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Hormone replacement therapy
Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT) or postmenopausal hormone therapy (PHT, PMHT), is a form of hormone therapy used to treat symptoms associated with female menopause.[1][2] These symptoms can include hot flashes, vaginal atrophy, accelerated skin aging, vaginal dryness, decreased muscle mass, sexual dysfunction, and bone loss. They are in large part related to the diminished levels of sex hormones that occur during menopause.[1][2]
The main hormonal medications used in HRT for menopausal symptoms are estrogens and progestogens, among which progesterone is the major naturally-occurring female sex hormone and also a manufactured medication used in menopausal hormone therapy.[1] Though both can have symptomatic benefits, progestogen is specifically added to estrogen regimens when the uterus is still present. Unopposed estrogen therapy promotes endometrial thickening and can increase the risk of cancer, while progestogen reduces this risk.[3][4] Androgens like testosterone are sometimes used as well.[5] HRT is available through a variety of different routes.[1][2]
The results of the Women's Health Initiative (WHI) suggest both potential risks and benefits across different organ systems. Long term follow up of the WHI participants, however, has found no difference in all-cause, cardiovascular, or cancer mortality with HRT.[6] Later studies suggested that risk can differ depending on route of administration.[7] "Bioidentical" hormone replacement – a development in the 21st century using manufactured compounds having "exactly the same chemical and molecular structure as hormones that are produced in the human body",[8] and are based mainly on steroids from plants[9] – has inadequate clinical research to determine its efficacy and safety, as of 2017.[10]
The current indications for use from the United States Food and Drug Administration (FDA) include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or vaginal atrophy, and prevention of osteoporosis.[11]
Medical uses
Approved uses of HRT in the United States include short-term treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and prevention of osteoporosis.[11] The American College of Obstetrics and Gynecology (ACOG) approves of HRT for symptomatic relief of menopausal symptoms,[12] and advocates its use beyond the age of 65 in appropriate scenarios.[13] The North American Menopause Society (NAMS) 2016 annual meeting mentioned that HRT may have more benefits than risks in women before the age of 60.[14]
A consensus expert opinion published by The Endocrine Society stated that when taken during perimenopause or the initial years of menopause, HRT carries fewer risks than previously published, and reduces all cause mortality in most scenarios.[15] The American Association of Clinical Endocrinologists (AACE) has also released position statements approving of HRT in appropriate scenarios.[10]
Women receiving this treatment are usually post-, peri-, or surgically menopausal. Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity, defined as beginning twelve months after the final natural menstrual cycle. This twelve month time point divides menopause into early and late transition periods known as 'perimenopause' and 'postmenopause'.[4] Premature menopause can occur if the ovaries are surgically removed, as can be done to treat ovarian or uterine cancer.
The Women's Health Initiative (WHI) was a study of over 27,000 women beginning in 1991. Successive analyses have found sometimes contradictory results, with the most recent publication in 2017 finding no difference for all cause mortality with HRT.[6] The effects of HRT on most organ systems vary by age and time since the last physiological exposure to hormones, and there can be differences in individual regimens, factors which have made analyzing effects difficult.[6] Demographically, the vast majority of data available is in postmenopausal American women with concurrent pre-existing conditions, and with a mean age of over 60 years.[16]
Menopausal symptoms
HRT is often given as a short-term relief from menopausal symptoms during perimenopause.[17] Potential menopausal symptoms include:[1][2]
- Hot flashes - vasomotor symptoms
- Vulvovaginal atrophy - atrophic vaginitis and dryness
- Dyspareunia - painful sexual intercourse due to vaginal atrophy and lack of lubrication
- Bone loss - decreased bone mineral density, which can eventually lead to osteopenia, osteoporosis, and associated fractures
- Decreased sexual desire
- Defeminization - diminished feminine fat distribution and accelerated skin aging[18][19]
- Sleep disturbances and joint pain
The most common of these are loss of sexual drive and vaginal dryness.[4][20]
Heart disease
The effect of HRT in menopause appears to be divergent, with lower risk when started within five years, but no impact after ten.[21][22][23] There may be an increase in heart disease if HRT is given twenty years post-menopause.[24] There is, however, no actual difference in long-term mortality from HRT, regardless of age.[6]
A Cochrane review suggested that women starting HRT less than 10 years after menopause had lower mortality and coronary heart disease, without any strong effect on the risk of stroke and pulmonary embolism.[21] Those starting therapy more than 10 years after menopause showed little effect on mortality and coronary heart disease, but an increased risk of stroke. Both therapies had an association with venous clots and pulmonary embolism.[21]
HRT also improves cholesterol levels. With menopause, HDL decreases, while LDL, triglycerides and lipoprotein a increase, patterns that reverse with estrogen. Beyond this, HRT improves heart contraction, coronary blood flow, sugar metabolism, and decreases platelet aggregation and plaque formation. HRT may promote reverse cholesterol transport through induction of cholesterol ABC transporters.[25]
Blood clots
Effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism may vary with different estrogen and progestogen therapies, and with different doses or method of use.[16] Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots,[16][26] whereas when used orally, the risk of blood clots and pulmonary embolism is increased.[21] Skin and vaginal routes of hormone therapy are not subject to first pass metabolism, and so lack the anabolic effects that oral therapy has on liver synthesis of vitamin K-dependent clotting factors, possibly explaining why oral therapy may increase blood clot formation.[27] While a 2018 review found that taking progesterone and estrogen together can decrease this risk,[26] other reviews reported an increased risk of blood clots and pulmonary embolism when estrogen and progestogen were combined, particularly when treatment was started 10 years or more after menopause and when the women were older than 60 years.[16][21]
Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause,[28] and that the association is absent or even preventative when given by non-oral routes.[7] Ischemic stroke risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy[24] and no difference in mortality at long term follow up.[6] When oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until 5 years from menopause, cohort studies in Swedish women have suggested an association with hemorrhagic and ischemic stroke.[28] Another large cohort of Danish women suggested that the specific route of administration was important, finding that although oral estrogen increased risk of stroke, absorption through the skin had no impact, and vaginal estrogen actually had a decreased risk.[7]
Endometrial cancer
In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.[29] The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease.[30]
Endometrial cancer has been grouped into two forms in the context of hormone replacement. Type 1 is the most common, can be associated with estrogen therapy, and is usually low grade. Type 2 is not related to estrogen stimulation and usually higher grade and poorer prognosis.[31] The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen.[31] The extensive use of high-dose estrogens for birth control in the 1970s is thought to have resulted in a significant increase in the incidence of type 1 endometrial cancer.[32]
Paradoxically, progestogens do promote the growth of uterine fibroids, and a pelvic ultrasound can be performed before beginning HRT to make sure there are no underlying uterine or endometrial lesions.[31]
Breast cancer
Studies regarding the association of breast cancer with hormone replacement have been mixed and vary with the type of replacement used; some evaluations suggest an increased risk, though in others it is decreased.[33]
There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone.[6] The risk may be reduced with bioidentical progesterone,[34] though the only prospective study that suggested this was underpowered due to the rarity of breast cancer in the control population. There have been no randomized controlled trials to date.[33] The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of administration.[35]
The WHI also found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer, though estrogen is usually only given alone in the setting of a hysterectomy due to the effect of unopposed estrogen on the uterus.[36][37]
HRT has been more strongly associated with risk of breast cancer in women with a lower range body mass indices (BMIs). No breast cancer association has been found with BMIs of over 25.[38] It has been suggested by some that the absence of significant effect in some of these studies could be due to selective prescription to overweight women who have higher baseline estrone, or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate.[39]
For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen for local symptoms. Observational studies of systemic HRT after breast cancer are generally reassuring. If HRT is necessary after breast cancer, estrogen-only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy.[40]
Colorectal cancer
