This document provides an overview of menopause, including definitions, physiological changes, diagnosis, and treatments. It discusses the average age of menopause and influential factors. It defines menopause, premature ovarian failure, and the menopausal transition period. It then covers changes to the hypothalamus-pituitary-ovarian axis, ovaries, endometrium, central thermoregulation, and other areas. It provides details on evaluating abnormal uterine bleeding and discusses treatment options like hormone replacement therapy, antidepressants, clonidine, gabapentin, and complementary therapies.
This document discusses menopause and related topics. It defines menopause as the permanent cessation of menstruation resulting from loss of ovarian activity. Natural menopause is recognized after 12 months of amenorrhea without other causes. Women in the UK typically experience menopause between ages 45-55. The document also discusses premenopause, perimenopause, postmenopause, premature ovarian insufficiency, symptoms, diagnosis, and management including hormone replacement therapy.
The document discusses menopause, including natural and induced causes. Natural menopause is defined as the permanent cessation of menstruation for 12 months due to ovarian failure. Symptoms include hot flashes, night sweats, and mood changes. Long term risks include osteoporosis and increased risk of cardiovascular disease. Hormone replacement therapy can help treat symptoms and prevent osteoporosis, but has risks like breast cancer if used long term. Lifestyle changes and non-hormonal treatments can also help manage menopause symptoms.
This document discusses a 52-year-old woman presenting with hot flashes and depression for 14 months without a period. It defines perimenopause, menopause and postmenopause, and lists common menopausal symptoms. It provides guidance on diagnosing and managing menopause, as well as addressing potential risks and benefits of hormone replacement therapy. Laboratory tests are not necessary to diagnose menopause in most women over age 45. Lifestyle changes and short-term hormone therapy are recommended for managing vasomotor symptoms.
Menopause is the permanent cessation of menstruation at the end of reproductive life due to loss of ovarian activity, usually occurring between ages 42-58. After menopause, women experience various physiological symptoms like loss of skin elasticity, osteoporosis, urogenital atrophy, and psychological changes like mood swings, difficulty sleeping, and forgetfulness due to hormonal changes. Surgical menopause occurs when the ovaries are removed during a hysterectomy, causing more severe symptoms. Management of menopause symptoms includes hormone replacement therapy, cognitive behavioral therapy, exercise, and counseling.
Premature ovarian failure is defined as ovarian failure occurring spontaneously before age 40. It is characterized by amenorrhea and elevated FSH and low estrogen levels. The incidence is approximately 1 in 1000 before age 30 and 1% just before age 40. Causes include genetic factors, autoimmune conditions, chemotherapy or radiation exposure, tuberculosis, smoking, and metabolic or surgical issues. Clinically, it presents with amenorrhea, hot flashes, and symptoms of low estrogen. Diagnosis is based on amenorrhea for 3 months and elevated FSH levels on two occasions one month apart. Management involves treating any underlying cause, hormone replacement therapy to prevent osteoporosis and cardiovascular disease, and in some cases ovulation induction or egg donation for
This document discusses menopause and postmenopause. It defines menopause as the permanent cessation of menstruation due to loss of ovarian activity, usually occurring between ages 45-50. The document describes the hormonal changes, symptoms, risks, diagnosis, and treatment options associated with menopause including hormone replacement therapy and lifestyle modifications.
Menopause typically occurs between ages 49-52 as the ovaries gradually slow production of eggs and reproductive hormones, causing menstrual periods to stop. It may be induced by surgery or occur prematurely under age 40. Symptoms include hot flashes, mood changes, and increased risk of osteoporosis and heart disease due to hormonal changes. Hormone replacement therapy can help treat symptoms but also carries risks if used long term. Maintaining a healthy lifestyle through diet, exercise, avoiding smoking and limiting alcohol can also help manage menopausal effects.
This document discusses menopause and related topics. It defines menopause as the permanent cessation of menstruation resulting from loss of ovarian activity. Natural menopause is recognized after 12 months of amenorrhea without other causes. Women in the UK typically experience menopause between ages 45-55. The document also discusses premenopause, perimenopause, postmenopause, premature ovarian insufficiency, symptoms, diagnosis, and management including hormone replacement therapy.
