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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Chronopharmacology Menstrual Cycle and Menopause

The menstrual cycle includes the follicular, ovulatory, and luteal phases that are accompanied by substantial hormonal changes. Therefore, it cannot be assumed that a premenopausal woman has the same kinetic profile as a man in the same age range. Although there are increasing numbers of studies that control for menstrual cycle phase, few studies have encompassed all the different phases of the menstrual cycle. A compounding confounder is that investigators do not use consistent definitions of the menstrual cycle phases. As a result, published data are conflicting about whether menstrual cycle phases significantly influence pharma-cokinetics, although the weight of evidence suggests that the phases of the menstrual cycle do not have a clinically significant impact (94).

The Menopause

The menopause is defined by the World Health Organization as the point in time of permanent cessation of menstruation due to loss of ovarian function. Clinically, the menopause is characterized by persistent amenorrhea for a period of twelve months. Laboratory findings in the menopause generally reveal low serum estradiol levels with elevated follicle stimulating hormone (FSH) levels. The specific levels may vary depending on the assay used. The perimenopause, or climacteric, is defined as the period of diminishing ovarian function preceding the menopause to one year following the final menses, generally lasting between 2 and 8 years. Currently, the average age of menopause in the United States is approximately 51 years and the average life expectancy is approximately 80 years. Consistent with this, almost one half of the average woman's life is spent in the post-menopausal period.

Menopause

The menopause is associated with a gradual change in the vagina which can take up to 5 to 8 years to stabilise. The length and the diameter decrease with age and the pH can rise to between 6 and 8 increasing the risk of infection. Elasticity and blood supply decrease with age and the upper vagina may atrophy. The epithelium becomes thinner which is an important consideration in intravaginal drug delivery since this would lead to an increased permeability. Vaginal secretions and hence lubrication decrease and become more watery. The levels of several enzymes increase, such as E-glucuronidase, acid phosphatase and nonspecific esterases, in postmenopausal women.

Difference between Male and Female Cancer Incidence Rates How Can It Be Explained

The ontogenetic component has a wave-like shape for both males and females, with peaks at early ages and around ages of climacterics for females, and between ages 55 and 65 for males. The peaks correspond to the ages of hormonal imbalance where this component largely influences risks of morbidity and mortality. A similar pattern of morbidity is observed for many human chronic diseases (see 11 , 12 , 13 , 14 ). In principle, one can use these patterns to model the ontogenetic component. However, these rates, in essence, reflect not only the ontogenetic changes, but also the other factors responsible for the manifestation of the disease. Thus, to model the ontogenetic changes at advanced ages influencing unrepaired lesion formation, we use the function with a pronounced peak around some specific age, and zero otherwise. The peak is around the age of menopause for females, and the pattern is shifted

Thyroid Hormone Therapy

Patients with thyroid cancer are usually treated with T4 to lower TSH secretion below normal, thereby deliberately causing subclinical if not overt thyrotoxicosis. One potential consequence of this is bone mineral loss, even in children 79 , but especially in postmenopausal women with thyroid carcinoma 171-173 . This may be prevented by estrogen or bisphosphonate therapy. More importantly, using the smallest T4 dose necessary to suppress TSH has no significant effects on bone metabolism and bone mass in men or women with thyroid cancer 174 .

Humans and Rodents Both Exhibit Gender Differences in Plasma GH Profiles

Release of GH from the pituitary gland is not constant over time, but rather is intermittent, or pulsatile. GH secretion in humans begins at the end of the first trimester of gestation. Integrated daily GH secretion in humans is greatest during adolescence and declines with age thereafter. Notable sex differences in the neuroendocrine regulation of pituitary GH release have been observed in humans. Premenopausal women have two- to threefold higher daily GH secre

Breast carcinoma continued

Reconstruction May be performed concurrently with surgical excision. Latissi-mus dorsi or transverse rectus abdominis myocutaneous flap are used. Systemic therapy Chemotherapy Used in premenopausal women, rapidly progressive disease, visceral involvement, oestrogen receptor negative tumours and where hormonal treatment has failed. Many regimen options (e.g. 5-fluorouracil, cyclophosphamide, methotrexate, adriamycin) with response rates in 50 using a combination of drugs. A promising new agent is herceptin, a monoclonal antibody against HER-2 protein (tumour cell growth promoter).

Explanations for Difference in Prevalence by Gender

The possibility of some biological or psychological difference between men and women has received the most research. Of interest is the observation that the gender difference between men and women was reduced in those over 55 years of age in the OPCS National Survey of Psychiatric Morbidity 62 . This certainly fits with the idea that the hormonal changes around the menopause might reduce the prevalence of depression in women. Other more social explanations would also fit. Furthermore, it is not clear that this result is consistently found in all datasets.