In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer. However, the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones.[41]
Ovarian cancer
A 2015 meta-analysis found that HRT was associated with an increased risk of ovarian cancer, with women using HRT having about one additional case of ovarian cancer per 1,000 users.[42] This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT.[43] Regarding the specific subtype, there may be a higher risk of serous cancer, but no association with clear cell, endometrioid, or mucinous ovarian cancer.[43]
Sexual function
HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40–69 years suggest that 75% of women remain sexually active after menopause.[4] With increasing life spans, women today are living one third or more of their lives in a postmenopausal state, a period during which healthy sexuality can be integral to their quality of life.[44] A major complaint among postmenopausal women is decreased libido and sexual function, and many may seek medical consultation.[5][45] Several hormonal changes take place during this period, including a decrease in estrogen and an increase in follicle-stimulating hormone. For most women, the majority of change occurs during the late perimenopausal and postmenopausal stages.[4] Decrease in sex hormone-binding globulin (SHBG) and inhibin (A and B) also occurs. Testosterone, a hormone more commonly associated with males, is also present in women at a lower level. It peaks at age 30, but declines gradually with age, so there is little variation across the lifetime and during the menopausal transition.[4] With surgical menopause, testosterone declines more sharply and can result in more severe symptoms.[4] HRT can help with sexual difficulties related to pain and lubrication.[5]
Not all women are responsive, especially those with preexisting sexual difficulties.[20] Estrogen replacement can restore vaginal cells, pH levels, and blood flow to the vagina, all of which tend to deteriorate at the onset of menopause. Pain or discomfort with sex appears to be the most responsive component to estrogen.[20] It also has been shown to have positive effects on the urinary tract.[20] Reduced vaginal atrophy and increased sexual arousal, frequency and orgasm have also been noted.[20]
The effectiveness of hormone replacement can decline in some women after long-term use.[20] A number of studies have also found that the combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone.[20] Findings on a relatively new form of HRT called tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties, suggest that it has the ability to improve mood, libido, and physical symptoms of surgically menopausal women to a greater degree than ERT. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been observed.[5] Tibolone has been used in Europe for almost two decades but is not available North America at this point.[5]
Neurodegenerative disorders
HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50–55 years.[24] HRT can also improve executive and attention processes outside of the context of dementia in postmenopausal women.[46]
Muscle and bone
There is a decrease in hip fractures, which persists after the treatment is stopped, though to a lesser degree.[24][47]
Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle.[48]
Side effects
Some common and uncommon side effects include:[49]
- Headache
- Upset stomach, stomach cramps or bloating
- Diarrhea
- Appetite and weight changes
- Changes in sex drive or performance
- Nervousness
- Brown or black patches on the skin
- Acne
- Swelling of hands, feet, or lower legs due to fluid retention
- Changes in menstrual flow
- Breast tenderness, enlargement, or discharge
- Sudden difficulty wearing contact lenses
- Double vision
- Severe abdominal pain
- Yellowing of skin or eyes
- Severe depression
- Unusual bleeding
- Loss of appetite
- Skin rash
- Lassitude
- Fever
- Dark-colored urine
- Light colored stool
- Chorea[50]
The following are absolute and relative contraindications to HRT:[51]
Absolute contraindications
- Undiagnosed vaginal bleeding
- Severe liver disease
- Pregnancy
- Severe coronary artery disease
- Aggressive breast, uterine or ovarian cancer
Relative contraindications
- Migraine headaches
- History of breast cancer
- History of ovarian cancer
- Venous thrombosis
- History of uterine fibroids
- Atypical ductal hyperplasia of the breast
- Active gallbladder disease (cholangitis, cholecystitis)
- Well-differentiated and early endometrial cancer - once treatment for the malignancy is complete, is no longer an absolute contraindication.
History and research
The extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin, one of the earlier forms of estrogen to be introduced.[52][53] From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an 8-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet.[52] It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium.[52] This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera).[52]
The Women's Health Initiative trials were conducted between 1991 and 2006 and were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy women.[52] Their results were both positive and negative, suggesting that during the time of hormone therapy itself, there are increases in invasive breast cancer, stroke and lung clots. Other risks include increased endometrial cancer, gallbladder disease, and urinary incontinence, while benefits include decreased hip fractures, decreased incidence of diabetes, and improvement of vasomotor symptoms. There also is an increased risk of dementia with HRT in women over 65, though when given earlier it appears to be neuroprotective. After the cessation of HRT, the WHI continued observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist.[24] Other studies have also suggested an increased risk of ovarian cancer.[43]
The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its Data Monitoring Committee (DMC) due to perceived health risks, though this occurred a full year after the data suggesting increased risk became manifest. In 2004, the arm of the WHI in which post-hysterectomy patients were being treated with estrogen alone was also closed by the DMC. Clinical medical practice changed based upon two parallel Women's Health Initiative (WHI) studies of HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. One portion of the parallel studies followed over 16,000 women for an average of 5.2 years, half of whom took placebo, while the other half took a combination of CEEs and MPA (Prempro). This WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined CEEs and progestins exceeded their benefits. The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.[54]
Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier, between age 50 to 59, but higher when begun after age 60. In older patients, there was an apparent increased incidence of breast cancer, heart attacks, venous thrombosis, and stroke, although a reduced incidence of colorectal cancer and bone fracture. At the time, The WHI recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks.[54] Some of the WHI findings were again found in a larger national study done in the United Kingdom, known as the Million Women Study (MWS). As a result of these findings, the number of women taking HRT dropped precipitously.[55] In 2012, the United States Preventive Task Force (USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits.[56][57]
In 2002 when the first WHI follow up study was published, with HRT in post menopausal women, both older and younger age groups had a slightly higher incidence of breast cancer, and both heart attack and stroke were increased in older patients, although not in younger participants. Breast cancer was increased in women treated with estrogen and a progestin, but not with estrogen and progesterone or estrogen alone. Treatment with unopposed estrogen (i.e., an estrogen alone without a progestogen) is contraindicated if the uterus is still present, due to its proliferative effect on the endometrium. The WHI also found a reduced incidence of colorectal cancer when estrogen and a progestogen were used together, and most importantly, a reduced incidence of bone fractures. Ultimately, the study found disparate results for all cause mortality with HRT, finding it to be lower when HRT was begun during ages 50–59, but higher when begun after age 60. The authors of the study recommended that women with non-surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk.[54]
The data published by the WHI suggested supplemental estrogen increased risk of venous thromboembolism and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed.[58] These results were later supported in trials from the United Kingdom, but not in more recent studies from France and China. Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women.[59][60]
Neither the WHI nor the MWS differentiated the results for different types of progestogens used. MPA – the type most commonly used in the United States – was the only one examined by the WHI, which in its analysis and conclusions extrapolated the benefits versus risks of MPA to all progestins. This conclusion has since been challenged by several researchers as unjustified and misleading, resulting in unreasonable, unnecessary avoidance by many women of HRT. In addition, subsequent findings released by the WHI showed that all cause mortality was not dramatically different between the groups receiving CEEs, those receiving estrogen and a progestogen, and those not on therapy.[61] In addition, the WHI trial was limited by low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens.[57] The double blinding limited validity of study results due to its effects on patient exclusion criteria. Patients who were experiencing symptoms of the menopausal transition were excluded from the study, meaning that younger women who had only recently experienced menopause were not significantly represented. As a result, while the average age of menopause is age 51, study participants were on average 62 years of age. Demographically, the vast majority were Caucasian, and tended to be slightly overweight and former smokers.