The document discusses menopause, including natural and induced causes. Natural menopause is defined as the permanent cessation of menstruation for 12 months due to ovarian failure. Symptoms include hot flashes, night sweats, and mood changes. Long term risks include osteoporosis and increased risk of cardiovascular disease. Hormone replacement therapy can help treat symptoms and prevent osteoporosis, but has risks like breast cancer if used long term. Lifestyle changes and non-hormonal treatments can also help manage menopause symptoms.
This document discusses a 52-year-old woman presenting with hot flashes and depression for 14 months without a period. It defines perimenopause, menopause and postmenopause, and lists common menopausal symptoms. It provides guidance on diagnosing and managing menopause, as well as addressing potential risks and benefits of hormone replacement therapy. Laboratory tests are not necessary to diagnose menopause in most women over age 45. Lifestyle changes and short-term hormone therapy are recommended for managing vasomotor symptoms.
Menopause is the permanent cessation of menstruation at the end of reproductive life due to loss of ovarian activity, usually occurring between ages 42-58. After menopause, women experience various physiological symptoms like loss of skin elasticity, osteoporosis, urogenital atrophy, and psychological changes like mood swings, difficulty sleeping, and forgetfulness due to hormonal changes. Surgical menopause occurs when the ovaries are removed during a hysterectomy, causing more severe symptoms. Management of menopause symptoms includes hormone replacement therapy, cognitive behavioral therapy, exercise, and counseling.
Premature ovarian failure is defined as ovarian failure occurring spontaneously before age 40. It is characterized by amenorrhea and elevated FSH and low estrogen levels. The incidence is approximately 1 in 1000 before age 30 and 1% just before age 40. Causes include genetic factors, autoimmune conditions, chemotherapy or radiation exposure, tuberculosis, smoking, and metabolic or surgical issues. Clinically, it presents with amenorrhea, hot flashes, and symptoms of low estrogen. Diagnosis is based on amenorrhea for 3 months and elevated FSH levels on two occasions one month apart. Management involves treating any underlying cause, hormone replacement therapy to prevent osteoporosis and cardiovascular disease, and in some cases ovulation induction or egg donation for
This document discusses menopause and postmenopause. It defines menopause as the permanent cessation of menstruation due to loss of ovarian activity, usually occurring between ages 45-50. The document describes the hormonal changes, symptoms, risks, diagnosis, and treatment options associated with menopause including hormone replacement therapy and lifestyle modifications.
Menopause typically occurs between ages 49-52 as the ovaries gradually slow production of eggs and reproductive hormones, causing menstrual periods to stop. It may be induced by surgery or occur prematurely under age 40. Symptoms include hot flashes, mood changes, and increased risk of osteoporosis and heart disease due to hormonal changes. Hormone replacement therapy can help treat symptoms but also carries risks if used long term. Maintaining a healthy lifestyle through diet, exercise, avoiding smoking and limiting alcohol can also help manage menopausal effects.
Menopause is the time in a woman's life when her period stops. It usually occurs naturally, most often after age 45. Menopause happens because the woman's ovaries stop producing the hormones estrogen and progesterone. A woman has reached menopause when she has not had a period for one year.
Recent advances in endometriosis were discussed. Endometriosis is a chronic disease where endometrial tissue grows outside the uterus, affecting around 10% of women. Dienogest, a progestin, was shown to be effective in reducing endometriosis-associated pelvic pain in randomized controlled trials. Dienogest 2mg daily for 24 weeks provided pain relief similar to leuprolide acetate but with fewer side effects. Long-term use of dienogest for 65 weeks maintained pain relief with a favorable safety profile. Dienogest was as effective as goserelin in reducing postoperative recurrence of endometriosis at 24 months.
Recent advancement in infertility final pptLalitaSharma39
This document provides an overview of recent advancements in infertility management. It begins with definitions of infertility and its types. It then discusses various causes of female infertility including age, smoking, STIs, weight, chemotherapy, genetic factors, and issues with the fallopian tubes, uterus, cervix, and vagina. Tests for infertility and treatment options like laparoscopy, medication, and assisted reproductive technologies are also outlined. Specific ART procedures described in detail include IUI, IVF, GIFT, ZIFT, ICSI, and ovary transplants.
