production associated with growing longer before reproducing offsets the cost of delay. If gains from growing longer continue to pay off after menopause, as the grandmother hypothesis proposes, then a should be adjusted accordingly. It is. These authors found that the late age at maturity for humans (high a) combined with our long life spans (low M) result in an aM similar to that of the other great apes. The delay in maturity for humans is as predicted if the gains from growing longer before reproducing pay off throughout adulthood, during both childbearing and grandmothering years. The grandmother hypothesis combined with CM accounts for several distinctive features of human life history, including long life spans after menopause, late age at maturity, short interbirth intervals, and high fertility. Other hypotheses have been offered to...

[KLOHnihdeen Pregnancy Category C

Epidural use causes analgesia at presynaptic and postjunctional al-pha-2-adrenergic receptors in the spinal cord due to prevention of pain signal transmission to the brain. tv2, distribution, epidural 19 min elimination 22 hr. Uses Oral, Transdermal Mild to moderate hypertension. A diuretic or other antihypertensive drugs, or both, are often used concomitantly. Non-FDA Approved Uses Alcohol withdrawal, atrial fibrillation, attention deficit hyperactivity disorder, constitutional growth delay in children, cyclosporine-associated nephro-toxicity, diabetic diarrhea, Gilles de la Tourette's syndrome, hyperhidrosis, hypertensive emergencies, mania, menopausal flushing, opiate detoxification, diagnosis of pheochromocy-toma, postherpetic neuralgia, psychosis in schizophrenia, reduce allergen-induced inflammatory reactions in extrinsic asthma, restless leg syndrome, facilitate smoking cessation, ulcerative colitis.

Ovarian factor infertility

Human menopausal gonadotropins (hMG, Pergonal, Metrodin) ovulation induction with is another option for the treatment of ovulatory dysfunction. Because of its expense and associated risk of multiple gestations, gonadotropin therapy should be reserved for patients who remain refractory to CC therapy. The pregnancy rate with gonadotropin therapy is 25 per cycle. This is most likely the result of recruitment of more follicles with gonadotropin therapy. The incidence of multiple gestations with gonadotro-pin therapy is 25 to 30 .

Sources of Estrogens in Women

The estrogen compounds to which target tissues in women, including the vascular system, may be exposed are multiple and they arise from endogenous and exogenous sources. The naturally occuring estrogens 17 -estradiol (E2), estrose (E1), and estriol (E2) are C18 steroids and are derived from cholesterol in steroidogenic cells. In the premenopausal women, the primary source of estrogens are the ovaries. E1 and E3 are primarily formed in the liver from E2 (10). After menarche, when circulating E2 levels increase and begin to cycle, levels range from 10 to 80 pg mL during the follicular phase to 600 pg mL at midcycle. Following ovulation, progesterone is secreted from the luteinized cells during the luteal phase of the cycle. Progesterone has two main functions in the body, namely, transformation of the endometrium after estrogen priming (luteomimetic effect) and opposition to estrogen (anti-estrogenic effect), limiting proliferation of the endometrium. After menopause, estrogen...

Effects of Estrogen on Endothelial Function

The onset of menopause provides a natural model of estrogen deprivation in which the effects of the endogenous hormone on vascular function can be evaluated. In studies of changes in branchial artery diameter after reactive hyperemia, responses were greater in premenopausal than in postmenopausal women (31). Importantly, blood-flow responses to the NO donor glyceryl trinitrate (GTN) were similar in the two groups, indicating comparable vascular smooth muscle responses to NO. The responses in postmenopausal women were comparable to those observed in men (31). In agreement with these findings, sex hormone deprivation after ovariectomy or premature ovarian failure, is associated with a decline in endothelial-dependent vasodilation, whereas the response to GTN is unaltered (32,33). Another natural model of changes in estrogen levels is the menstrual cycle. In young women, endothelium-dependent vasodilation in the branchial artery paralleled serum estradiol levels, and furthermore, there...

Effects of Estrogen on Hemostatic Factors

Hepatic expression of the genes for several coagulation and fibrinolytic proteins are regulated by estogen through ERs (18). Elevated levels of fibrinogen, von Willebrand factor, and factor VII are thought to be important risk markers for ischemic heart disease. These factors have been reported to be increased in postmenopausal women (51). Use of HRT in postmenopausal women has been shown to decrease fibrinogen levels but also to decrease plasma concentration of the anticoagulant protein anti-thrombin III and protein S, and to increase factor VII activity (52). On the other hand, reduced fibrinolytic activity is associated with atherosclerosis and has been attributed to increased levels of the antifibrinolytic factor plasminogen activator inhibitor-1 (PAI-1) (53). Increased PAI-1 levels have been found in postmenopausal women, and a close relationship between low fibrinolytic activity, high PAI-1 and hyperinsulinemia has been observed in various populations (54). Even small doses of...

Effects of Estrogen on Lipids and Lipoproteins

Estradiol at plysiological levels has an antioxidant capacity that is independent of its effects on serum lipid concentrations. Thus, administration of 17 -estradiol in postmenopausal women can decrease the oxidation of LDL cholesterol, which could enhance endothelial NO bioactivity (62). This antioxidant effect may be as a result of ER-mediated changes in the expression of genes for enzymes that regulate the local production and degradation of superoxide. Recent evidence suggests that remnant lipoprotein particles (RLPs) are the most atherogenic particles among the triglyceride-rich lipoproteins. In particular, RLPs appear to be associated with impaired endothelial function and with severity of atherosclerosis and were identified as an independent risk factor for CVD in women (63). In this context, a recent randomized study demonstrates a favorable effect of HRT on lipoprotein remnant metabolism in postmenopausal women, without significantly affecting triglycerides (64).

Effects of Estrogen on Inflammatory Markers

Recent studies have indicated that oral estrogen therapy may increase levels of CRP in healthy postmenopausal women suggesting that estrogen may initiate or aggravate inflammation (67,68). In contrast, animal studies failed to demonstrate such proinflammatory effects of estrogen when given by subcutaneous implantation or injection (69). In this regard, a recent study in postmenopausal women showed that oral but not transdermal estrogen therapy increased CRP by a first pass hepatic effect (70). Additionally, although oral HRT may increase CRP it reduces other inflammatory markers including E-selectin vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM)-1, and soluble thrombomodulin (71), indicating that the increase in CRP after oral HRT may be related to metabolic hepatic activation and not to an increased inflammatory response. However, because CRP is a predictor of adverse cardiovascular prognosis and may be involved in the process of atherosclerosis, the route...

Candida vulvovaginitis

Candida vulvovaginitis accounts for one-third of vaginitis. Up to 75 of women report having had at least one episode of candidiasis. The condition is rare before menarche. It is less common in postmenopausal women, unless they are taking estrogen replacement therapy.