|Relative Risk CEEs/MPA vs. placebo at 5.2 years (95% CI[note 1])
(n = 8102)
(n = 8506)
|Absolute Risk per 10,000 Women-Years
|Coronary heart disease events
( non-fatal myocardial infarction, death)
|1.29 (1.02–1.63)
1.32 (1.02–1.72)
1.18 (0.70–1.97)
|Invasive breast cancer[lower-alpha 1]
|1.26 (1.00–1.59)
|1.41 (1.07–1.85)
|Pulmonary embolism
|2.13 (1.39–3.25)
|Colorectal cancer
|0.63 (0.43–0.92)
|Endometrial cancer
|0.83 (0.47–1.47)
|Hip fracture
|0.66 (0.45–0.98)
|Death due to causes other than above
|0.92 (0.74–1.14)
|Global Index[lower-alpha 2]
|1.15 (1.03–1.28)
|Deep vein thrombosis[lower-alpha 3]
|2.07 (1.49–2.87)
|Vertebral fractures[lower-alpha 3]
|0.66 (0.44–0.98)
|Other osteoporotic fractures[lower-alpha 3]
|0.77 (0.69–0.86)
|Sources: See template.
The WHI reported statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia."[62] The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with Prempro, the specific proprietary combination of CEEs and MPA studied.
After the increased clotting found in the first WHI results was reported in 2002, the number of Prempro prescriptions filled reduced by almost half. Following the WHI results, a large percentage of HRT users opted out of them, which was quickly followed by a sharp drop in breast cancer rates. The decrease in breast cancer rates has continued in subsequent years.[63] An unknown number of women started taking alternatives to Prempro, such as compounded bioidentical hormones, though researchers have asserted that compounded hormones are not significantly different from conventional hormone therapy.[64]
The other portion of the parallel studies featured women who were post hysterectomy and so received either placebo progestogen or CEEs alone. This group did not show the risks demonstrated in the combination hormone study, and the estrogen-only study was not halted in 2002. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in the estrogen-only study participants, risks of stroke and pulmonary embolism were increased slightly, predominantly in patients who began HRT over the age of 60.[65]
Several other large studies and meta-analyses have reported reduced mortality for HRT in women younger than age 60 or within 10 years of menopause, and a debatable or absent effect on mortality in women over 60.[66][67][68][69][15][70]
Though research thus far has been substantial, further investigation is needed to fully understand differences in effect for different types of HRT and lengths of time since menopause.[71][72][73]
Available forms
There are five major human steroid hormones: estrogens, progestogens, androgens, mineralocorticoids, and glucocorticoids. Estrogens and progestogens are the two most often used in menopause. They are available in a wide variety of FDA approved and non–FDA-approved formulations.[8]
In women with intact uteruses, estrogens are almost always given in combination with progestogens, as long-term unopposed estrogen therapy is associated with a markedly increased risk of endometrial hyperplasia and endometrial cancer.[1][2] Conversely, in women who have undergone a hysterectomy or do not have a uterus, a progestogen is not required, and estrogen can be used alone. There are many combined formulations which include both estrogen and progestogen.
Specific types of hormone replacement include:[1][2]
- Estrogens – bioidentical estrogens like estradiol and estriol, animal-derived estrogens like conjugated estrogens (CEEs), and synthetic estrogens like ethinylestradiol
- Progestogens – bioidentical progesterone, and progestins (synthetic progestogens) like medroxyprogesterone acetate (MPA), norethisterone, and dydrogesterone
- Androgens – bioidentical testosterone and dehydroepiandrosterone (DHEA), and synthetic anabolic steroids like methyltestosterone and nandrolone decanoate[74][75]
A 2016 review of clinical research on tibolone – a synthetic medication – found it was more effective than placebo and less effective than combination hormone therapy in postmenopausal women, although it may cause bleeding, increase the risk of recurrent breast cancer in women with a history of breast cancer, and increase the risk of stroke in women over age 60 years.[76]
Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes.[77] Sometimes an androgen, generally testosterone, can be added to treat diminished libido.[78][79]
Continuous versus cyclic
Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progestogens taken for about two weeks every month or every other month, a schedule referred to as 'cyclic' or 'sequentially combined'. Alternatively, 'continuous combined' HRT can be given with a constant daily hormonal dosage.
|0.5–1 mg/day
|1–2 mg/day
|2–4 mg/day
|Estradiol valerate
|0.5–1 mg/day
|1–2 mg/day
|2–4 mg/day
|Estradiol acetate
|0.45–0.9 mg/day
|0.9–1.8 mg/day
|1.8–3.6 mg/day
|Conjugated estrogens
|0.3–0.45 mg/day
|0.625 mg/day
|0.9–1.25 mg/day
|Esterified estrogens
|0.3–0.45 mg/day
|0.625 mg/day
|0.9–1.25 mg/day
|0.75 mg/day
|1.5 mg/day
|3 mg/day
|1–2 mg/day
|2–4 mg/day
|4–8 mg/day
|5–15 μg/day
|Nasal spray
|150 μg/day
|300 μg/day
|600 μg/day
|Transdermal patch
|25 μg/dayb
|50 μg/dayb
|100 μg/dayb
|Transdermal gel
|0.5 mg/day
|1–1.5 mg/day
|2–3 mg/day
|25 μg/day
|30 μg/day
|0.5 mg 2x/week
|0.5 mg/day
|IM or SC injection
|Estradiol valerate
|4 mg 1x/4 weeks
|Estradiol cypionate
|1 mg 1x/3–4 weeks
|3 mg 1x/3–4 weeks
|5 mg 1x/3–4 weeks
|Estradiol benzoate
|0.5 mg 1x/week
|1 mg 1x/week
|1.5 mg 1x/week
|SC implant
|25 mg 1x/6 months
|50 mg 1x/6 months
|100 mg 1x/6 months
|Footnotes: a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.