LONG ACTING REVERSIBLE CONTRACEPTIVES (LARC).pptxI-Jay Nic
Long-acting reversible contraceptives (LARCs) provide effective birth control for several years through implants or intrauterine devices (IUDs). Implants are small rods placed under the skin that release progestin hormones, while IUDs are T-shaped devices placed in the uterus. Both methods are over 99% effective, safe for nearly all women, and can be used immediately after childbirth or abortion. Common types include implants like Implanon that last 3 years and copper IUDs like Paragard that are effective for 10-12 years. LARCs offer highly effective, long-term pregnancy prevention with few user responsibilities.
This document provides clinical practice guidelines for menopause. It defines menopause and related terms like peri-menopause. It describes the evaluation and assessment of patients, including history, examinations, and recommended lab tests. It also outlines the stages of menopause based on the STRAW+10 criteria and discusses common menopausal symptoms like vasomotor symptoms, genitourinary symptoms, and menstrual problems.
This document provides biographical information on Prof. Narendra Malhotra, including his professional designations, affiliations, awards, publications, special interests, and tests for ovarian reserve. He is a professor, past president of several medical organizations, managing director of health care companies, and director of IVF clinics. He has authored or edited numerous medical publications on gynecology and obstetrics. His special research interests include high risk obstetrics, ultrasound, assisted reproductive technology, and genetics.
The document discusses endocrinology in pregnancy, summarizing the roles and functions of various hormones produced by the fetus, placenta, and mother. It describes how some hormones are up-regulated from non-pregnant levels (quantitative) while others are unique to pregnancy (qualitative). Key hormones discussed include hCG, produced by the placenta to maintain the corpus luteum early in pregnancy; estrogen and progesterone, also produced by the placenta; and human placental lactogen, which increases throughout pregnancy and functions in metabolism and fetal nutrition. The precise levels and roles of multiple hormones are summarized.
This document provides information about menopause. It begins by defining menopause as the permanent cessation of menstruation and ovarian activity, typically occurring between ages 45-55. It then discusses various aspects of menopause like symptoms, causes, diagnosis, and management. Key points include that menopause marks the end of a woman's reproductive years; common symptoms are hot flashes, night sweats, and mood swings; and treatment options include lifestyle changes, supplements, medications, and hormone replacement therapy. The document also covers related topics like abnormal menopause, psychological impacts, and the role of midwives in menopause care.
Fresh Vs Frozen Embryo Transfer What’s The Current Practice? : Dr Sharda Jain Lifecare Centre
1. Dr. Sharda Jain is a renowned expert in infertility and IVF in India, holding leadership roles in several professional organizations related to gynecology and women's health.
2. She has received numerous awards and recognition for her contributions, including being included in a list of the top 20 most influential women in healthcare in India.
3. Her areas of focus and advocacy have included campaigns against female feticide and increasing access to healthcare for women.
Cesarean scar pregnancy (CSP) occurs when a pregnancy is implanted in the myometrium at the site of a previous cesarean section scar. The risk factors include previous cesarean section, manual removal of placenta, or other uterine trauma. Transvaginal ultrasound is the primary diagnostic tool, showing an empty uterine cavity with the gestational sac embedded in the cesarean section scar. Treatment depends on gestational age, beta-hCG levels, viability, and involves options like expectant management, medical management with methotrexate, surgical evacuation or resection, or hysterectomy in severe cases. Combination treatments are often most effective in terminating the pregnancy while preserving the uterus.
Allison Taylor, MD, with the Center for Women's Health in Wichita, KS, presented about perimenopause and hormone therapy during a Women's Connection July 9, 2013, at Corporate Caterers. The event is sponsored by Via Christi Health.
1) Anti-Müllerian hormone (AMH) is produced by granulosa cells and reflects the ovarian follicle pool, making it a useful marker of ovarian reserve that is not affected by hormones or the menstrual cycle.
2) AMH levels decline with age in a predictable pattern and lower levels predict a poorer response to fertility treatments, while higher levels indicate greater risk of ovarian hyperstimulation syndrome.
3) AMH alone or in combination with antral follicle count is currently the best assessment of ovarian reserve compared to other hormonal or ultrasound markers. AMH can predict both poor and excessive responses to fertility medication.
1. The document discusses emerging treatments for endometriosis, including levonorgestrel-releasing intrauterine devices (LNG-IUD), gonadotropin-releasing hormone antagonists (GnRHan), aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and progesterone antagonists.