Data From Randomized Clinical Trials

The first large clinical trial assessing HRT for secondary prevention in women with established coronary CHD was the Heart and Estrogen Progestin Replacement Study (HERS) (6). The HERS trial was a double-blind, placebo-controlled randomized study with combined continuous oral HRT (CEE 0.625 mg and medroxyprogesterone acetate MPA 2.5 mg daily) in almost 3000 postmenopausal women, mean age 66.7 years, with pre-existing CHD for more than 4.5 years. The study failed to demonstrate any overall differences in vascular events between the placebo and active treatment groups. There was an increase in the rate of coronary and thromboembolic events among HRT users in the first year of follow-up despite an improvement in lipid parameters. By the fourth year, the rate of vascular events in the HRT group was below that of the placebo group. However, recently published data from the extension of the HERS study to 6 years (HERS II) have shown that the trend toward reduction in cardiovascular events...

Primary Nursing Diagnosis

Nonsurgical management includes medications to assist in the excretion of calcium by the kidneys. Medical therapy, however, has not been shown to affect the clinical outcome of primary hyperparathyroidism. Postmenopausal women with primary hyperparathyroidism may receive estrogen replacement therapy. The patient may be placed on a low-vitamin D diet that is high in calories, but calcium restrictions are generally not beneficial. To increase calcium excretion, the patient needs a large fluid intake, at least 2 to 3 L per day, and 8 to 10 g of salt per day. Foods high in fiber will assist the patient to have normal bowel function.

The State of the Vascular Endothelium

It appears that a woman's age and the number of years since menopause are potential factors modifying the influence of HRT on CHD. In this regard, in the Nurses' Health Cohort Study, the women ranged in age from 30 to 55 years at enrollment and almost 80 , commenced estrogen therapy within 2 years of menopause (5). In contrast, the mean age of participants was 63 years in the WHI and 67 years in HERS thus, these women had on average been postmenopausal for 10 years at the time of enrollment. In light of the above observations it is possible that HRT could be beneficial in younger women, before plaque complications set in, but may not inhibit progression from complicated plaques to coronary events in older women.

HRT and Genetic Factors

Thus the estrogen associated risk for thrombosis may be increased in the presence of the prothrombin 20210 G A variant, the factor V Leiden mutation or platelet antigen-2 polymorphisms (95-97). A common sequence variation of the ER gene is associated with the magnitude of the response of HDL cholesterol levels to HRT in women with coronary disease (19). The same ERP genotype is also related to changes in the levels of SHBG, another index of estrogen action (95). It is also interesting that in the HERS trial high levels of Lp(a), which is largely genetically determined, were an independent risk factor for CHD events in the placebo group. HRT lowered Lp(a) levels and the cardiovascular benefit of HRT was significantly related to the initial Lp(a) levels and the magnitude of the reduction in the level (98). It appears therefore, that genetic factors may also contribute to the net clinical effect of HRT regarding CVD in postmenopausal women.

Iiifigo staging systems

Although cervical cancer is staged clinically, the results of surgical staging can be used for treatment planning. The staging procedure can be performed through a laparotomy (transperitoneal or extraperitoneal) or laparoscopically. Surgical staging allows for a complete pelvic and paraaortic lymphadenectomy. Nodal tissue obtained at the time of surgery can detect microscopic disease. Staging offers an opportunity to resect bulky metastatic lymph nodes and allows for individualization of the radiation field. In premenopausal women, oophoropexy can be done at the same time to protect the ovaries from radiation damage.

Treatment of earlystage Iblla carcinoma

Radical surgery leaves the vagina in more functional condition, while radiation therapy results in a reduction in length, caliber, and lubrication of the vagina. In premenopausal women, ovarian function can be preserved with surgery. The surgical approach also provides the opportunity for pelvic and abdominal exploration and provides better clinical and pathologic information with which to individualize treatment.

Conclusions and Future Directions

There are several plausible explanations for the divergent findings from the clinical trials and the observational studies regarding the effect of HRT on CVD in postmeno-pausal women. Some discrepancies may be methodological in nature and others may have a biological basis related to the pleiotropic effects of estrogens and the characteristics of the study population. The later may be related to age, time since menopause, state of the arterial endothelium and stage of atherogenesis. Genetic factors may also contribute to the heterogeneity of the population. The cardiovascular effects of estrogen are certainly far more complex than was initially thought. Unraveling these effects remain a challenge for future research. Despite the disappointing outcomes from the clinical trials, there is considerable evidence to support the beneficial effects of estrogens in the early stages of atherogenesis (during the menopausal transition and the early years of postmenopause). In clinical practice it...

Effects of Estrogen on Risk Factors for Diabetes

The changes in lipid metabolism that occur with the menopause, including increased total and LDLC, triglycerides and Lp(a), and decreased HDL-C, resemble those of type 2 diabetes and the metabolic syndrome (12). Adverse changes in carbohydrate metabolism also emerge with the menopause including decreased insulin sensitivity and insulin secretion (128). These together with increased central adiposity contribute to the increased risk of CVD in postmenopausal women. The effects of estrogen on lipid parameters are discussed in detail in the first part of this chapter. A number of observational studies have also reported that estrogen improves insulin resistance in postmenopausal women, a factor that is predictive for the development of type 2 diabetes (125,129). Estrogen therapy also appears to prevent central fat distribution, a factor that is strongly associated with insulin resistance (126). Thus, estrogen can potentially prevent the insulin resistance associated with central obesity...

Effects of HRT on Carbohydrate Metabolism in Women With Diabetes

There is a degree of reluctance among health care professionals to prescribe HRT to women with diabetes. A community-based survey in London found that diabetic postmenopausal women were less than half as likely as the general population to be prescribed HRT (137). Doctors and health care professionals perceive HRT as detrimental for diabetic women because of fear about glycemic control as is also the case with the oral contraceptive pill (138). Yet there is no evidence that HRT results in deterioration of glycemic control in women with diabetes. Oral estradiol has been shown to improve glucose metabolism and insulin sensitivity in diabetic women (132,139), whereas transdermal estradiol was found not to affect glycemic control (140). The addition of norethisterone does not appear to adversely affect glycemic control, although it may reduce any benefit seen with oral 17 -estradiol alone. In women with IGT, Luotola and associates (141) reported that natural estrogen progestogen...