Route of administration
The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration:[1][2]
- Oral administration – tablets, capsules
- Transdermal administration – patches, gels, creams
- Vaginal administration – tablets, creams, suppositories, rings
- Intramuscular or subcutaneous injection – solutions in vials or ampoules
- Subcutaneous implant – surgically-inserted pellets placed into fat tissue
- Less commonly sublingual, buccal, intranasal, and rectal administration, as well as intrauterine devices
More recently developed forms of drug delivery are alleged to have increased local effect lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels.[1][2] Transdermal and transvaginal estrogen, in particular, avoid first pass metabolism through the liver. This in turn prevents an increase in clotting factors and accumulation of anti-estrogenic metabolites, resulting in fewer adverse side effects, particularly with regard to cardiovascular disease and stroke.[80]
Bioidentical hormone therapy
Bioidentical hormone therapy (BHT) is the usage of hormones that are chemically identical to those produced in the body. Although proponents of BHT claim advantages over non-bioidentical or conventional hormone therapy, the FDA does not recognize the term 'bioidentical hormone', stating there is no scientific evidence that these hormones are identical to their naturally occurring counterparts.[81][82] There are, however, FDA approved products containing hormones classified as 'bioidentical'.[10][8]
Bioidentical hormones can be used in either pharmaceutical or compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and regulatory oversight.[81] Most classifications of bioidentical hormones do not take into account manufacturing, source, or delivery method of the products, and so describe both non-FDA approved compounded products and FDA approved pharmaceuticals as 'bioidentical'.[8]
Bioidentical hormones in pharmaceuticals may have health benefits over their animal derived counterparts, including a potentially decreased risk of venous thromboembolism, cardiovascular disease, and breast cancer.[81] As of 2012, guidelines from the North American Menopause Society, the Endocrine Society, the International Menopause Society, and the European Menopause and Andropause Society endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk.[81][83]
Compounding for HRT is generally discouraged by the FDA and medical industry in the United States due to a lack of regulation and standardized dosing.[81][82] The U. S. Congress did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the Federal Food, Drug, and Cosmetic Act (FDCA), but they have encountered obstacles in this role since that time. After 64 patient deaths and 750 harmed patients from a 2012 meningitis outbreak due to contaminated steroid injections, Congress passed the 2013 Drug Quality and Security Act, authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs, and reinforcing FDCA regulations for traditional compounding.[84]
In the United Kingdom, on the other hand, compounding is a regulated activity. The Medicines and Healthcare products Regulatory Agency regulates compounding performed under a Manufacturing Specials license and the General Pharmaceutical Council regulates compounding performed within a pharmacy. All testosterone prescribed in the United Kingdom is bioidentical, with its use supported by the National Health Service. There is also marketing authorisation for male testosterone products. National Institute for Health and Care Excellence guideline 1.4.8 states: "consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective". The footnote adds: "at the time of publication (November 2015), testosterone did not have a United Kingdom marketing authorisation for this indication in women. Bio-identical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour."
Society and public perception
Wyeth controversy
Wyeth, now a subsidiary of Pfizer, was a pharmaceutical company that marketed the HRT products Premarin (CEEs) and Prempro (CEEs + MPA).[85][86] In 2009, litigation involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications.[85][86][87] The documents showed that Wyeth commissioned dozens of ghostwritten reviews and commentaries that were published in medical journals in order to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light.[85][86][87] Starting in the mid-1990s and continuing for over a decade, Wyeth pursued an aggressive "publication plan" strategy to promote its HRT products through the use of ghostwritten publications.[87] It worked mainly with DesignWrite, a medical writing firm.[87] Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals.[85]
These favorable publications emphasized the benefits and downplayed the risks of its HRT products, especially the "misconception" of the association of its products with breast cancer.[87] The publications defended unsupported cardiovascular "benefits" of its products, downplayed risks such as breast cancer, and promoted off-label and unproven uses like prevention of dementia, Parkinson's disease, vision problems, and wrinkles.[86] In addition, Wyeth emphasized negative messages against the SERM raloxifene for osteoporosis, instructed writers to stress the fact that "alternative therapies have increased in usage since the WHI even though there is little evidence that they are effective or safe...", called into question the quality and therapeutic equivalence of approved generic CEE products, and made efforts to spread the notion that the unique risks of CEEs and MPA were a class effect of all forms of menopausal HRT: "Overall, these data indicate that the benefit/risk analysis that was reported in the Women's Health Initiative can be generalized to all postmenopausal hormone replacement therapy products."[86]
Following the publication of the WHI data in 2002, the stock prices for the pharmaceutical industry plummeted, and huge numbers of women stopped using HRT.[88] The stocks of Wyeth, which supplied the Premarin and Prempro that were used in the WHI trials, decreased by more than 50%, and never fully recovered.[88] Some of their articles in response promoted themes such as the following: "the WHI was flawed; the WHI was a controversial trial; the population studied in the WHI was inappropriate or was not representative of the general population of menopausal women; results of clinical trials should not guide treatment for individuals; observational studies are as good as or better than randomized clinical trials; animal studies can guide clinical decision-making; the risks associated with hormone therapy have been exaggerated; the benefits of hormone therapy have been or will be proven, and the recent studies are an aberration."[52] Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors.[52] These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS.[52] In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion.[89][90] Pfizer, a company that produces Provera and Depo-Provera (MPA) and has also engaged in medical ghostwriting, continues to market Premarin and Prempro, which remain best-selling medications.[52][87]
According to Fugh-Berman (2010), "Today, despite definitive scientific data to the contrary, many gynecologists still believe that the benefits of [HRT] outweigh the risks in asymptomatic women. This non-evidence–based perception may be the result of decades of carefully orchestrated corporate influence on medical literature."[86] As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS.[91] The positive perceptions of many physicians of HRT in spite of large trials showing risks that potentially outweigh any benefits may be due to the efforts of pharmaceutical companies like Wyeth.[87][52]
- Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.
- A subset of the events was combined in a "global index", defined as the earliest occurrence of coronary heart disease events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.
- Not included in Global Index.
- Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
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- Pinkerton, JV; Pickar, JH (February 2016). "Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy". Menopause. 23 (2): 215–23. doi:10.1097/GME.0000000000000523. PMC 4927324. PMID 26418479.
- Singer, Natasha (4 August 2009). "Medical Papers by Ghostwriters Pushed Therapy". The New York Times. Retrieved 13 July 2018.
- Fugh-Berman AJ (September 2010). "The haunting of medical journals: how ghostwriting sold "HRT"". PLoS Med. 7 (9): e1000335. doi:10.1371/journal.pmed.1000335. PMC 2935455. PMID 20838656.
- Steve Kent May; Steve May (20 January 2012). Case Studies in Organizational Communication: Ethical Perspectives and Practices: Ethical Perspectives and Practices. SAGE. pp. 197–. ISBN 978-1-4129-8309-9.
- Miller VM, Harman SM (November 2017). "An update on hormone therapy in postmenopausal women: mini-review for the basic scientist". Am. J. Physiol. Heart Circ. Physiol. 313 (5): H1013–H1021. doi:10.1152/ajpheart.00383.2017. PMC 5792205. PMID 28801526.