2. It finds that LNG-IUD is effective for pain control and reduction in endometriosis lesions. GnRHan provide immediate hormone suppression with fewer side effects than agonists. AIs reduce estrogen levels through multiple pathways and show promise when combined with other drugs, though require further research. SERMs and progesterone antagonists aim to block estrogen and progesterone's
OVARIAN REJUVENATION - ROLE OF PLATELET RICH PLASMA THERAPY BY DR SHASHWAT JANIDR SHASHWAT JANI
The document discusses ovarian rejuvenation using platelet-rich plasma (PRP) injections. PRP is extracted from a patient's own blood and contains growth factors that may reawaken dormant follicles in the ovaries. The procedure involves extracting blood, centrifuging it to separate PRP from other blood components, and injecting the PRP into the ovaries under ultrasound guidance, usually once a month for three months. The goal is to stimulate egg maturation and development, helping patients conceive. Side effects are minimal and may include pain, fever, or internal bleeding. Follow-up monitors hormone levels to check for signs of improved ovarian function.
Recurrence of endometriosis is fairly common; some studies suggest the rate of recurrence to be as high as 40%. Most common cause of recurrence is incomplete resection in primary surgery and microscopic foci which escapes detection.
Cervical cancer is the second most common cancer in women globally. It is caused by persistent infection with human papillomavirus (HPV), with types 16 and 18 causing over 70% of cases. Screening through cervical smears has significantly reduced cervical cancer rates in developed nations. Treatment depends on the stage of cancer, ranging from conization for early stage IA1 to chemoradiation for later stages. Prognosis is best for early stage disease, with 5-year survival rates over 90% for stage IA tumors.
Role of Stem Cells in Obstetrics and Gynecology PracticeAsha Jain
Role of Stem Cells in Obstetrics and Gynecology Practice
Talk delivered at 4th Biennial International ISCSGCON 2021
on Febuary 13,2021 by Dr. Asha Jain
Uterine leiomyomas, or fibroids, are benign tumors that develop in the smooth muscle of the uterus. They are very common, affecting 20-40% of women during their reproductive years. While most fibroids do not cause symptoms, the most common complaint is abnormal uterine bleeding. Treatment options include medical management to control symptoms, surgical removal of fibroids (myomectomy), or hysterectomy for women who have completed childbearing. Myomectomy aims to conserve fertility but carries risks of heavy bleeding and potential complications. Laparoscopic myomectomy is gaining popularity for select fibroid cases but closure of the uterine wall can be challenging.
Menopause is defined as the absence of menstrual periods for at least 12 months. It typically occurs between ages 45-55, though can happen as early as age 30. Menopause is caused by a loss of responsiveness of the ovaries to hormones like FSH and LH, causing lower estrogen and progesterone levels. Common symptoms include irregular periods, hot flashes, mood changes, and increased risk for osteoporosis and heart disease. Treatment options include hormone replacement therapy, antidepressants, lifestyle changes, and lubricants to relieve vaginal dryness.
This document discusses obstetric analgesia options for labor pain. It describes:
1. Labor pain is intense and often worse than deep lacerations for many women. Regional techniques like epidural analgesia are recommended for pain relief during labor.
2. Epidural analgesia is the most common technique and involves threading a catheter into the epidural space to administer local anesthetics. Proper monitoring and maintenance is required to ensure adequate pain relief without motor block or hypotension.
3. Other options discussed include systemic opioids, inhaled gases, non-pharmacologic methods, and spinal or combined spinal-epidural techniques. The goal is providing effective pain management while avoiding negative effects on the
This document provides an overview of menopause including definitions, phases, physiological and psychological changes, treatments, and counseling considerations. It defines menopause as the permanent cessation of menstruation due to loss of ovarian activity, usually occurring between ages 45-55. The phases include pre-menopause, peri-menopause, menopausal, and post-menopausal. Physiological changes discussed include increased risk of heart disease, osteoporosis, urinary issues, and genital changes. Treatments covered are non-hormonal options as well as hormone replacement therapy. Counseling aims to understand individual needs and priorities in decision making.
The document discusses the physiology of menopause. It begins by defining menopause and perimenopause. It then describes the declining ovarian follicle pool starting in a woman's late 30s. This leads to compensated and decompensated ovarian failure as follicle numbers drop below 1000. During this transition, FSH and LH levels rise while estrogen levels drop. Other hormonal changes include reductions in androgens and progesterone. The consequences of menopause include short-term symptoms like hot flashes as well as long-term risks for osteoporosis and cardiovascular disease due to lowered estrogen levels.