Diagnostic evaluation

It is reasonable to pursue a period of observation in a premenopausal woman with an adnexal mass if the mass is not clinically suspicious on ultrasonography. Adnexal masses that are mobile, purely cystic, unilateral, less than 8 to 10 cm in diameter, and have smooth internal and external contours by ultrasound are highly unlikely to be malignant and can be followed for two months the majority of physiologic cysts will regress during this time. E. The threshold for surgical intervention is lower in postmenopausal women those with cysts greater than 3 cm should undergo exploratory surgery, laparotomy, or laparoscopy.

Effects of HRT on Lipids in Women With Diabetes

Serum lipid parameters show an overall beneficial change on HRT in postmenopausal diabetic women. Unopposed oral estradiol increases HDL-C and reduces LDL-C, whereas the addition of norethisterone may not alter this beneficial effect (132,148). Oral CEE 0.625 mg daily has been shown to reduce total and LDL-Cin women with diabetes, although increasing HDL-C (149). In one study, the increase in HDL-C was less than among nondiabetic women (150). Not all studies have shown an increase in triglycerides with oral CEE (149), although one showed a greater increase among women with diabetes Regarding Lp(a), no significant differences were found among the groups studied in the NHANES III survey. However, in a randomized controlled study combined continuous HRT (CEE + MPA) has shown beneficial effects on Lp(a) in postmenopausal women with type 2 diabetes (153). Also, a significant reduction in Lp(a) and triglycerides has been reported following treatment with tibolone (154).

Risk Factors for Breast Cancer

Late menopause Obesity Weight gain G. Conclusions. Seventy-five percent of women with newly diagnosed breast cancer demonstrate no specific, identifiable risk factor. Most premenopausal breast cancer cases are genetically determined. In contrast, many postmenopausal cases are environmentally related.

HRT and Risk of Cardiovascular Disease in Women With Diabetes

CVD is the most common cause of death in type 2 diabetes. This increased risk is particularly apparent in women with diabetes in which the relative protection afforded by the female sex is lost (107). For women without diabetes, prospective cohort surveys such as the Nurse's Health Cohort Study, suggest that estrogen therapy decreases the risk of CHD in postmenopausal women who were initially healthy at the time of enrollment (5). However, data from the HERS and WHI clinical trials have questioned the validity of epidemiological evidence by reporting an increased risk of CHD among women assigned to HRT (6,7). With respect to the effect of HRT on the progression of atherosclerosis, Dubuison and associates (174) conducted a cross-sectional analysis and found that the beneficial effect of ERT HRT on carotid intima-media wall thickness a common measure of subclinical atherosclerosis was similar in diabetic and nondiabetic postmenopausal women. In the HERS trial, nearly 23 of the...

Calendar Time And Information Time

At the planning stage the sample size is usually calculated based on information regarding the expected difference between treatments, its corresponding variability, and the desired statistical power for a predetermined risk of type I error. After the study is initiated, patients are enrolled to receive the treatment for a fixed length of time until he or she reaches either the end of the study or the time of analysis with survival as one of the primary endpoints. The Postmenopausal Estrogen Progestin Interventions (PEPI), for example, is a trial funded by the U.S. National Institutes of Health to evaluate the effects of unopposed estrogen and combined estrogen-progestin therapy on four major cardiovascular disease risk factors in postmenopausal women (Espeland et al., 1995). These four risk factors include plasma HDL-cholesterol, systolic blood pressure, two-hour postoral glucose serum insulin, and plasma fibrinogen. Table 10.5.1 gives the five treatments to be assessed in the PEPI....

The Uterus Benign Conditions Leiomyoma

Leiomyomas are benign tumors of smooth muscle origin. They are the most common uterine tumors, with a prevalence of 20 in women over the age of 35. The prevalence is even higher in women of African descent. The tumors are estrogen-dependent and often regress with menopause.

Follicular Growth and Ovulation Estrogen and Progestin Production

Estrogen Follicular Growth

Ethinylestradiol (EE) is more stable metaboli-cally, passes largely unchanged through the liver after oral intake and mimics estradiol at estrogen receptors. Mestranol itself is inactive however, cleavage of the C-3 methoxy group again yields EE. In oral contraceptives, one of the two agents forms the estrogen component (p. 256). (Sulfate-)conjugated estrogens can be extracted from equine urine and are used for the prevention of post-menopausal osteoporosis and in the therapy of climacteric complaints. Because of their high polarity (sulfate, glu-curonide), they would hardly appear suitable for this route of administration. For transdermal delivery, an adhesive patch is available that releases estradiol transcutaneously into the body. Indications for estrogens and progestins include hormonal contraception (p. 256), hormone replacement, as in postmenopausal women for prophylaxis of osteoporosis bleeding anomalies, menstrual complaints. Concerning adverse...

Normal MR Anatomy of the Female Genital Organs

The uterus is best depicted using T2-weighted sagittal sequences. In women of reproductive age, the uterus is approximately 6-9 cm in length. In the premenopausal woman, three distinct zones are recognized (1) the highsignal intensity endometrium of varying thickness, depending on the menstrual cycle (2) the hypointense junc-tional zone, anatomically corresponding to the innermost layer of the myometrium and (3) the outer layer of the myometrium of intermediate signal intensity. Four zones are distinguished in the cervix by high-resolution MRI (1) the hyperintense mucous within the endocervical canal, (2) the cervical mucosa of intermediate to high signal intensity, (3) the hypointense cervical stroma surrounding the mucosa, and, (4) an additional layer of in- termediate signal intensity in continuity with the uterine myometrium representing smooth muscle (Fig. 1). In postmenopausal patients, the uterine corpus, but not the cervix, regresses and decreases in size.

The Uterus Malignant Conditions Cervical Cancer

Parametrial Invasion Mri Pelvis

Endometrial cancer images on T2-W sequence as either diffuse or focal widening of the endometrial canal 1, 37, 38 ,42 (Fig. 5). The hormonal milieu determines the normal endometrial width (approximately 13 mm for reproductive age women or post-menopausal women on hormone replacement therapy (HRT) vs 3 mm for postmenopausal women not on HRT). Disruption or irregularity of the junctional zone signifies myometrial invasion. Invasion is further classified as superficial, 50 ,

Concerns about Tamoxifen

Much controversy surrounded the associations between tamoxifen use and the detection of endometrial cancer. However, it was possible to provide a reasonable picture of the actual incidence of endometrial cancer and provide a balanced view of the concerns. Reviews154-156 of the literature in the mid-1990s only identified about 400 cases of endometrial cancer associated with tamoxifen use worldwide. Millions of women had taken tamoxifen over many years. The increase in the incidence of endometrial cancer was found predominately in postmenopausal women and there was not a strong association between the duration of tamoxifen use and the risks of developing endometrial carcinoma. Based on the known long genesis of cancer in humans, it was inappropriate to suggest that the detection of endometrial cancer was caused by short courses of tamoxifen. It is also important to point out that DNA adducts were found to be absent from uterine samples of patients taking tamoxifen.157 Detection bias,...