- Sorkin, Andrew Ross; Wilson, Duff (2009-01-25). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times.
- "Pfizer Sizes Up: Closes $68B Wyeth Deal". 2009-10-19.
- Tao M, Teng Y, Shao H, Wu P, Mills EJ (2011). "Knowledge, perceptions and information about hormone therapy (HT) among menopausal women: a systematic review and meta-synthesis". PLoS ONE. 6 (9): e24661. Bibcode:2011PLoSO...624661T. doi:10.1371/journal.pone.0024661. PMC 3174976. PMID 21949743.
- "Hormone therapy for brain performance: No effect, whether started early or late". www.sciencedaily.com.
External links
- Menopause treatment, Hormone Health Network, The Endocrine Society
- Sexual Health and Menopause Online, The North American Menopause Society
- Menopause, US Food and Drug Administration


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failed states Compared by Economy > Trade > Exports > Export growth
DEFINITION: Export volume indexes are derived from UNCTAD's volume index series and are the ratio of the export value indexes to the corresponding unit value indexes. Unit value indexes are based on data reported by countries that demonstrate consistency under UNCTAD quality controls, supplemented by UNCTAD's estimates using the previous year's trade values at the Standard International Trade Classification three-digit level as weights. For economies for which UNCTAD does not publish data, the export volume indexes (lines 72) in the IMF's International Financial Statistics are used.".

subset: commoncrawl


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Friday, February 28, 2014
Right Where I am
I remember once reading an article about a man who said that even if you lived 100 years, you'd only get to see 100 Autumns. At the time, I remember being in awe of such a drastic statement. Can you imagine, thinking each season of your life that you only had a limited number left? It seemed to me like such a profound thing to even consider.
Now, it's probably been at least 10 years since I've read that article, but I still remember the sentiment that the man portrayed. And the more I think about it, the more I wonder...
Have I experienced all my Autumns?
It's kind of funny how much of life we take for granted. We spend a lot of time lamenting that one day, it will be gone from us, that it can be taken so easily. We wonder if we will have the lives we think we are supposed to have- the right job, the house, the kids, the vacation. We toil and trouble and work hard for things that we think we are supposed to want, and sometimes, we get so caught up in those ideas, that we miss what is going on around us.
Where I live, the summers and winters tend to be the dramatic seasons, while spring and fall just sort of breeze in and out with no second thought. Sometimes I've barely put away my winter coat at the end of March before it's May and the weather has gotten too warm for my sweaters. It's like I've jumped the whole month between work and obligations and worry and suddenly, even if I live until 100, I'm coming up short.
The more time passes, the more I realize how much I am content to enjoy the moment. I don't mean that I don't want to plan ahead or think about the future. But my generation is, as were those before us, obsessed with getting to where we need to be as quickly as possible without enjoying the ride. We'd rather time travel then take the train, enjoying what's passing by as we ride to our destinations. As a result, there are millions of amazing things we will never experience, and maybe never even know we missed.
It's sobering to think about, if you ask me. I have goals and ideas that I look toward with hope. But I wonder if they consume my life. I wonder if those things will still hold their appeal once I arrive. Surely if these things were meant to be formulated, they would have. God would have put them into a specified plan. We'd all be married at the same age, with a baby on the way, and live in our happy little homes with no thought for the outside world.
My point is that our time here on earth is limited, and I fear that I limit it more and more by rushing it. Some days it's all I can do to get through the work day so I can get to whatever excitement lays before me. But my attitude dose not speed up time any. It just leaves me with one less day to reflect on later in life.
My life needs more sunsets- more moments of stopping to stare in awe into the sky and just enjoy the moment, live for the second. I explained it a few weeks back to a group of friends this way: A sunset is not tangible. You can't touch it. You can't reach out and change the way it's happening. And it's not the same to hear about it from someone else or see it secondhand in a picture. You just have to be there.
I don't know if I'll make it to a hundred. I don't know if I'll accomplish all that I've set out for myself to dream of. But I have the chance, right here and now, to enjoy the journey. I don't want to miss another second of this life I've been given by jumping ahead. I am happy to be right here, right now- right where I am.
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Getting Ready with Mindy Kaling
Behind-the-scenes at the Costume Designers Guild awards.
Like most of girl world, there's no one we'd rather be besties with than Mindy Kaling. Chalk it up to the countless GIFS of her characters from both The Office and The Mindy Project, her simultaneously enlightening and relatable Instagram (because we too are all about that Lupita Nyong'o color-block lifestyle and rainbows of Stila liquid liners) or her unreal talent and unbeatable comedic timing, and, for lack of a better word, chops.
And so when we learned that Kaling would be kind enough to share with us a diary from her night at the Costume Designers Guild Awards this past weekend, we mildly freaked out over at TC HQ. After all, we've been having slight withdrawal symptoms while her eponymous show, The Mindy Project has been on hiatus, and can think of no better way to get our Kaling fix.
The look? A subtly smoky eye, Jimmy Choo pumps and a custom teal gown by none other than Salvadore Perez, who just so happens to be president of the Guild and costume designer on Kaling's eponymous show, The Mindy Project. NBD, right?! Oh, and painfully pretty loose waves and a Jimmy Choo clutch juuuust big enough to house all of the essentials—namely, a tube of Kevyn Aucoin lip gloss. As if we didn't fan-girl hard enough before.


text: I stopped Looked around And realised…. Some people are ambitious and want to make £thousands and possibly £millions. At one time that was me. I discovered that not many actually do it because we aren't prepared to make the sacrifices. We aren't prepared to work the hours, miss out on time with the family, work consistently hard for the years it … Read More


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University of Kragujevac is the fourth largest university in Serbia. It educates 15000 students, and employs a thousand professors and lecturers in 12 different Faculties. It has participated in numerous national and international projects, including the following:
– West Balkan Bologna Promoters Network C032B06
– Development of lifelong learning framework in Serbia JP 145010-2008
– Internal Quality Assurance at Serbian Universities SM 145677-2008
– Strenghtening Quality Assurance System within Western Balkans HEIs in Support of National and Regional Planning JP 158999-2009
– Governance and Management Reform in Higher Education in Serbia (GOMES) JP 158926-2009
– National Platform for Knowledge Triangle in Serbia JP 158881- 2009
– Improvement of Students' Internship in Serbia (ISIS) 5110985 TEMPUS-1-2010-RS
– Enhancing the quality of distance learning at Western Balkan higher education institutions ([email protected]) 511126
– Strengthening the Student Role in Governance and Management at the Universities of Serbia in line with the Bologna Process (SIGMUS) 511332-TEMPUS-1-2010-RS
– Development of Career Guidance Aimed at Improving Higher Education in Serbia SM 517119-2011
– Education of Teachers in the field of Ecological Food Production and Management JP 516964-2011
Faculty of Education – Faculty that will be leading this project within the University – dates back to 1898 (first as an independent teacher training college, and in the last several decades as a part of University of Kragujevac). It employs a faculty of 51 and enrols 1,200 students. Its primary purpose is to educate ISCED 1 teachers (at the bachelor and master levels), but also to educate Early childhood education and care teachers (at the bachelor and master levels), education and care providers in Centers for abandoned children (at the bachelor and master levels), as well as students of the newly established Master of education policy program. The Faculty is very open to new ideas and pro-active. Since 2006 it has participated in the following TEMPUS projects as the leading Faculty within the University of Kragujevac:
– Developing Human Rights Education at the Heart of Higher Education, JP 517319-2011
– Harmonization and Modernization of the Curriculum for Primary Teacher Education (HAMOC) JP 516762-2011
– Master Programme for Subject Teachers in Serbia (MASTS) JP 511170-2010
– Education Policy Study Programme in Serbia and Montenegro (EPSP) JP 159074-2009
– Modernizing Teacher Education in a European Perspective JP 159048-2009
– Curriculum Reform in Teacher Education JEP 41074-2006
University of Kragujevac will be the applicant organization in this project. As such, it will be in charge of the operational and financial management of the project. It will ensure proper organization of activities, good communication between the partners, adequate reporting and timely production of the outputs of the project. The Faculty of Education will also lead another work package and participate in all others. The Faculty will contribute the know-how in the school form and questionnaire development and multi-level modelling for the School Performance Feedback and Effectiveness Factors work packages, and be heavily involved in the Effective Professional Development work package, considering its long history and experience in preparing teachers for the world of work, in both initial education and in in-service training.