Menopause is the time in a woman's life when her period stops. It usually occurs naturally, most often after age 45. Menopause happens because the woman's ovaries stop producing the hormones estrogen and progesterone. A woman has reached menopause when she has not had a period for one year.
Recent advances in endometriosis were discussed. Endometriosis is a chronic disease where endometrial tissue grows outside the uterus, affecting around 10% of women. Dienogest, a progestin, was shown to be effective in reducing endometriosis-associated pelvic pain in randomized controlled trials. Dienogest 2mg daily for 24 weeks provided pain relief similar to leuprolide acetate but with fewer side effects. Long-term use of dienogest for 65 weeks maintained pain relief with a favorable safety profile. Dienogest was as effective as goserelin in reducing postoperative recurrence of endometriosis at 24 months.
Recent advancement in infertility final pptLalitaSharma39
This document provides an overview of recent advancements in infertility management. It begins with definitions of infertility and its types. It then discusses various causes of female infertility including age, smoking, STIs, weight, chemotherapy, genetic factors, and issues with the fallopian tubes, uterus, cervix, and vagina. Tests for infertility and treatment options like laparoscopy, medication, and assisted reproductive technologies are also outlined. Specific ART procedures described in detail include IUI, IVF, GIFT, ZIFT, ICSI, and ovary transplants.
LONG ACTING REVERSIBLE CONTRACEPTIVES (LARC).pptxI-Jay Nic
Long-acting reversible contraceptives (LARCs) provide effective birth control for several years through implants or intrauterine devices (IUDs). Implants are small rods placed under the skin that release progestin hormones, while IUDs are T-shaped devices placed in the uterus. Both methods are over 99% effective, safe for nearly all women, and can be used immediately after childbirth or abortion. Common types include implants like Implanon that last 3 years and copper IUDs like Paragard that are effective for 10-12 years. LARCs offer highly effective, long-term pregnancy prevention with few user responsibilities.
This document provides clinical practice guidelines for menopause. It defines menopause and related terms like peri-menopause. It describes the evaluation and assessment of patients, including history, examinations, and recommended lab tests. It also outlines the stages of menopause based on the STRAW+10 criteria and discusses common menopausal symptoms like vasomotor symptoms, genitourinary symptoms, and menstrual problems.
This document provides biographical information on Prof. Narendra Malhotra, including his professional designations, affiliations, awards, publications, special interests, and tests for ovarian reserve. He is a professor, past president of several medical organizations, managing director of health care companies, and director of IVF clinics. He has authored or edited numerous medical publications on gynecology and obstetrics. His special research interests include high risk obstetrics, ultrasound, assisted reproductive technology, and genetics.
The document discusses endocrinology in pregnancy, summarizing the roles and functions of various hormones produced by the fetus, placenta, and mother. It describes how some hormones are up-regulated from non-pregnant levels (quantitative) while others are unique to pregnancy (qualitative). Key hormones discussed include hCG, produced by the placenta to maintain the corpus luteum early in pregnancy; estrogen and progesterone, also produced by the placenta; and human placental lactogen, which increases throughout pregnancy and functions in metabolism and fetal nutrition. The precise levels and roles of multiple hormones are summarized.
This document provides information about menopause. It begins by defining menopause as the permanent cessation of menstruation and ovarian activity, typically occurring between ages 45-55. It then discusses various aspects of menopause like symptoms, causes, diagnosis, and management. Key points include that menopause marks the end of a woman's reproductive years; common symptoms are hot flashes, night sweats, and mood swings; and treatment options include lifestyle changes, supplements, medications, and hormone replacement therapy. The document also covers related topics like abnormal menopause, psychological impacts, and the role of midwives in menopause care.
Fresh Vs Frozen Embryo Transfer What’s The Current Practice? : Dr Sharda Jain Lifecare Centre
1. Dr. Sharda Jain is a renowned expert in infertility and IVF in India, holding leadership roles in several professional organizations related to gynecology and women's health.
2. She has received numerous awards and recognition for her contributions, including being included in a list of the top 20 most influential women in healthcare in India.
3. Her areas of focus and advocacy have included campaigns against female feticide and increasing access to healthcare for women.