Malignant Tumors of the Cervix and Uterus

Endometrial tumor is indicative of myometrial invasion. The junctional zone, however, cannot always be delineated in postmenopausal women, which makes correct imaging interpretation difficult in these cases. Deep my-ometrial invasion is suggested by the presence of hyper-intense tumor in the outer half of the myometrium. Intravenous administration of gadolinium compounds is helpful for MR staging of endometrial carcinoma, with the cancer demonstrating less pronounced contrast-enhancement compared with the surrounding tissues. Contrast-enhanced images further improve the differentiation of vital tumor from necrosis or hematometra.

Diseases of Bone Epidemiology and Diagnosis

Amongst the metabolic bone diseases, osteoporosis is by far the most frequent one. The World Health Organization defines osteoporosis as a BMD of 2.5 standard deviations (SD) or more below the mean for young healthy individuals. According to this definition, approximately 30 of all postmenopausal women and 20 of all men older than 60 years of age have osteoporosis. The incidence of osteoporosis and of osteoporotic fractures increases with age while only 4-5 of all women 60-70 years of age are found to have low BMD, this proportion rises to 50 in women aged 80 years or older. Similarly, according to the Dubbo Osteoporosis Epidemiological Study (DOES), the incidence of osteoporotic fractures is approximately 2000 per 100 000 person-years in the age group 60-70 years, but rises to almost 8000 per 100 000 person-years in women aged 80 years or more. One-third of women and one-sixth of men at age 90 years are estimated to have suffered a hip fracture.22 The pathogenesis of osteoporosis is...

Osteoporosis and Fracture Risk

Osteoporosis is a reduction in bone mass and bone microarchitecture leading to increased bone fragility and fracture risk. The most common cause of osteoporosis is increased bone turnover with excessive bone resorption (destruction) that exceeds bone formation. Among women, this is often caused by estrogen deficiency following menopause. A second large and independent contributor is glucocorticoid use. Later in life, a combination of vitamin D insufficiency, reduced 1,25(OH)2-vitamin D3 production and inadequate calcium nutrition contribute to bone loss in both men and women. Both menopause and glucocorticoid use cause an imbalance between the processes of bone resorption (removal) and formation, leading to bone loss. A woman can experience a loss of up to 5 of her bone mass per year during the first half decade postmenopause. There exists a correlation between the reduction in bone mineral density1-4 and or increased bone turnover5-7 with increased fracture risk.

Clinical Use of Alendronate Fosamax

Alendronate (ALN) has had the most extensive clinical use to date in terms of the number of patients, over 4 million, and duration of monitored treatment, over 10 years. Its ability to reduce hip and other fractures is documented in large randomized placebo-controlled clinical trials, and 10 years of follow-up data are available from the extension of phase III ALN clinical trials.8 ALN is widely used for the treatment and prevention of osteoporosis in postmenopausal women and glucocorticoid-treated patients of both genders.9-16 ALN has been proven effective in significantly reducing the incidence of both vertebral and nonvertebral fractures, including those of the hip. The reduced risk of vertebral fracture is also associated with less height loss,17 as well as a significant reduction in the number of days where patients experience disability.18 Because ALN acts via a nonhormonal pathway, it has also been effectively used to increase bone mass associated with a number of different...

Goals Of Clinical Trials

The objective of this study is to evaluate the efficacy and safety of the test drug under investigation with a placebo in the treatment of postmenopausal women with osteoporosis. investigation at dose y, frequency z, compared to a placebo, in the treatment of postmenopausal women with osteoporosis. 2. This trial is a randomized, double-blind, placebo-controlled trial conducted in x centers to evaluate the safety of the test drug under investigation at dose y, frequency z, compared to a placebo, in the treatment of postmenopausal women with osteoporosis.

Genetic Considerations

The patient often appears thin and chronically ill. Her abdomen may be grossly distended, but her extremities are thin and even wasted. When you palpate the abdominal organs, you may be able to feel masses. During the vaginal examination, you may be able to palpate an ovary in postmenopausal women that feels like the size of an ovary in pre-menopausal women. An ovarian tumor may feel hard like a rock or pebble, may feel rubbery, or may have a cystlike quality. Palpation of an irregular, nodular ( handful of knuckles ), insensitive bilateral mass in the pelvis strongly suggests the presence of an ovarian tumor.

Mechanism of Action at the Tissue Level

Osteoporosis and other types of bone loss are associated with increased bone turnover and elevated levels of bone resorption. Osteoclastic bone resorption is a 2-week process that begins the bone remodeling process. Resorption itself can be effectively slowed or controlled by inhibiting osteoclast generation, reducing osteoclast activity, or both. ALN is one of the most effective inhibitors of bone resorption. ALN improvement of mechanical strength, reflected in a reduction in fracture risk, is caused by an increase in bone mass and mineralization (discussed above) as well as by an improvement in architecture, attributable to a reduction in bone turnover. A higher number of bone remodeling sites, where excessive osteoclastic destruction of bone takes place, leads to loss of bone tissue, formation of areas of stress concentration, and increased fracture risk. By reducing turnover, bisphosphonates reverse this condition. Effects on bone turnover can be estimated by measuring either...

Experimental Disease Models

One of the most significant current clinical trials involving the endocrine modulation of breast cancer is the Study of Raloxifene and Tamoxifen, or STAR. This is a large phase III, double-blind trial in which postmenopausal women are assigned to take tamoxifen (20mgday_ or raloxifene (60mgday_ for 5 years. The primary aim of this trial is to compare these two selective estrogen receptor modulators (SERMs) directly for efficacy and safety parameters with respect to breast cancer, coronary heart disease, and osteoporosis. In particular, the effects of long-term raloxifene therapy on preventing the occurrence of invasive breast cancer in postmenopausal women who are identified as being at risk for the disease will be investigated. Endocrine therapy has been practiced since the turn of the twentieth century. Pioneering studies by George Beatson in 1896 showed that surgical removal of the ovaries, the primary source of endogenous estrogen, from premenopausal women with metastatic breast...

HMG CoA Reductase Inhibitors

Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 1994 121(12) 936-941. 187. Gilligan DM, et al. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994 90(2) 786-791.

Standard rate method See standardisation

For example, hormone replacement therapy in menopausal women seeks to reduce the risk of fracture in this population, notably due to osteoporosis. To judge the efficacy of a new treatment using the robust criterion of a lessening of the risk of compression fractures would require a follow-up of more than 10 years. It is permissible, at least at the beginning, to judge this efficacy by the comparative evolution of the bone mineral density, which allows for a considerably shorter study.