The operational and financial management has been established in previous projects and it functions very well. At the level of the Faculty of Education, a small team in charge of the project consists of three sub-teams: program and communication (lead Prof. Jelena Teodorovic), operational (lead Prof. Violeta Jovanovic) and financial (lead Prof. Ilijana Cutura). The tree sub-teams, supported by apt administrative assistants, work very closely together on ensuring that activities run smoothly, that communication between the partners is productive and respectful, that timelines are respected and that proper documentation is in place. The team has a very good communication with the financial and operational personnel at the Rectorate of the University of Kragujevac, which re-checks the documentation and its coherence with EACEA rules and Serbian laws and bylaws, and performs necessary legal and financial activities (signs University-level papers, transfers funds, orders equipment, etc). The efficient running of the activities is institutionalized by procedures and forms that have been put in place in recent years, ever since the University and Faculty started participating more frequently in international projects.


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The Duke ophthalmology second-year medical student selective offers a comprehensive rotation with exposure to each ophthalmic subspecialty. Each selective consists of a two-week rotation through the Duke Department of Ophthalmology and is offered five times over a 12-month period.
During the two-week selective, the student is offered daily didactic lectures by renowned faculty on a variety of ophthalmic topics as well as hands-on training to become more familiar with the most commonly used examination equipment. Illustrative handouts as well as reading materials are provided in a binder. During this rotation, the student will be exposed to patient care in the clinics as well as the operating rooms for the following subspecialties: cornea/refractive and external disease, oculofacial surgery, vitreoretinal diseases, neuro-ophthalmology, pediatric ophthalmology, glaucoma, and comprehensive ophthalmology.
Medical students will observe ophthalmic photography procedures as well as learn how the ophthalmic technician works up patients through visual acuity examinations and refractions. The student will also observe low vision and visual rehabilitation clinic evaluations and rotate into the anatomy labs for a hands-on eye and orbital dissection. There is exposure to the ophthalmic research faculty and their projects to allow interested students to learn about the ophthalmology laboratories as they consider their options for third year. The student also experiences one on-call night with the ophthalmology resident during the rotation for exposure to ophthalmic emergencies. Additionally, the program has both a general ophthalmology and pediatric elective.
Course director Jullia Rosdahl, MD, PhD. Contact: firstname.lastname@example.com
Electives for second-year medical students
Course description from Duke Medical School Bulletin.
OPHTHAL-220C. OPHTHALMOLOGY. This ophthalmology selective is designed to introduce the second year medical student to the medical and surgical aspects of comprehensive ophthalmology, including subspecialties (neuro-ophthalmology, external disease, oculoplastics, cornea, refractive surgery, pediatrics, strabismus, glaucoma, and vitreoretinal disease). There will be didactic instruction with patient care exposure in the clinic setting and operating room. Enrollment: max 5.
Course director Jullia Rosdahl, MD, PhD. Contact: email@example.com
Electives for second-year medical students
Course description from Duke Medical School Bulletin.
OPHTHAL-252C. GENERAL OPHTHALMOLOGY. A clinical preceptorship in which the student participates and observes the regular house staff activities including clinics, night call, conferences, lectures, patient care, and treatment including surgery. The use of specialized ophthalmic apparatus is emphasized. Prerequisites: OPHTHAL 420C recommended, but not required. Credit: 4. Enrollment: max 4.
Course director Jullia Rosdahl, MD, PhD. Contact: email@example.com
OPHTHAL-255C. PEDIATRIC OPHTHALMOLOGY. A clinical preceptorship in which the student participates in the outpatient pediatric ophthalmology clinic. The student will encounter the more common ocular disorders of childhood including ocular motility disturbances, congenital cataracts and glaucoma, and congenital genetic and metabolic disorders. In addition, adult motility disorders and neuro-ophthalmic disease such as thyroid eye disease, cranial nerve palsies, and optic nerve abnormalities will be encountered. The diagnosis and treatment aspects are heavily emphasized and opportunities to observe surgery are provided. The course meets by arrangement and requires a minimum of five days per credit. Credit: 4. Enrollment: max 3.
Course directors: Edward Buckley, MD and Sharon Freedman, MD. Contact: firstname.lastname@example.com
For additional information about registration, contact Duke Medical School Office of the Registrar


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A recent failed test-case when testing some code against different Servlet API libraries has made me look more closely at how ServletException deals with exception chaining.
I'd pretty much taken this for granted before, but it turns out to be not entirely trivial. So it seems worth spelling out exactly how it works, and what steps you need to take to use it safely.
The underlying problem is that the ServletException class pre-dates the introduction of standardised support for a "cause" within Throwable. As with many such classes from before the introduction of "cause", ServletException provides its own mechanism for exception chaining – in its own case, a "rootCause" property.
Since the introduction of standard "cause" support in Throwable, ServletException thus has both its own "rootCause" property and the inherited "cause" property. However, the relationship between these two mechanisms is left entirely unspecified, with the Javadoc for ServletException's constructor and "getRootCause" methods making no mention of whether or how they interact with the inherited "cause" mechanism.
The result is that the interaction between "rootCause" and "cause" may differ between Servlet API implementations, and care may be necessary when populating these properties.
- ServletException provides constructors that take a "rootCause", together with a "getRootCause" method that returns it, as well as other constructors that do not take a "rootCause" and for which "getRootCause" returns null.
- ServletException's underlying Throwable base class provides constructors that take a "cause" and other constructors that do not, plus an "initCause" method that can be used to populate the cause after construction if and only if it is not already set, together with a "getCause" method that returns the "cause" (if any).
- ServletException does not specify whether supplying a "rootCause" also populates its "cause" or leaves it unpopulated. Different Servlet API implementations are potentially free to handle this differently.