Cesarean scar pregnancy (CSP) occurs when a pregnancy is implanted in the myometrium at the site of a previous cesarean section scar. The risk factors include previous cesarean section, manual removal of placenta, or other uterine trauma. Transvaginal ultrasound is the primary diagnostic tool, showing an empty uterine cavity with the gestational sac embedded in the cesarean section scar. Treatment depends on gestational age, beta-hCG levels, viability, and involves options like expectant management, medical management with methotrexate, surgical evacuation or resection, or hysterectomy in severe cases. Combination treatments are often most effective in terminating the pregnancy while preserving the uterus.
Allison Taylor, MD, with the Center for Women's Health in Wichita, KS, presented about perimenopause and hormone therapy during a Women's Connection July 9, 2013, at Corporate Caterers. The event is sponsored by Via Christi Health.
1) Anti-Müllerian hormone (AMH) is produced by granulosa cells and reflects the ovarian follicle pool, making it a useful marker of ovarian reserve that is not affected by hormones or the menstrual cycle.
2) AMH levels decline with age in a predictable pattern and lower levels predict a poorer response to fertility treatments, while higher levels indicate greater risk of ovarian hyperstimulation syndrome.
3) AMH alone or in combination with antral follicle count is currently the best assessment of ovarian reserve compared to other hormonal or ultrasound markers. AMH can predict both poor and excessive responses to fertility medication.
1. The document discusses emerging treatments for endometriosis, including levonorgestrel-releasing intrauterine devices (LNG-IUD), gonadotropin-releasing hormone antagonists (GnRHan), aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and progesterone antagonists.
2. It finds that LNG-IUD is effective for pain control and reduction in endometriosis lesions. GnRHan provide immediate hormone suppression with fewer side effects than agonists. AIs reduce estrogen levels through multiple pathways and show promise when combined with other drugs, though require further research. SERMs and progesterone antagonists aim to block estrogen and progesterone's
OVARIAN REJUVENATION - ROLE OF PLATELET RICH PLASMA THERAPY BY DR SHASHWAT JANIDR SHASHWAT JANI
The document discusses ovarian rejuvenation using platelet-rich plasma (PRP) injections. PRP is extracted from a patient's own blood and contains growth factors that may reawaken dormant follicles in the ovaries. The procedure involves extracting blood, centrifuging it to separate PRP from other blood components, and injecting the PRP into the ovaries under ultrasound guidance, usually once a month for three months. The goal is to stimulate egg maturation and development, helping patients conceive. Side effects are minimal and may include pain, fever, or internal bleeding. Follow-up monitors hormone levels to check for signs of improved ovarian function.
Recurrence of endometriosis is fairly common; some studies suggest the rate of recurrence to be as high as 40%. Most common cause of recurrence is incomplete resection in primary surgery and microscopic foci which escapes detection.
Cervical cancer is the second most common cancer in women globally. It is caused by persistent infection with human papillomavirus (HPV), with types 16 and 18 causing over 70% of cases. Screening through cervical smears has significantly reduced cervical cancer rates in developed nations. Treatment depends on the stage of cancer, ranging from conization for early stage IA1 to chemoradiation for later stages. Prognosis is best for early stage disease, with 5-year survival rates over 90% for stage IA tumors.
Role of Stem Cells in Obstetrics and Gynecology PracticeAsha Jain
Role of Stem Cells in Obstetrics and Gynecology Practice
Talk delivered at 4th Biennial International ISCSGCON 2021
on Febuary 13,2021 by Dr. Asha Jain
Uterine leiomyomas, or fibroids, are benign tumors that develop in the smooth muscle of the uterus. They are very common, affecting 20-40% of women during their reproductive years. While most fibroids do not cause symptoms, the most common complaint is abnormal uterine bleeding. Treatment options include medical management to control symptoms, surgical removal of fibroids (myomectomy), or hysterectomy for women who have completed childbearing. Myomectomy aims to conserve fertility but carries risks of heavy bleeding and potential complications. Laparoscopic myomectomy is gaining popularity for select fibroid cases but closure of the uterine wall can be challenging.
Menopause is defined as the absence of menstrual periods for at least 12 months. It typically occurs between ages 45-55, though can happen as early as age 30. Menopause is caused by a loss of responsiveness of the ovaries to hormones like FSH and LH, causing lower estrogen and progesterone levels. Common symptoms include irregular periods, hot flashes, mood changes, and increased risk for osteoporosis and heart disease. Treatment options include hormone replacement therapy, antidepressants, lifestyle changes, and lubricants to relieve vaginal dryness.