Screening And Prevention

Clearly, prevention of disease is more desirable than simply early detection, and both of these cancers have been targeted for cancer prevention efforts. For breast cancer, retinoids have been investigated with experimental evidence suggesting that they may prevent breast cancer. When almost 3000 women with breast cancer were randomized to fenretinoid vs. control, the incidence of contralateral breast cancer was not significantly altered. However, this study suggested a possible benefit for premenopausal patients adjusted hazard ratio 0.66, 95 confidence interval (CI) 0.14-1.07 .2 Tamoxifen has also been studied extensively to assess its ability to prevent breast cancer, initially prompted by data showing a reduced incidence of contralateral breast cancer in patients enrolled in adjuvant trials of this agent. Several prevention trials with tamoxifen have been reported, unfortunately yielding conflicting results. The National Surgical Adjuvant Breast and Bowel Project P-1 (NSABP) study...

Endocrinological Aspects

Several studies have underlined the high prevalence of psychiatric symptoms and disorders in endocrine diseases. More recently, the role of sex hormones in the differential spectrum of mood disorders in women versus men 42 and the role of hormone replacement therapy as an adjuvant treatment in mood disorders 49-51 are receiving increasing recognition and attention. The underlying biology may be related to the integration and cross-talk of signal-processing cascades from membrane-bound neurotransmitter receptors with those from nuclear ligand-activated transcription factors such as hormone receptors for oestrogen, progesterone and testosterone.

What to tell parents

An explanation for the presenting symptom(s) is required and need for further investigations. Further discussions depend on results of these investigations. Long-term hormone replacement therapy, management of intercurrent infections (see above) and importance of glucose monitoring needs to be discussed. Child minders need to be informed about the risk of adrenal insufficiency during an intercurrent illness. Babies with anomalies of the optic nerve may have reduced visual acuity or be blind. Implications of associated anomalies, particularly the brain will require discussion.

Administration of TSHSuppressive Doses of LThyroxine

Subclinical hyperthyroidism is also associated with high bone turnover 38 , and may induce bone loss according to meta-analyses, especially in postmenopausal women 39,40 . It has not been demonstrated that this results in a higher fracture rate 41 , but again it seems prudent that the endocrinologist monitors the risk in individual patients (by taking a history with respect to the well-known risk factors for osteoporosis, and performing bone densimetry in selected cases) and takes appropriate action in high risk patients (ensuring sufficient calcium intake, and considering supplementation with vitamin D).

Gonadotropin Releasing Hormone Analogs

Gonadotropin releasing hormone analogs (GnRH) cause a temporaty medical menopause resulting in hypogonadism and hypoestrogenism by acting on the pituitary to reduce gonadotropin synthesis and secretion. Most of the side effects experienced occur because of the hypoestrogenic state including hot flashes, vaginal dryness, mood lability and decreased libido. The GnRH agonists have been shown to work well in reducing pain symptoms associated with endometriosis such as dys-menorrhea, dyspareunia, and noncyclic pelvic pain. GnRH agonists are often initiated with the onset of menses, but a more rapid response is observed with mid-luteal administration. A limit of 6 months per treatment course is required due to loss of bone mineral density during therapy, but this can be extended via the addition of 'add-back' therapy with estrogens. Retreatment with these drugs is supported by limited data. Several investigators have studied the use of GnRH agonists as surgical adjuncts. Their use...

Sex Differences in Metabolic Pathways

Some evidence suggests that CYP3A activity may be influenced by endogenous sex hormones (58). Endogenous hormones and their fluctuations in premenopausal women may be one explanation for reported differences in metabolism between pre-menopausal and postmenopausal women. For example, studies of tirilazad pharmacokinetics suggest higher clearance in premenopausal women than in postmenopausal women or in men (59), and the relationship between menopausal status and clearance was consistent when examined in different ways (60, 61). Other investigators have failed to find an influence of menstrual cycle phases (as surrogates for endogenous hormone changes) on CYP3A activity (62). One study showed no effect of exogenous sex hormones (oral contraceptives) on CYP3A activity (63). CYP3A 4 5 genotyping may be important in differentiating CYP3A isozyme activity, although this is a controversial area. Recently, the apparent sex difference in CYP3A has been postulated to be due to a higher hepatic...

Drug Metabolism Interactions of Particular Importance to Women

While numerous studies have evaluated the effect of oral contraceptives and postmenopausal hormone replacement on drug clearance, many were flawed by poor study design. Table 21.1 lists studies that were of crossover or sequential design such that each subject was evaluated in the contraceptive phase and placebo phase. These study designs minimize the effect of interindividual variability. In most studies there was no effect of hormonal therapy on drug metabolism, but in some there were interactions that inhibited or increased the metabolism of concurrently administered drugs. Higher clearance rates primarily reflect the ability of oral contraceptives to increase the activity of glucuronyltransferases. The mechanisms by which oral contraceptives decrease drug metabolism are unknown. We also do not know to what extent the estrogen or the progesterone components of oral contraceptives participate in these interactions (58). Although postmenopausal hormone replacement is becoming less...