Evolution of Antiestrogens to Raloxifene

We have obtained valuable clinical information about this group of drugs that can be applied in other disease states. Research does not travel in straight lines and observations in one field of science often become major discoveries in another. Important clues have been garnered about the effects of tamoxifen on bone and lipids so it is possible that derivatives could find targeted applications to retard osteoporosis or atherosclerosis. The ubiquitous application of novel compounds to prevent diseases associated with the progressive changes after menopause may, as a side effect, significantly retard the development of breast cancer. The target population would be postmenopausal women in general, thereby avoiding the requirement to select a high risk group to prevent breast cancer.

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

It has been established that HRT is beneficial in reducing osteoporosis and alleviating climacteric symptoms. HRT has also been shown to have beneficial effects on risk factors for CVD. However, data from recent clinical trials indicate that HRT, in the form of continuous combined CEE with MPA, has no cardioprotective effects and is not recommended for primary or secondary prevention of CVD in postmenopausal women. Data on HRT in postmenopausal women with diabetes are scarce but are of major importance, because these women are characterized by hyperandrogenicity, insulin resistance, and dyslipidemia and are at a higher risk for developing CHD. Evidence from the available data suggest that short-term unopposed oral estradiol has a beneficial effect on glucose homeostasis, lipid profile, and other components of the metabolic syndrome, which may be compatible with a reduced risk of CHD. The addition of a progestogen may attenuate some of these favourable effects. On the other hand, HRT...

Clinical Trial Issues

Males with prepubertal hypogonadotropic hypogonadism require the combined treatment with human chorionic gonadotropin (hCG) plus human menopausal gonadotropins to initiate sperm production and fertility. In those with a selective deficiency of GnRH, such as Kallmann's syndrome, pulsatile GnRH therapy has been shown to stimulate testosterone production and spermatogenesis.

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...

Sexual Desire and Aging

Male Steriod Facies

Among women, biological changes leading to menopause may extend over a 20-year period, with onset generally in the mid 30s and occasionally extending beyond the mid 50s. After menopause, the intensity of sexual response may be reduced, and for some postmenopausal women intercourse may be painful due to vaginal dryness. For many women, estrogen replacement therapy can relieve vaginal dryness and other symptoms of menopause and may help restore sexual desire.

Tamoxifens Legacy A Menu of Medicines

Gnrh Tumour Removal

Figure 7 The endocrine options in the early 1970s for the patient with metastatic breast cancer. Surgery to remove endocrine organs (ablative surgery) which secreted estrogenic hormones or their precursors. In the case of postmenopausal patients, additive high-dose estrogens, androgens, or progestins were standard therapy. Figure 7 The endocrine options in the early 1970s for the patient with metastatic breast cancer. Surgery to remove endocrine organs (ablative surgery) which secreted estrogenic hormones or their precursors. In the case of postmenopausal patients, additive high-dose estrogens, androgens, or progestins were standard therapy. The clinical success of tamoxifen encouraged an important re-evaluation of inhibitors for the aromatase enzyme system. In other words, block the synthesis of estrogens from androgen precursors. Early nonspecific inhibitors such as aminoglutethimide had many side effects, especially since there was a necessity to coadminister the drug with a...

Cortisol release and its modification by glucocorticoids

Stimulation of spermatogenesis in gonadotropin (FSH, LH) deficiency can be achieved by injection of HMG and HCG. HMG or human menopausal gonadotropin is obtained from the urine of postmenopausal women and is rich in FSH activity. HCG, human chorionic gonadotropin, from the urine of pregnant women, acts like LH.


Glycolic acid has been recognized as an important adjunctive therapy in a variety of conditions including photodamage, acne, rosacea, striae albae pseudofolliculitis barbae, hyper-pigmentation disorders, actinic keratoses, fine wrinkles, lentigines, melasma and seborrheic keratoses 5 . Moreover, it can reduce UV-in-duced skin tumor development and it has been proposed as a therapeutic modality against skin exfoliative conditions such as ichthyosis, xeroderma and psoriasis. In post-menopausal women a cream containing 0.01 estradiol and 15 glycolic acid, applied to one side of the face for 6 months, induces a significant improvement in reversing markers (rete peg pattern, epidermal thickness) of skin aging 6 .

Thyroid Drugs

Special Concerns Geriatric clients may be more sensitive to the usual adult dosage of these hormones. Use with extreme caution in the presence of angina pectoris, hypertension, and other CV diseases, renal insufficiency, and ischemic states. Use with caution during lactation. Side Effects Thyroid preparations have cumulative effects, and over-dosage (e.g., symptoms of hyperthy-roidism) may occur. CV Arrhythmias, palpitations, angina, increased HR and pulse pressure, cardiac arrest, aggravation of CHF. GI Cramps, diarrhea, N&V, appetite changes. CNS Headache, nervousness, mental agitation, irritability, insomnia, tremors. Miscellaneous Weight loss, hyper-hidrosis, excessive warmth, irregular menses, heat intolerance, fever, dyspnea, allergic skin reactions (rare). Decreased bone density in pre- and postmenopausal women following long-term use of levothyroxine.

Patenting Problems

In 1973, Nolvadex, the ICI brand of tamoxifen (as its citrate salt), was approved by the Committee on the Safety of Medicines in the UK for the treatment of breast cancer. Although tamoxifen was approved for the treatment of advanced breast cancer in postmenopausal women on 30 December 1977 in the US (ICI Pharmaceuticals Division received the Queen's Award for Technological Achievement in the UK on 6 July 1978), the patent situation was unclear. ICI Pharmaceuticals Division was repeatedly denied patent protection in the USA (with an exclusion of claims for a cancer treatment) until the 1980s because of the perceived primacy of the earlier Merrill patents229 and because no advance (that is, a safer, more specific drug) was recognized by the US Patent Office. In other words, the clinical development of tamoxifen advanced steadily for more than a decade in the USA without the assurance of exclusivity. This situation also illustrates how unlikely the usefulness of tamoxifen was considered...

Alendronate sodium

D Action Kinetics Alendronate inhibits osteoclast activity, thereby preventing bone resorption. It appears to reduce fracture risk and reverse the progression of osteoporosis. Alendronate does not inhibit bone mineralization. It is well absorbed orally and is initially distributed to soft tissues, but then quickly redistributed to bone. The drug is not metabolized and is excreted through the urine. However, the tV2, terminal is believed to be more than 10 years, due to slow release from the skeleton. Uses Prevention and treatment of osteoporosis in postmenopausal women (concomitant estrogen therapy is not recommended due to lack of experience). Prevention of fractures in postmenopausal women with osteoporosis. Paget's disease of bone. Contraindications In hypocalce-mia. Those with severe renal insufficiency (creatinine clearance less than 35 mL min). Lactation. Special Concerns Use with caution in those with upper GI problems, such as dysphagia, symptomatic esophageal diseases,...