- ServletException does not specify whether setting a "cause" via its "initCause" method also sets its "rootCause" (and if so, whether this is only permitted if no "rootCause" was supplied on construction, or whether it can be called even if a "rootCause" is already present). Different Servlet API implementations are potentially free to handle this differently.
So when you're creating a ServletException with an underlying cause, this leaves you not knowing:
- Whether to just supply the cause to the ServletException's constructor as its "rootCause" (on the basis that this should "obviously" take the given value as being both the "rootCause" and the "cause").
- Or whether to also call the resulting instance's "initCause" method so as to ensure that the "cause" is populated properly (on the basis that ServletException doesn't explicitly say that it populates the "cause", so there is no reason to think that supplying a "rootCause" has any effect on its "cause").
- Or whether to ignore the ServletException "rootCause" constructor and instead just call the inherited "initCause" method (on the basis that in the absence of an existing "rootCause" this can safely be called to set the "cause" and should "obviously" also set the "rootCause").
If you get this wrong, you can potentially end up with a ServletException that has a "rootCause" but no "cause" (and thus, for example, doesn't show the underlying cause in its stack trace); or with a call to "initCause" that fails with an IllegalStateException due to the "cause" having already being populated during construction; or with a ServletException that has a "cause" but no "rootCause".
This isn't entirely academic, because Servlet API implementations do actually differ in how they handle this. For example:
- The Servlet API 2.5 reference implementation in Glassfish does automatically populate the "cause" when you supply a "rootCause" (by passing the "rootCause" to the appropriate superclass constructor during the ServletException's construction).
- The reference implementations provided by Apache Tomcat for earlier Servlet API versions do not popluate the "cause" when you supply a "rootCause", and the "cause" remains empty unless and until you populate it yourself. (Theoretically, nothing prevents the use of two entirely different exceptions as the "rootCause" and "cause", which could get rather confusing, especially if done accidentally).
- Other implementations and subsequent releases remain free to take either approach.
- Although I've not seen, and can't really imagine, a ServletException implementation whose "initCause" takes the "rootCause" into account (e.g fails if it is already set but otherwise populates it in addition to the "cause"), this is potentially possible and stranger things have happened.
So as far as I can see, the safest way to ensure that both the "rootCause" and "cause" are populated (without being dependent on the particular implementation of a particular Servlet API library) is to supply the underlying exception to the ServletException constructor but then also call the "initCause" method to populate the "cause" if and only if it has not already been populated by the constructor.
That is, you need code along the lines of:
ServletException e = new ServletException(message, cause); if (e.getCause() == null) { e.initCause(cause); };
Obviously, if you need to do this in multiple places it makes sense to encapsulate it in a method or to provide your own subclass of ServletException that does this in its constructor.


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An entire high school in New Zealand paid tribute to a beloved teacher at his funeral by performing the traditional Haka routine.
Students from Palmerston North Boys' High School carried out the dance in front of a hearst carrying Dawson Tamatea, 55, this weekend - and the powerful performance was captured on video.
Read: Dionne Warwick Remembers Bobbi Kristina: 'She Was a Sweetheart'
Mr. Tamatea was a physical education and math teacher at the school for almost 30 years. He passed away in his sleep, according to reports, on July 20. He leaves behind a wife and three children.
The Haka is the traditional war dance of the Maori people of New Zealand.
The dance is also used to honor guests at ceremonies, as well as the countries professional sports teams like Rugby, soccer and basketball to perform in order to intimidate the opponent.
The school wrote on its YouTube channel: "We are extremely proud of our boys' performance and we know that Mr. Tamatea would be too."
Thousands attended Mr. Tamatea's funeral and the school posted the dance on its Facebook page where students, past and present, paid tribute to the beloved teacher.
Read: High School Has Awesome Song and Dance for Graduation
One viewer commented: "Powerful, powerful stuff! I had goosebumps. Brilliant."
A former student added: "He would be proud at such a tribute."
Another former student wrote: "Awesome send off for a great man, well done boys did the school proud."
Watch Below: Little Boy Gives His Goldfish a Heartbreaking Funeral


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HÀ TĨNH — It is unnecessary to use advanced technology to clean the marine environment in the four central provinces hit by recent pollution as the coral reef ecosystem and seafood resources have shown signs of recovery.
The pollution investigation results were released yesterday in the central province of Hà Tĩnh.
Prof. and Dr Mai Trọng Nhuận from the research group said the seawater and sediment quality in the monitored areas off the coast of Hà Tĩnh, Quảng Bình, Quảng Trị and Thừa Thiên-Huế was within permissible limits for bathing, water sports, aquaculture and marine conservation areas.
Nhuận, from the Vietnam National University, Hà Nội, said thorough assessment is required before using advanced technology to tackle marine pollution.
Scientists believe that in the short term, the affected provinces need to conserve seafood resources areas or raise abalone in coral areas to clean the environment naturally, he said.
Đặng Ngọc Sơn, Vice Chairman of the Hà Tĩnh provincial People's Committee, said the local administration requested Hưng Nghiệp Formosa Hà Tĩnh Steel Co. Ltd, which admitted responsibility for the mass fish deaths along the central coast in June, address the incident's consequences, install environmental protection technology, and not pollute the environment again.
The pollution damaged about 400 hectares of coral and affected over 260,000 people who earn their living in sea-related activities.
Humanitarian aid
A joint programme of humanitarian aid for people in localities hit by drought, salt intrusion and mass fish deaths has mobilised more than VNĐ 204 billion (US$9.1 million) from organisations and inviduals over the past three months, said the Việt Nam Fatherland Front Central Committee at a meeting yesterday.
The fund has provided more VNĐ150 billion ($6.7 million) in financial aid to about 193,000 households in these localities, together with more than 1,800 tonnes of rice.
Regarding the VNĐ11.5 trillion ($500 million) pledged by Formosa to support local fishermen and recover the polluted maritime environment, Deputy Minister of Finance Nguyễn Hữu Chí said Formosa has sent half of the amount to the State Treasury. The remainder is expected on Sunday.
Ministries and authorised agencies will use the money to support fishermen, he said, adding that the use of the money will be strictly supervised to prevent loss and corruption. — VNS


text:
EP-107 Cash Drawer
The EP-107 is an upgraded version of the 3S-460 with a more robust construction. Features and Insert options are almost identical to the 3S-460.
EP-107 Features:
- Standard Size
- All Steel Construction
- Black or Off-White Coat Finish
- Media Slots are optional
- Three function centre key lock: Manual release, electronic release and drawer lock
- Insert options including 8 coin / 4 note, 8 coin / 6 (inclined) note or 5 coin / 4 note + 2 larger notes at the rear
- Drawer Status Switch Fitted
- Stainless Steel Money Clips
EP-107 Specifications:
Dimensions: 440 mm (W) x 460 mm (L) x 115 mm (H)*
*103 mm (H) without rubber feet
Ship Weight: 10 KG
Drawer Solenoid: 12V or 24 V
Warranty: 2 years
Interfaces: Any Receipt Printer, EPOS System or Computer interface (eg: USB, Serial)


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Photographer: B&T Capture/Bennie E. Palmore II
Over 1,500 guests celebrated the Las Vegas Woman Summer Soiree Cover Party at Tivoli Village. Swag bags were given to the first 300 women with samples, coupons and goodies. The event included the reveal of the cover featuring Soozi Jones Walker and Bobbi Miracle, the mother-daughter commercial real estate team at Commercial Executives Real Estate Services.