The Potential for Pregnancy While on a Trial Drug

What is the risk of pregnancy occurring in a study participant while a new drug is being developed The author is not aware of any published figures, but from the author's experience in industry and from questions to colleagues, pregnancy does occur during drug development, even in those patients apparently taking adequate contraceptive precautions. A typical NDA database for most drugs will involve between 2000-4000 patients, of which perhaps one-third are female and exposed to study medication. It is not surprising, therefore, that given an average failure rate of the contraceptive pill of 2 , or even with the most stringent compliance, a failure fate of 0.5 100 women years will result in occasional pregnancy (Trussell et al, 1990). Other methods, such as the diaphragm, condoms and IUDs, can carry even higher failure rates, depending on whether 'usual' or 'perfect compliance' calculation of 18-6 , 12-2 and 30.5 , respectively, are used (Trussell et al, 1990). If we assume an average...

Hypothalamicpituitarygonad Axis

Despite the significantly higher rates of depression in women, data on HPG abnormalities in psychiatric disorders remain remarkably limited. Early studies showed no differences in plasma concentrations of LH and FSH in depressed postmenopausal women compared with non-depressed matched control subjects 101 . However, a later study showed decreased plasma LH concentrations in depressed postmenopausal women compared to matched controls 102 . In a more recent study, significantly lower estra-diol levels were detected in women with depression, but the blood levels of other reproductive hormones fell within the normal range 103 . Because estradiol affects a number of neurotransmitter systems, including norepin-ephrine and serotonin, these results merit further study. The response to administration of exogenous GnRH in depressed patients has also been investigated. Normal LH and FSH responses to a high dose of GnRH (250 g) have been reported in male depressed and female depressed (pre- and...

Site Directed Delivery

The concept of designing a lipophilic ester prodrug has been applied to a variety of delivery systems and formulations as described above however, it is unclear if a prodrug can be used to provide targeted delivery. Continuous administration of 17- -estradiol, a principal estrogen, is required as an estrogen replacement therapy for the treatment of post-menopausal symptoms. Sustained delivery of the estrogen using an intravaginal ring would provide improved patient compliance since it is a relatively non-invasive local delivery device that can be self-administered with minimal systemic side effects. However the intravaginal rings are composed of hydrophobic polydimethylsiloxane in which 17-p-estradiol has poor solubility due to its polarity. A series of hydrophobic ester prodrugs of 17- -estradiol was designed in which their solubility was significantly improved in the polymer and the release rate was modified (Woolfson et al., 1999). In a clinical study, the 3-acetate ester of 17-...

Germ Cell Development In Humans And Infertility

Infertility is common among both men and women. Although human reproduction and fertility have been studied for many years, few genes have been identified that contribute to human germ cell production. However, several studies have demonstrated that the age at onset of menopause has a significant genetic component this property is likely to reflect the quantity and quality of female germ cells that are formed and differentiated. Family history is a significant predictor of early menopause (menopause at age < 47 years), and it is reflected by an increased risk of early menopause in women with affected siblings of approximately sixfold (Cramer et al., 1995). In addition, sibling studies have estimated the heritability of the timing of menopause to be high, and several studies have documented the role of discreet regions of the X chromosome in families with a history of early menopause and in those without a family history (Santoro, 2001 Taylor, 2001 Testa et al., 2001 Laml et al.,...

Regimens for Hormone Replacement

Reprinted with permission from Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems A comparative review. Am J Drug Deliv 2005 3 7-16. There are a number of alternative therapies for women who are symptomatic from menopausal hot flashes but cannot take estrogen therapy. Venlafaxine hydro-chloride and paroxetine are serotonin reuptake inhibitors that effectively reduce hot flash frequency and severity. Other drugs in this class, including fluoxetine, may also be effective, but there are few published data. Recent studies suggest that women

Serum methylmalonate and homocysteine levels

Also higher in serum than in plasma, in men than in premenopausal women, women taking hormone replacement therapy or oral contraceptive users and in elderly subjects and patients with several inborn errors of metabolism affecting enzymes in trans-sulphuration pathways of homocysteine metabolism. Thus, homocysteine levels are not widely used for diagnosis of cobalamin or folate deficiency. Homocysteine levels are useful, however, in thrombophilia screening and in assessing for cardiovascular risk factors (see Chapter 58).

Drug Delivery Vaginal

A bioadhesive polycarbophil gel, a lightly cross-linked polyacrylic acid, used to retain moisture and lubricate the vagina has recently been introduced onto the market (Replens, Columbia Laboratories). Clinical assessment of local tissue pH, in postmenopausal women, shows the polycarbophil gel produces a reduction in pH from about 6 to 4 and maintains the acidic pH for about 3-4 days after the last dose. Hydration of the vaginal tissue occurs through an increase in vaginal blood flow as determined by a laser Doppler measurement. In patients with a history of breast cancer who experienced vaginal dryness, vaginal irritation, or dyspareunia, the polycarbophil gel produced a statistically significant reduction in mean vaginal pH and an improvement in vaginal moisture, mucosa secretions, and elasticity scores, as well as significant improvement in vaginal health measures18.