Alendronate (Fosamax) has effects comparable to those of estrogen for both the treatment of osteoporosis (10 mg day or 70 mg once a week) and for its prevention (5 mg day). Alendronate (in a dose of 5 mg day or 35 mg week) can also prevent osteoporosis in postmenopausal women. D. Calcium. Maintaining a positive calcium balance in postmenopausal women requires a daily intake of 1500 mg of elemental calcium to meet this most women require a supplement of 1000 mg daily. E. Vitamin D. All postmenopausal women should take a multivitamin containing at least 400 IU vitamin D daily.

Complex Patenting

The reinvention of raloxifene is summarized as follows ''This invention provides new method for the treatment of bone loss comprising administering to a human in need of treatment an effective amount of a compound of Formula I.'' This is the generalization of the 2-phenyl-3-aroylbenzothiophene structure. The US patent no. 5,393,763 was a continuation of the application ser. no. 07 920,933 filed on July 28, 1992, which was abandoned. The chain of events that led to filing a patent application on July 28, 1992 is particularly interesting as the translational research published by the academic community had made the claim obvious for this class of drugs and for keoxifene in particular. In fairness, some of the relevant references were listed as 'other publications'96 in US patent no. 5,393,763. The Love publication144 on the bone-sparing effects of tamoxifen was a direct result of ongoing research at the University of Wisconsin Comprehensive Cancer Center that showed tamoxifen and...

Prevalent fractures

Figure 6 The effect of raloxifene on (a) bone mineral density and vertebral fracture in postmenopausal women with osteoporoisis79 and (b) breast cancer incidence168 in the MORE trial. At 36 months of the evaluable radiographs in 6828 women, risk of vertebral fracture was reduced in both study groups receiving raloxifene (60mgday -1 group RR, 0.62 95 CI, 0.5-0.8 120 mg day-1 group RR, 0.5 95 CI, 0.4-0.7). The cumulative incidence of breast cancer among subjects in the placebo group and those in the combined raloxifene group are represented as a percentage of all patients randomized to either group. Statistical significance of the difference between the groups was tested by a log-rank test (P 0.001). As a follow-up to the MORE trial, the CORE trial (Figure 7) was developed. The CORE study was designed to evaluate the long-term efficacy of 4 additional years of raloxifene therapy in reducing the incidence of invasive breast cancer in postmenopausal women with osteoporosis who previously...


Clinical manifestations. Endometrial hyperplasia should be suspected in women with heavy, prolonged, frequent, or irregular uterine bleeding. Abnormal uterine bleeding in perimenopausal or menopausal women is the most common clinical symptom of endometrial neoplasia, although such bleeding is usually (80 percent) due to a benign condition.

Axr Malrotation

Necrotising Enterocolitis Axr

At the time of radical hysterectomy for early-stage cervical carcinoma, the decision to remove or retain grossly normal ovaries in premenopausal patients involves weighing several competing factors. Ovarian conservation and lateral ovarian transplantation may be used when treating such patients 13 . When pelvic irradiation is planned, the ovaries are mobilized at the time of surgery. Then, with their vascular pedicle, they are transplanted near the peritoneum in each pericolic gutter (oophoropexy) and thus are removed from the radiation field. This information is vital to the radiologist so that normal ovaries will not be mistaken for an abnormal mass. 13. Parker M, Bosscher J, Barnhill D, Park R (1993) Ovarian management during radical hysterectomy in the premenopausal patient. Obstet Gynecol 82 187-190

Risk factors

Family history is highly significant in a first-degree relative (ie, mother, sister, daughter), especially if the cancer has been diagnosed premenopausally. Women who have premenopausal first-degree relatives with breast cancer have a three- to fourfold increased risk of breast cancer. Having several second-degree relatives with breast cancer may further increase the risk of breast cancer. Most women with breast cancer have no identifiable risk factors. B. Approximately 8 percent of all cases of breast cancer are hereditary. About one-half of these cases are attributed to mutations in the BRCA1 and BRCA2 genes. Hereditary breast cancer commonly occurs in premenopausal women. Screening tests are available that detect BRCA mutations.


Risk factors for breast cancer should be determined, including menarche before age 12 years, first live birth at age 30 years, and menopause at age 55 years the number of previous breast biopsies, the presence of atypical ductal hyperplasia on biopsy, obesity, nulliparity, increased age, the amount of alcohol consumed, and the number and ages of first-degree family members with breast cancer with two such relatives with breast cancer at any early age should be determined.


Hill and Hurtado (1991, 1996 p. 433) tested the classic version of the grandmother hypothesis of menopause do the benefits of help given to daughters outweigh the benefits of continued child bearing Ache demographic values show that, even under the most favourable assumptions, the effect of help on kin would have to be massively increased to give menopause a selective advantage. Ache women provide only 13 of the calorie income, and Hill and Hurtado note that the analysis needs to be repeated in populations in which women's contribution is much greater. Nonetheless, Hill and Hurtado (and Rogers, 1993) show that the effect would have to be almost unrealistically large.

Breast Cancer

Early menarche, late menopause, and late first pregnancy or nulliparity (more menstrual cycles more risk) Signs and symptoms that suggest a mass is breast cancer until proved otherwise fixation of breast mass to the chest wall or overlying skin, satellite nodules or ulcers on the skin, lymphedema peau d'orange, matted or fixed axillary lymph nodes, inflammatory skirt changes (red, hot skin with enlargement of the breast due to inflammatory cancer), prolonged unilateral scaling erosion of the nipple with or without discharge (may be Paget's disease of the nipple), microcalcifications on mammography, and any new breast mass in a postmenopausal woman.


Creswell, J.D., Egger, P., Fall, C.H., Osmond, C., Fraser, R.B. and Barker, D.J. (1997). Is the age of menopause determined in utero Early Human Development 49, 143-8. Hawkes, K., O'Connell, J.F. and Blurton Jones, N.G. (1997). Hadza womens time allocation, offspring provisioning, and the evolution of long post-menopausal lifespans. Current Anthropology 38, 551-77. Hill, K. and Hurtado, A.M. (1991). The evolution of reproductive senescence and menopause in human females. Human Nature 2, 315-50. Rogers, A.R. (1993). Why menopause Evolutionary Ecology 7, 406-20.