A fun twist on the event featured a food and wine tasting tour of various businesses within Tivoli. Additional bites were provided by Diamond Events & Catering and Oscar Catering. The crowd was entertained with music by High Flyin' Entertainment. As always, lavish raffle prizes were awarded to several lucky attendees. Thank you to all of the sponsors and guests for their continued support of Las Vegas Woman magazine.


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Principal component analysis : Use extended to Financial economics : Part 2
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I came across this interesting research paper published in one of the most coveted journals, (International Journal on Finance and Economics) which has used the PCA on the macroeconomic variables. So relating it to my previous post and the question of investigating the factor affecting stock returns, what they do is that they take individual stocks and regresses it on the PCA of macroeconomic variables. At the first glance this would appear an inappropriate use of the tool, however the question that it intends to ask is also very different. There has been or infact still is this great battle between the Capital Asset Pricing (CAPM) school of thought and Arbitrage Pricing Theory (APT) school of thought. What the essential difference between these two schools is that the CAPM says that the returns to a stock are sensitive to only one factor, i.e the market rate of returns (single factor model) which captures the effect of all the various factors, however the APT guys scream that it depends on a number of factors and market rate of return would be just one of them. So in this battle to prove their point the APT folks take stock returns as a dependent variable and as independent variables they use the PCA of many macroeconomic variables. They do this essentially so that they can prove that there are more than one factors playing a significant part in the explaining the returns on a stock, they do not care whether the economic intuition is lost in the process on one-upmanship.
Well anything is fair in war, but I think this path taken by APT guys of proving their point is a fair point. The variables that are thrown into the PCA are chosen with an economic intuition in mind, so its not correct to say this entire methodology is flawed on the pretext that the PCA of these macroeconomic variables have no economics intuition. If one really digs into the intuition behind PCA as explained in this article one can visualize what the PCA of macroeconomics variables would be representing, the principal underlying components that give rise to such a macroeconomic series (signals). This is an unconventional way of doing an econometric study, as in this is more of a qualitative than a quantitative study. I cannot make sense of a statement that 1 unit increase in my first PCA results in "x" unit increase in returns, this is an absurd statement, but nevertheless the methodology of answering the underlying question is not absurd.
The methodology for calculating the PCA for macroeconomics is same as what was used in the previous post. We can have a number of macroeconomic variables, however, I have done this demonstration with only 2 variables change in Mumbai inter-bank offer rates (MIBOR) rates and change in INR/USD exchange rates.
#### Calculating the PCA of macroeconomic variables ####
# Reading the relevant files
mibor <- read.csv("MIBOR.csv", na.strings="#N/A")
exchange <- read.csv("Exchange_rates.csv", na.strings="#N/A")
# Making sure that there are no missing values in the data, the missing values are replaced by linear interpolation
mibor[, 2] <- approx(as.Date(mibor$Dates, '%d-%b-%y'), mibor[ ,2], as.Date(mibor$Dates, '%d-%b-%y'))$y # approx() returns the interpolated values in column 'y'
exchange[, 2] <- approx(as.Date(exchange$Year,'%d-%b-%y'), exchange[ ,2], as.Date(exchange$Year, '%d-%b-%y'))$y # Similarly for exchange rates
# Now we will have to compute the change in MIBOR and exchange rates:
for(k in 2:nrow(mibor))
mibor$Change1[k] <- ((mibor$MIBOR[k] - mibor$MIBOR[k-1])/mibor$MIBOR[k-1])*100
for(j in 2:nrow(exchange))
exchange$Change[j] <- ((exchange$Exchange.rates[j] - exchange$Exchange.rates[j-1])/exchange$Exchange.rates[j-1])*100
# Creating matrix of the data
macro <- as.data.frame(rep(0, 2498))
macro$ex <- exchange$Change
macro$rate <- mibor$Change1
- In the above exercise I have just taken 2 variables merely for illustration, I would have to include more variables if I really intent to find evidences against the CAPM.
- Again the caveat of interpretation applies. Its difficult to interpret the PCA on macrovariables
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text:
IIT Roorkee Develops 'Inflatable Safety Helmet' For Motor-Cyclists
New Delhi: Each year nearly 1.2 million people die because of road crashes, and millions more are injured or disabled. In India, 69% of the total number of motor vehicles are motorized two-wheelers, considerably higher than in high-income countries and 27% of road deaths in India are among users of motorized two-wheelers. Keeping in view that the the traditional helmets do not offer sufficient protection to prevent injuries, a team from Indian Institute of Technology (IIT) Roorkee has developed an Inflatable Safety Helmet for motor-cyclists.
According to the institute, the concept of Inflatable Helmet is inspired from the inflatable space structures as they are suitable for many space applications at low cost.
"An inflatable structure can be folded to fit into the shroud of a small launch vehicle and can be deployed in space by a small amount of inflation gas," said a statement from IIT Roorkee.
"The traditional helmets do not offer sufficient protection to prevent injuries and are known for hindering agility and reducing the responsiveness of the rider. Traditional helmets are not much capable of reducing the peak acceleration, which can lead to more severe injuries," it said.
The inflatable helmet can be worn around the neck and remains folded as a collar.
The device is equipped with sensors to measure parameters such as acceleration, lean angle, velocity etc. to detect impact or collision. As soon as the impact is detected the helmet inflates and forms a cushion around the cranium. This cushion is more effective in reducing the impact and peak acceleration which is transferred to head.
The device is developed by three students, Mr. Sarang Nagwanshi, Mr. Mohit Siddha and Mr. Rajvardhan Singh, of B.Tech (Final Year) Mechanical Engineering, IIT Roorkee. The team is guided by Prof. Sanjay Upadhyay, Department of Mechanical & Industrial Engineering, IIT Roorkee.
"The product has been conceptualized and tested for effectiveness and feasibility, and it has shown positive results. But for mass production, we need more diligence from our side and industry support. So still we are working to make it consumer- friendly. We are also looking for industrial partnerships so that the product turns out to be cost effective and user-friendly," Prof. Sanjay Upadhyay said while speaking about the technology.
Speaking about their invention, Mr. Sarang Nagwanshi, said,"We got the idea of inflatable helmet while we were working on inflatable space antenna at ISRO during our internship. As this helmet is being developed for the first time in India we got very limited help from any external source and our learning curve was very steep. The results obtained are very encouraging and we are working towards converting this idea into a reality."
The team conducted Impact tests under standard testing conditions for helmets on mathematical models. The results indicate that inflatable safety helmets are capable of manifold reduction in the peak acceleration after impact created by the collision. The force which is experienced by the dummy head is found to be reduced by four times and falls far below the force experienced in case of conventional helmets. An inflatable airbag helmet reduces the head injury.
(Indebted to various sources)