Differential Timetables of Aging in Organs and Systems

Aging Organ Reproduction

In whichever organ and system considered, timetables of aging represent an approximation, for the onset of aging cannot be pinpointed precisely by any specific physiologic sign (such as menarche for ovarian maturation). A classic example of a unique timetable involving an organ that develops and ceases to function during a specific period of the life span is the ovary its function begins at adolescence (in humans, approximately 10-12 years) and stops at menopause when ovulation ceases (in humans, approximately 50 years) (Chapter 10).

Assisted Reproductive Technology

Donor oocytes Eggs that are removed from one woman's ovaries to be used by another for IVF. Indications often include premature ovarian failure, gonadal dys-genesis, recurrent IVF failure, natural menopause, and inheritable disorders. Donor oocytes are indicated when a woman has premature ovarian failure, has undergone natural menopause or if a woman has demonstrated poor oocyte recovery and embryo quality with her own eggs. The latter indication is most often seen in women of advanced maternal age. Chong AP, Rafael RW, Forte CC. Influence of weight in the induction of ovulation with human menopausal gonadotropin and human chorionic gonadotropin. Fertil Steril 1986 46(4) 599-603.

Avoidable Risk Factors

Hormonal use in postmenopausal women has been associated with a lower risk of colon cancer 153 , but not clearly with rectal cancer 154 . Several studies have shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) could reduce the incidence of colorectal polyps and the risk of CRC 155 . The potential for the use of NSAIDs as primary prevention is under investigation, but more evidence is needed 156 .

Specifiers for Mood Disorders

The rapid cycler specifier can be applied to bipolar I or II disorder. Cycling is the process of going from depression to mania, or hypomania, and back or vice versa. Cycles can be as short as a few days or as long as months or years. Rapid cycling involves the occurrence of four or more mood episodes during the previous twelve months. In extreme cases, rapid cyclers can change from depression to mania and back or vice versa in as short as a few days without a normal mood period between episodes. Seventy to ninety percent of rapid cyclers are both premenopausal and postmenopausal women. Rapid cycling is associated with a poorer prognosis.

The Role of the SN in Symptom Control and Rehabilitation

Some patients will require thyroid ablation with radioactive iodine therapy. This understandably has been reported as psychologically and physically very stressful for patients and their carers on top of the hormonal physical changes due to the reduction, change, or temporary cessation of hormone replacement therapy 16 . The role of the SN again is to offer psychological support and information alongside the MDT to deal with patient carer concerns about treatment. The SN's role is to reduce the psychological and physical impact of the therapy by providing

The Eyes Optical Components Cornea

Human Power

In a recent study, Acosta et al. (19) found that corneal thresholds to mechanical and chemical stimuli increased with age. Premenopausal women were more sensitive to corneal stimulation than men of similar ages, but overall differences in mechanical and chemical threshold between men and women were not significant. Also corneal mechanical threshold depended on age and iris color. Similar results were also noted by Roszkowska et al. (20) with regard to corneal sensitivity.

Proteomics and Cancer

Page et al. (1999) used immunoselection of cells before proteomic analysis. They used a double antibody magnetic affinity cell sorting technique to purify normal human luminal and myoepithelial breast cells from the reduction mammoplasties of ten premenopausal women. For this, two antibodies were used, one produced in rat and directed to the luminal epithelial marker EMA and the other produced in mouse and directed to the myoepithelial antigen CD-10. The use of antirat and antimouse magnetic beads allowed the separation of EMA and CD-10 expressing cells. Myoepithelial cells were then purified a second time using anti-CD-10 and anti-FAP antibodies to free them from F-19 positive fibroblasts. Purified luminal and myoepithelial cells were then subjected to proteomic analyses using 2-DE. One hundred and seventy different proteins were found to be differentially expressed between the two breast cell types and 51 of them were identified using MS MS. This work forms the basis for future...

Changes in Balance and Falls

Diagram Demonstrating Sleep Stages Eeg

Experiments in which they are tested in moving platforms with sensory input (primarily vision) absent. The elderly are much less tolerant of any loss or decline of sensory input (such as vision) (15,24). Falls of the elderly occur when engaging in ordinary activities, most often indoors. Trips and accidents account for the largest number of falls. It is to be noted that the incidence of falls declines with further aging, probably due to the reduced mobility of the very old. Some falls occur without any external cause and may be due to impaired peripheral (ocular, vestibular, and proprioceptive) and central (cerebellar and cortical) coordination (24) or, especially in postmenopausal women, to bone fractures due to osteoporosis (21) (Chapters 10 and 20). more severe osteoporosis and bone fragility, especially after menopause (Chapter 10), Changes in several cyclic functions with aging may be ascribed to changes in so-called biologic clocks the biological timepieces that govern the...