Cervical Cancer

Postmenopausal bleeding is cancer until proved otherwise endometrial cancer is the most common cancer If) present in this fashion (fourth most common cancer in women). Get an endometrial biopsy for any patient with postmenopausal bleeding (as well as a Pap smear and 3. Late menopause


CVD is the major cause of morbidity and mortality in Western societies. Although CVD is an uncommon cause of morbidity and mortality in premenopausal women, it is the most common cause of death among postmenopausal women (74). The pathophysi-ology of CVD involves atherosclerotic plaque development, inflammation and plaque disruption with development of overlying thrombosis. This can lead to vessel occlusion and organ ischemia with clinical sequelae (27,65). An established approach to prevent this condition is comprehensive risk reduction including both lifestyle measures and pharmacological interventions. Over the last decades, HRT was thought to be among these therapies with potential to reduce vascular disease in postmenopausal women (75,76).

Observational Data

Extensive observational data indicate that exogenous estrogen therapy appears to be cardioprotective. Investigators in a review of population-based, case-control, cross-sectional and prospective studies of estrogen therapy (with most using conjugated estrogens) and CHD, calculated that estrogen use reduces the overall relative risk of CHD by approx 50 (4). Observational studies comparing current hormone users with nonusers have shown consistent reductions in CHD risk ranging from 35 to 50 (76,77). A recent updated report from the Nurses' Health Cohort Study with 70,533 postmenopausal women followed up for 20 years, noted that overall, current use of ERT was associated with a relative risk of major coronary events of 0.61 (confidence interval CI , 0.52-0.71) when adjusted for age and the common cardiovascular risk factors (5). The findings from observational studies have been important in promoting the belief that HRT prevents CHD (77). Although the observational data are almost...


The conclusions of the HERS and WHI trials were diametrically opposite to the overwhelming observational evidence that HRT could be cardioprotective in postmenopausal women, raising the question regarding in which the clinical truth is. Several explanations for this apparent discordance have seen suggested. Some discrepancies may be the result of methodological differences between the observational and clinical studies as


The mechanisms by which diabetes abolishes the cardiovascular protective effects of female sex hormones in premenopausal women are not well understood. In fact, the loss of the natural sex advantage in women with diabetes is independent of other diabetes-associated conventional risk factors. After adjusting for differences in hypertension, dyslipidemia, and obesity, the cardiovascular risk still remains higher in diabetic women Given the central role of the endothelium in modulating vascular tone, lipid peroxidation, smooth muscle proliferation, and monocyte adhesion and the beneficial effects of estrogen in maintaining vascular health, it was hypothesized that diabetes may compromise the effects of estrogen on endothelial function, thereby increasing the potential for premature atherothrombosis. Indeed, recent clinical studies provide direct evidence that premenopausal women with diabetes have a significantly impaired regulation of vascular tone. In a recent study Di Carli and...

With diabetes

Healthy postmenopausal women undergo changes in lipoprotein and carbohydrate metabolism and in the pattern of body fat distribution similar to those of patients with diabetes. In fact, a picture resembling the metabolic syndrome emerges with the menopause (12). Replacement therapy with estrogen can improve the adverse impact of meno pause on lipid profile and bone mineral density, and there is evidence that estrogen may also improve carbohydrate metabolism and body fat distribution in healthy postmeno-pausal women (124-126). The role of HRT in preventing CVD in postmenopausal women, as discussed in detail in the first part of this chapter, remains highly controversial, but there is strong evidence that it may be beneficial in the early postmenopausal period and early stages of atherosclerosis. Postmenopausal women with diabetes are at risk of dyslipidemia, central obesity, hypertension, and accelerated atherosclerosis, all of which can contribute to an increased risk of CVD (127)....

Other drug therapies

There are compelling epidemiological reasons to consider the possibility that hormone replacement therapy in postmenopausal women with OSA, and use of anti-androgens in males with OSA, may be of therapeutic benefit. However, the results of such interventions in therapeutic trials have been disappointing 71 . However, the administration of medroxyprogesterone (MPG) to patients with the most severe form of OSAS, the obesity hypoventilation syndrome in which daytime hypercapnia and nocturnal sleep hypoventilation are integral clinical features, produces a beneficial ventilatory stimulant effect 71 . In contrast, a single placebo-controlled study of ten male patients with OSA treated with MPG did not demonstrate any difference in measured outcomes of AHI or total sleep time 72 . Furthermore, the significant range of adverse effects of this agent severely limit its applicability. There are no studies that show convincingly that hormone replacement therapy reduces sleep apnea severity in...


A hypothesis may be expressed in the null form (e.g., There is no relationship between hormone therapy and breast cancer in menopausal women ) or in the alternative form (e.g., The more that menopausal women use hormone therapy, the more likely it is that they will develop breast cancer ).

Sex hormones

Sex hormones are major regulators of bone turnover and remodeling in both genders. Estrogens reduce bone loss by inhibiting the generation of new osteoclasts, reducing the activation frequency of the BMU and promoting apoptosis of mature osteoclasts via mechanisms that are not well understood. Some of the effects of estrogen seem to be mediated via the modulation of growth factors and cytokines, while others are associated with binding to at least two different estrogen receptors (ERa, ERb). A reduction in circulating endogenous estrogen levels, as occurs during and after menopause, has been shown to prolong osteoclast survival and stimulate the recruitment and hence generation of osteoclasts. The result is an increase in the activation frequency of the BMU, reflected in a high bone turnover state.14 While there is no doubt that androgens (i.e., testosterone, dihydrotestosterone) play a dominant role in male bone health, it also appears that circulating estradiol levels are important...

Hormone Regulation

Sex hormones may also affect secretion of adiponectin, because women have higher plasma levels of adiponectin than men, independent of body composition (14). Of the sex hormones, estrogen does not seem to account for the gender-related difference in adiponectin level, because premenopausal women have higher estrogen levels and lower adiponectin concentrations than postmenopausal females and estradiol levels actually have a strong negative correlation with serum adiponectin levels, females would be expected to have lower adiponectin concentrations than men (19). Testosterone may lower adiponectin levels by possibly inhibiting its secretion, however. In mice, removal of the testes led to an increase in adiponectin, although administration of testosterone reduced adiponectin levels (27). Although one study has demonstrated no association between adiponectin and free testosterone concentrations in women, this relationship remains to be explored in men (19).