Differential Diagnosis

A comprehensive history and physical examination are indicated to rule out other possible causes of the emotional and physical symptoms of PMS. The differential diagnosis includes premenstrual molimina, hypothyroidism, perimenopause and major mood or anxiety disorders. Most ovulatory women experience some physical changes (e.g., breast tenderness, bloating, and food cravings) during the luteal phase. If these physical symptoms do not interfere with normal life functions, the term molimina can be applied. Hypothyroidism can share many of the same symptoms as PMS however there should be no cyclic variation. A thyroid stimulating hormone level is a sufficient screen, if warranted by clinical suspicion. There is also considerable overlap between the symptoms of perimenopause and those of PMS. Many women experience symptoms of emotional irritability, cyclic mastalgia, bloating and hot flashes as part of the perimenopause. It is likely that similar pathophysiologic factors mediate symptoms...

Preparation for Ablative 131I Therapy

The patient should be informed of possible damage of 131I therapy to radiation-sensitive tissues. Usually this is done by the nuclear medicine physician, but the endocrinologist may play a role as well. Many patients in their reproductive years are concerned with gonadal damage. The standard advice is to refrain from pregnancy and not father a child during the first 4 to 6 months after 131I therapy. About 20-30 of women experience transient amenorrhea or menstrual irregularities in the first year after treatment 27,28 . Apart from a greater miscarriage rate in the first year 131I therapy seems to have no effect on fertility or the outcome of subsequent pregnancies, but menopause occurs on average 1.5 year earlier 29 . In men, spermatogenesis can be transiently suppressed associated with a rise of serum FSH, related to the total amount of 131I 30 . The risk of permanent male infertility is very low in men likely to receive a cumulative dose of > 17 GBq sperm banking may be considered.

Effects on Female Fertility

In normally menstruating women, ovarian function depends on pituitary production of follicle-stimulating hormone (FSH), which stimulates the ovarian follicular granulosa cells to develop and produce estradiol. This causes feedback inhibition of the pituitary maintaining FSH at a low level. At puberty approximately 200 000 ovarian follicles are present and functioning in the ovary. This number progressively declines with age to approximately 400 at the time of menopause. Fertility in women can be assessed from the menstrual history and by measuring FSH levels. Persisting amenorrhea with FSH levels more than 30IU L implies the onset of menopause. Following administration of high activities of 131I, menstrual irregularities have been reported in 20-30 of premenopausal female patients 5 . Amenorrhea has been reported to occur within 6 months after treatment but lasted only for a short time (less than 6 months in most patients). In our retrospective analysis of 409 female patients under...

Burden of Disease

Interestingly, there has been a striking decline in CRC in women compared with men. This may in part be due to the increasing penetration of oral contraceptives and, particularly, hormone replacement therapy (HRT) 43 , both of which have consistently been associated with a decreased risk of CRC. However, this may be sheer speculation. There has been an overview of all the case-control and cohort studies investigating this association separately for oral contraceptive and HRT users. Overall, the risk of CRC in users of oral contraceptives (compared with never-users) was reduced by 18 RR 0.82, 95 confidence interval (CI) 0.74-0.92 44 . For HRT, the risk of CRC was reduced, overall, by 20 among users compared with non-users (RR 0.8, 95 CI 0.78-0.82) 45 .

Late Complications

The risk of permanent damage to the ovaries after ablative radioiodine treatment appears to be low and most patients can be reassured they can have normal pregnancies after 131I treatment. During the first year after 131I therapy, middle-aged women may developed temporary amenorrhea and elevated serum gonadotropin concentrations 153 and women of all ages have a higher than expected rate of spontaneous miscarriage 154 , yet there are no measurable effects of 131I on fertility, birth defect, birth-weight and prematurity rates 155 . Still, 131I therapy may be associated with early menopause 156 . In a study by Vini et al. 157 of 496 women under the age of 40 at the time of diagnosis, 65 of whom had received 3 GBq (81mCi) of 131I while the remainder had received subsequent treatment with a cumulative activity of 8.5-59 GBq (230-1595 mCi) for persistent disease, transient amenorrhea or menstrual irregularities lasting up to 10 months occurred in 83 patients (17 ). No cases of permanent...

Prevention

Researchers are also studying the antioxidant affects of vitamin E and selegiline hydrochloride in preventing brain damage caused by toxic free radicals to slow the rate of progression of AD. Studies of estrogen replacement therapy in menopausal women showed a reduced risk of developing AD by 30 to 40 percent. In 2002, a synthetic form of beta-amyloid protein (AN-1792) vaccine was being investigated in clinical trials.

Storage iron

In healthy subjects, the serum ferritin concentration correlates with iron stores, as assessed by quantitative phlebotomy or tissue biopsy. This has led to the widespread use of immunoassays for serum ferritin as a convenient, non-invasive measure of iron stores. Normal concentrations of serum ferritin range from about 15 to 300 ig L, and are higher in men (median about 90 g L) than in premenopausal women (median 30 g L). In women, after the menopause, serum ferritin concentrations increase but remain below levels in men. In neonates, the concentration in cord blood (median approximately 100 g L) rises further over the first 2 months of life as fetal haemoglobin is broken down, and thereafter falls to low levels (median 20-30 g L) throughout childhood and adolescence.

Risk Factors

For breast cancer, the major risk factor is prolonged and unopposed exposure to estrogen. Well-established risk factors thus include early onset of menarche (before age 14), nulliparity, completion of first live birth after age 30, and delayed menopause.2 The incidence of breast cancer increases with age, doubling with every decade until menopause. Smoking, either directly or through second-hand exposure, has also been implicated as a possible risk factor.2'4'5 Women with a family history of breast cancer and those who carry germline mutations of BRCA1 or BRCA2 are also at high risk for developing breast cancer. For instance, women with one first-degree relative with a history of breast cancer have a 1.5-2.0 relative risk of developing the disease, but the risk is even further increased (relative risk approximately 20.0) if the first-degree relative had bilateral premenopausal onset of the cancer. Relative risk has been estimated at 4.0-6.0 if two first-degree relatives have had...

Adjuvant Therapies

Treatment course with tamoxifen is considered standard for adjuvant therapy for this group of women, although ovarian ablation can be considered for selected premenopausal patients. Adjuvant multiagent chemotherapy is also recommended for the majority of women with localized breast cancer independent of nodal, menopausal or hormone receptor status, since it has also been shown to improve survival in this setting. Recent data suggest that incorporation of the anthracyclines enhances outcomes with adjuvant chemotherapy for this malignancy an analogous role for the taxanes has not been determined. Finally, there is also fairly strong evidence that women with a high risk of locoregional recurrence after mastectomy may benefit from adjuvant radiotherapy. This high-risk group includes women with four or more positive lymph nodes or a locally advanced primary cancer. The role of adjuvant radiation therapy for women with 1-3 positive lymph nodes has not yet been defined. Overall, the role of...

Replacement Therapy

Patients undergoing total thyroidectomy should be aware that they will need thyroid hormone replacement therapy. This life-long therapy may alternate between the use of triiodothyronine (T3) and levothyroxine (T4) depending on the need for postoperative scans in the follow-up period. Patients need to be warned that cessa tion of thyroid hormone replacement therapy will result in hypothyroidism in approximately 10 days in the case of T3 and approximately 1 month in the case of T4.

A Growth Factors

Growth factors known to have a role in the early phases of wound repair have been applied topically to excisional wounds of experimental animals and patients in order to accelerate their healing (reviewed by Fu et al., 2005). Recombinant human EGF and FGF-2 (rhEGF, rhFGF-2) were reported to accelerate the healing of burn wounds in human patients by 1-4 days (Brown et al., 1989 Fu et al., 1998). TGF-p and human growth factor (hGF) were reported to accelerate normal wound repair in both young and old rats (Puolakkainen et al., 1995 Roberts, 1995). Topical application of TGF-P increased the rate of re-epithelialization and contraction in rat and pig incisional wounds and in guinea pig and pig punch wounds (Franzen et al., 1995). Collagen synthesis was increased, leading to increased strength of scar tissue (Roberts, 1995). Intravenous delivery of 100-500 g kg of TGF-P to old rats prior to wounding or 4 hr after wounding increased the tensile strength of scar tissue to the level seen in...

Medical Treatment

The mainstay of medical therapy focuses on the principle that endometriosis is an estrogen-dependent condition. Many clinical observations show that estrogen is essential for the growth of endometriosis. Endometriosis has been shown to regress and become inactive in states of amenorrhea and menopause. Therefore, treatment of endometriosis often relies on drugs that suppress ovarian steroids and induce a hypoestrogenic state that causes atrophy of ectopic endometrium. The most widely used agents to achieve this goal are oral contraceptives and GnRH agonists. The evidence-based support for medical therapy is mostly observational.

Initial Treatment

Hormone replacement therapy with L-thyroxine (L-T4) should be started immediately after thyroidectomy. Unlike papillary and follicular thyroid tumors, medullary carcinoma is not dependent on TSH for both growth and function, thus there is no need to treat patients with L-T4 suppressive therapy the daily dose should be tailored by measuring serum FT3, FT4, and TSH aiming to keep their values within the normal range. Unilateral or bilateral adrenalec-tomy must be performed before total thyroidec-tomy, when a pheochromocytoma has been documented, because of the risk of a life-threatening hypertensive crisis during the induction of anesthesia for the neck surgical treatment. Preoperative screening for pheochro-mocytoma should be conducted in all patients with a diagnosis of medullary thyroid carcinoma since the patient may be an index case of a familial form, presented as apparently sporadic. Although pheochromocytoma is usually bilateral, a 10-year interval is the mean period between the...

Etiology

The etiology of PMS is not completely known, but appears to be multi-factorial. Fluctuating hormones across the menstrual cycle play a role, since PMS is not observed in prepubertal girls or in menopausal women. Recent studies have also suggested a role for serotonin and other neurotransmitters in the etiology of PMS.