SHE study

Soy Health Effects Study (SHE) conducted under a National Institutes of Health grant to study the potential benefits of a dietary supplement of soy on the health of postmenopausal women. Subjects for the study consisted of women aged 45-74 y who attended screening and baseline visits and were subsequently enrolled in the Soy Health Effects (SHE) Study. The SHE Study is a randomized, double-blind, placebo-controlled trial designed to investigate the extent to which isoflavone use improves heart disease risk factors, bone density and quality of life in postmenopausal women. To be eligible for the SHE Study, women had to be at least 2 y postmenopausal, not using HRT for _ 3 mo, and not currently using lipid-lowering drugs, antidiabetic medications, tamoxifen, or soy protein or herbal supplements. Women with a history of uncontrolled hypertension, stroke or transient ischemic attack, cancer diagnosed


Lasofoxifene (Figure 10) is a novel nonsteroidal SERM that is in clinical trials for the prevention and treatment of osteoporosis in postmenopausal women.195 It is a diaryltetrahydronaphthalene derivative referred to as CP336156. The structure of CP336156 is reminiscent of nafoxidine (Figure 3) if it were to be demethylated in vivo. There are two diastereometric salts. CP336156 is the L enantiomer that has 20 times the binding affinity of the D enantiomer. Studies with human MCF-7 breast cancer cells and blocks N-nitrosomethylurea-induced mammary carcinomas in rats.198 In a phase III clinical trial conducted by Pfizer199 involving 410 postmenopausal women randomly assigned to CP336156 (0.25 or 1 mgday _ 1), raloxifene (60 mgday_ 1), or a placebo, CP336156 increased bone mineral density at the lumbar spine by about 2 after 2 years of treatment, compared to no increase with raloxifene and a 2 decrease in the placebo group. Changes in bone turnover markers were also greater with CP336156...

Disease Basis1 Early Onset of Menses and Late Menopause Onset of the menstrual cycle before the age of 12 and menopause after 50 are associated with increased risk of developing breast cancer. Patients with a positive family history of breast cancer are at increased risk for developing the disease. However, 85 of women with breast cancer have a negative family history. Family history includes immediate relatives - mother, sisters, and daughters. If a family member was postmenopausal (50 or older) when she was diagnosed with breast cancer, the lifetime risk is only increased by 5 . If the family member was premenopausal, the lifetime risk is 18.6 . If the family member was premenopausal and had bilateral breast cancer, the lifetime risk is 50 .

Sex differences

It should be noted that female specific issues may have significant effects on drug distribution and metabolism. For example, pregnancy may increase the elimination of certain drugs, reducing their efficacy. In addition, oral contraceptive use can affect the metabolism of drugs. The effects of menopause, menstruation, and hormone replacement on the pharmaco-kinetics of drugs are largely unknown.


The incidence of CAD in premenopausal women is less than in age-matched males (181). One possible explanation is the effect of estrogen. Estrogen may have important effects on vascular function that are not totally explained on the basis of an improved lipoprotein profile (182). Diabetic women have the same cardiovascular risk as nondia-betic men, suggesting that they are denied the cardiovascular protection of estrogen enjoyed by other premenopausal women (182). Estrogen's possible beneficial effects include not only inhibition of platelet aggregation (183), but also its antioxidative effect and antiproliferative effects on vascular smooth muscle. Several investigators have demonstrated that estrogen improves endothelium-dependent vasodilation in ovariectomized animals (184,185) and postmenopausal women (186-188). The mechanism may be enhanced eNOS production (188,189) or, alternatively, suppression of a prostaglandin H synthase-dependent vasoconstrictor prostanoid (190). Lim and...

Clinical features

The first symptoms often develop near the age of puberty the peak age at which reported symptoms occur is 15-25 years, but narcolepsy and other symptoms have been noted as early as 2 years, and at 6 months of age in the case with HCRT gene mutation 35 . A second, smaller peak of onset has been noted between 35 and 45 years and near menopause in women.

Subgroup analyses

Subgroup analyses can be done using tabulated data supplied by trialists, for example, if separate data tables for men, for women and for each specific age group are provided for each trial. It is worth noting that this could be extremely time consuming for trialists, especially if the necessary cross-tabulations were not done for their own analyses. It is conceivable for a small trial that a trialist may have to generate as many data tables as there are patients. To look at categories of patients defined by more than one baseline characteristic, for example, post-menopausal women with oestrogen-receptor-positive and node-negative status, is likely to prove impractical for both trialist and reviewer.

Raloxifene and Bone

The 1995 patent and the December 10, 1997 FDA approval of raloxifene for the treatment and prevention of osteoporosis were based, in part, on earlier studies performed in 1987 by Jordan and coworkers96 which showed that raloxifene preserved bone density in ovariectomized rats (Figure 4a) and prevented rat mammary carcinogenesis (Figure 4b).91 The discovery that raloxifene and related compounds might prevent osteoporosis96 laid the foundation for subsequent confirmation of bone data in animals.97-99,163 These discoveries also led to clinical trials that demonstrated maintenance of bone density in postmenopausal women at risk for osteoporosis.78 These data were remarkably similar to those observed with tamoxifen.144 However, the actual proof that raloxifene could be useful to treat osteoporosis was obtained in the MORE trial (Figure 5), which was a multicenter, randomized, blinded, placebo-controlled osteoporosis treatment trial. A total of 7705 women aged 31-80 years in 25 countries...


Rats and is significantly more potent than raloxifene in this regard.186 Interestingly, arzoxifene has also been shown to be only partially cross-resistant with tamoxifen in models of drug-resistant breast and endometrial cancer187,188 however, recent evidence indicates that it is superior to raloxifene as a chemopreventive in rat mammary carcinogenesis.182,189,190 In a small phase I study in 32 pre- and postmenopausal women with locally advanced or metastatic breast cancer who had previously received endocrine therapy, arzoxifene (10, 20, 50, and 100mg) did not produce any significant responses, suggesting cross-resistance between arzoxifene and tamoxifen.191 In a phase II study in 119 pre- and postmenopausal women with advanced or metastatic breast cancer, two doses of arzoxifene (20 versus 50mgday_ 1) were compared in patients who had either tamoxifen-sensitive or tamoxifen-resistant disease and 20 mg arzoxifene was found to be as effective as 50 mg in the treatment of metastatic...


Leiomyoma (fibroids) benign tumors most common indication for hysterectomy (when they grow too large or cause symptoms). Malignant transformation is rare ( 1 ). Look for rapid growth during pregnancy or use of oral contraceptives with regression after menopause (estrogen-dependent). Fibroids may cause infertility myomectomy may restore fertility. Other symptoms include pain and menorrhagia metrorrhagia. Anemia due to leiomyoma is an indi cation for hysterectomy. D&C rules out endometrial cancer and malignant transformation in women 40. Patients may present with polyp protruding through cervix. Dysfunctional uterine bleeding (BUB) defined as abnormal uterine bleeding not associated with tumor, inflammation, or pregnancy. DUB is the most common cause of abnormal uterine bleeding and is a diagnosis of exclusion. Over 70 of cases are associated wi th anovulatory cycles (unopposed estrogen). The age of the patient is important. After rnenarche and just before menopause, DUB is extremely...



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