Mucosa

The innermost layer of tissue in the uterus is the mucous membrane, or endometrium. It lines the uterine cavity as far as the internal os, where it becomes continuous with the lining of the cervical canal. The endometrium contains numerous uterine glands that open into the uterine cavity and that are embedded in the cellular framework or stroma of the endometrium. Numerous blood vessels and lymphatic spaces are also present. The appearance of the endometrium varies considerably at the different stages in reproductive life. It begins to reach full development at puberty and thereafter exhibits dramatic changes during each menstrual cycle. It undergoes further changes before, during, and after pregnancy during the menopause and in old age. These changes are for the most part hormonally induced and controlled by the activity of the ovaries. The endometrium is divided into three layers, the stratum compactum, the stratum spongiosum, and the stratum basale, which are functionally distinct,...

The Transition

The reproductive life span can be divided into three phases the reproductive years, the perimenopause, and the postmenopause. The perimenopause can be further subdivided into early and late stages. The greatest stability and efficiency of ovarian function is between the ages of 25 and 34. Ovulatory variability is greatest before the age of 20 and after the age of 40 years, resulting in an increased frequency of anovulatory cycles, erratic cycle length, and abnormal uterine bleeding. The early perimenopause is characterized by slowly declining ovarian function, increasing frequency of anovulatory cycles, irregular cycle lengths, fluctuating gonadotropin levels, and an overall increase in FSH and luteinizing hormone (LH) levels. FSH levels, in particular, may fluctuate widely, changing with each cycle, largely due to a decrease in the number of ovarian follicles. With loss of ovarian follicles as well as granulosa cells, inhibin levels, which normally provide negative feedback on the...

Vasomotor Symptoms

Vasomotor instability or the hot flash is a common complaint of the perimenopausal and menopausal woman, affecting 60 to 85 of all women. Hot flashes usually occur suddenly, though some women may experience an aura or premonition of the impending hot flash, and generally begin with an intense feeling of heat in the face and thorax. Visible flushing or reddening of the face and neck often follows, with a rise in heart rate and skin blood flow. Skin resistance drops rapidly, resulting in increased skin conductance of heat and a sensation of skin warmth. An increase in peripheral blood flow, heart rate, and finger temperature can result in palpitations and profuse sweating. Although hot flashes occur for 0.5 to 5.0 years on average after last menses, they may persist beyond five years, and up to 10 of women experience hot flashes for greater than 15 years. Their frequency ranges from 5 to 50 per day, with an average duration of 4 minutes. Women who have undergone surgical menopause are...

Combined Agents

Reprinted with permission from Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems A comparative review. Am J Drug Deliv 2005 3 7-16. many women, resulting in night sweats, multiple episodes of awakening, and overall nonrestful sleep. The resulting decreased sleep efficiency caused by hot flashes may explain the associated chronic fatigue and irritability from which many menopausal women suffer. The most effective treatment for hot flushes is estrogen, which can be given through a variety of regimens, that are described below and listed in Tables

Available Doses

Reprinted with permission from Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems A comparative review. Am J Drug Deliv 2005 3 7-7 6. given neurontin have fewer hot flashes than those given placebo. Low dose progestins are effective in the treatment of menopausal symptoms to a moderate degree, but still a form of hormonal therapy and may be a source of concern in patients with a history of breast cancer. Two antihypertensives, clonidine and methyldopa, have been used to treat vasomotor symptoms, suggesting a role for adrenoreceptors in the physiology of these symptoms. Low dose clonidine, is partially effective in the relief of hot flashes, but for many women, adequate therapy requires substantial doses and severe side effects. Methyldopa, at doses of 500 to 1000 mg d, has been shown to be twice as effective as placebo for the treatment of hot flashes. Veralipride is a dopam-ine antagonist that has been shown to be active in the hypothalamus, effectively...

Ovulation Induction

Polycystic Ovarian Syndrome Etiology

The World Health Organization (WHO) has provided a simplified classification system for disorders of ovulation. This grouping system describes the etiology of anovulation, and the most appropriate treatment for patients with ovulatory dysfunction is determined by their classification. WHO Group I patients have low follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels and low estradiol levels. These patients have hypothalamic-pituitary hypofunction, either congenital or acquired and have a negative progestin challenge test due to low endogenous estradiol levels. WHO group II patients have normal FSH and LH levels, and normal estradiol levels. Most anovulatory patients fall within this category, and > 90 of these patients have polycystic ovarian syndrome (PCOS). These patients will have a positive progestin challenge test due to normal endogenous estradiol levels. WHO group III patients have elevated FSH and LH levels. Gonadotropins are elevated (often in the...

Black cohosh root

The alcoholic extract of black cohosh root is widely used by women in Europe and now the USA as a treatment for menopausal symptoms.54-56 Virtually all of the clinical studies have been done with one preparation, Remifemin, originally developed in Europe and now marketed in the USA. Many men with prostate cancer on hormonal therapy are using Remifemin or other black cohosh root preparations as treatment for their hot flashes and other symptoms of male menopause. Black cohosh was one of the medicinal plants widely used by various American Indian tribes and adapted by early European settlers as a treatment for rheumatism. The use of black cohosh for menopausal symptoms became widespread during the 1800s in both America and Europe. At present, virtually all significant clinical and laboratory investigation on black cohosh have been performed by European investigators. Numerous clinical trials, including randomized controlled trials, have compared Remifemin with placebo and a variety of...

The Menstrual Cycle

Reproductive cycles begin at puberty as the hypothalamic pulse generator is activated and GnRH is secreted. Menstrual cycles are the most irregular during the 2 years after menarche and during the 3 years before menopause. Once a cyclic pattern is established, the menstrual cycle serves as a highly sensitive indicator of an intact hypothalamic pituitary ovarian (H-P-O) axis. To the clinician, the monthly cycle of endometrial degeneration and regeneration provides confirmation that the infertile patient has ovulatory cycles.

Females Males

Syndrome Albright

Precocious puberty is defined as the onset of puberty before the age of 8 in girls and age 9 in boys. These ages are 2.5 standard deviations below the mean age of puberty in North American children. This disorder is five times more common in girls than boys. It is classified as either central (GnRH-dependent) or peripheral (GnRH-independent) depending on whether the inciting event has activated the H-P-G axis. In central precocious puberty (CPP), activation of the hypothalamic-pituitary axis occurs, leading to premature sexual development that typically follows the normal pattern of puberty except that it is early. In peripheral precocious puberty (PPP), steroid production is independent of activation of the central axis, as is the case in gonadal or adrenal tumors or McCune-Albright syndrome. Precocious puberty is often idiopathic, especially in girls, however, a work-up is indicated in order to rule out significant pathology. If left untreated, final adult height will be compromised...

Miscellaneous

In this same vein, cancer always needs to be ruled out in the presence of any bleeding that occurs in a postmenopausal woman who is not taking hormone replacement therapy. The mechanisms by which heavy abnormal bleeding occurs in conditions such as uterine myomas and endometrial cancer are not well understood, but in many cases large and fragile surface blood vessels are present, seemingly related to the release of angiogenic factors produced by the tumors themselves. Progesterone levels may be used to assess for either regular or irregular ovulation. Other hormonal testing may be needed to delineate the nature of ovulatory dysfunction (e.g., PCOS, impending menopause, or hyperprolactinemia). In general, not reliable to exclude endometrial polyps or submucosal myomas in premenopausal women endometrial thickness < 5 mm in postmenopausal women makes endometrial cancer very unlikely. Particularly when there is a distinct possibility of an anatomic lesion, a variety...

17251227 Com 10 C

Daly E, Vessey MP et al. (1996) Risk of venous thromboembolism in users of hormone replacement therapy (see comments). Lancet, 348, 977-980. Grady D, Wenger NK et al. (2000) Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen progestin Replacement Study. Annals ofInternal Medicine, 132(9), 689-696. Nash HA, Alvarez-Sanchez F et al. (1999) Estradiol-delivering vaginal rings for hormone replacement therapy. American Journal of Obstetrics and Gynecology, 181, 1400-1406. Oger E and Scarabin PY (1999) Assessment of the risk for venous thromboembolism among users of hormone replacement therapy. Drugs and Aging, 14, 55-61. Rioux JE, Devlin C et al. (2000) 17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis (see comments). Menopause, 7, 156-161.

Prognostic Factors

In many clinical situations the appropriate treatments and the patients' final choice of therapeutic option may differ depending on circumstances. Nevertheless there may be groups of patients, perhaps pre-menopausal women with breast cancer, who might choose a different approach from that chosen by post-menopausal women with the same disease. The Q-TWiST methodology extends to this situation and can also be used for comparing patient groups receiving the same treatment. From such studies one may conclude, for example, that pre-menopausal women gain additional disease-free equivalent days by use of a particular therapy when compared with the post-menopausal women receiving the same treatment. More generally one can make comparisons between treatments within each of these patient groups. In describing a Q-TWiST analysis, Cole et al. (1994) present the mean times spent in TOX, TWiST and REL for four groups of women according to treatment (Short or Long chemotherapy) received. The...

Maturation of PDGFs

In addition to its critical role in the growth and development of many tissues and the regulation of the overall growth, particularly prenatal one, IGF-1 is also implicated in various pathophysiological conditions, and is thought to play a particularly prominent role in tumorigenesis. Previously, the potent mitogenic activity of IGF-I in cell culture made it an obvious candidate risk factor in cancer development. To date, a significant amount of data had been accumulated suggesting the important role of this growth factor in various cancers including prostate, breast, colon and lung cancers 31-36 . In the prostate, IGF-I is a mitogen for prostate epithelial cells. Various clinical studies revealed strong positive association between IGF-I levels and prostate cancer risk 31 . In breast cancer, also a positive relation between circulating IGF-I concentration and risk of breast cancer was found among premenopausal but not postmenopausal women, suggesting the use of plasma IGF-I...

From PMS To PPD

From PMS To PPD

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