This document discusses obstetric analgesia options for labor pain. It describes:
1. Labor pain is intense and often worse than deep lacerations for many women. Regional techniques like epidural analgesia are recommended for pain relief during labor.
2. Epidural analgesia is the most common technique and involves threading a catheter into the epidural space to administer local anesthetics. Proper monitoring and maintenance is required to ensure adequate pain relief without motor block or hypotension.
3. Other options discussed include systemic opioids, inhaled gases, non-pharmacologic methods, and spinal or combined spinal-epidural techniques. The goal is providing effective pain management while avoiding negative effects on the
This document provides an overview of menopause including definitions, phases, physiological and psychological changes, treatments, and counseling considerations. It defines menopause as the permanent cessation of menstruation due to loss of ovarian activity, usually occurring between ages 45-55. The phases include pre-menopause, peri-menopause, menopausal, and post-menopausal. Physiological changes discussed include increased risk of heart disease, osteoporosis, urinary issues, and genital changes. Treatments covered are non-hormonal options as well as hormone replacement therapy. Counseling aims to understand individual needs and priorities in decision making.
The document discusses the physiology of menopause. It begins by defining menopause and perimenopause. It then describes the declining ovarian follicle pool starting in a woman's late 30s. This leads to compensated and decompensated ovarian failure as follicle numbers drop below 1000. During this transition, FSH and LH levels rise while estrogen levels drop. Other hormonal changes include reductions in androgens and progesterone. The consequences of menopause include short-term symptoms like hot flashes as well as long-term risks for osteoporosis and cardiovascular disease due to lowered estrogen levels.
The survey found that over half of women experienced issues like inability to orgasm, vaginal dryness, and loss of libido during menopause. While some HRT users saw benefits, many did not, and over a third said their relationships were strained by menopause symptoms. Women received limited advice on alternatives from doctors and often turned to other sources like books and the internet to research options besides HRT.
Based on the information provided:
- The woman is 40 years old, which is below the typical age of menopause (around 50 years).
- She has not had any periods for 1 year.
To diagnose menopause in this woman:
1. I would do a beta human chorionic gonadotropin (hCG) test to rule out pregnancy.
2. I would check a follicle stimulating hormone (FSH) level. An FSH level over 35 mIU/ml would support the diagnosis of menopause.
3. I would do an ultrasound of the pelvis to examine the ovaries and rule out other potential causes of amenorrhea like polycystic
The document discusses strategies for women to thrive during and after menopause. It describes common menopause symptoms like hot flashes and provides lifestyle recommendations to support hormone balance and health. These include following a Mediterranean diet, exercising regularly, managing stress, and considering herbal remedies and supplements. The goal is for women to feel fit, fun, and fabulous at any age during and after the menopause transition through a whole-person approach to health.
Menopause is defined as the permanent stopping of menstrual periods and the inability to bear children, which typically occurs between ages 49-52. It is caused by the natural decline of reproductive hormones. Common signs and symptoms include irregular periods, hot flashes, sleep problems, and mood changes. While menopause requires no treatment, options to relieve symptoms include hormone therapy, antidepressants, and lifestyle changes like exercise and stress reduction. Long-term risks include heart disease, osteoporosis, and weight gain.
This document discusses menopause and the options for hormone replacement therapy (HRT). It covers the physiology of menopause, effects of declining estrogen levels, and risks like hot flashes, bone loss, and cardiovascular disease. It presents both benefits and risks of HRT, as well as non-hormonal options and lifestyle interventions like diet, exercise and supplements that can help manage menopause symptoms and health risks. The key decision is choosing treatments that improve quality of life based on each woman's individual symptoms, risk factors and medical history.
1) The document discusses the clinical features, differential diagnosis, and investigations of menopause. It describes various symptoms that can occur during perimenopause and menopause such as hot flashes, sleep issues, mood changes, and changes to the skin, hair, cardiovascular and genitourinary systems.
2) Differential diagnoses are provided for different symptoms. Investigations like hormonal tests and imaging can help determine if symptoms are due to menopause or other potential medical conditions.
3) Natural menopause is diagnosed if a woman over age 40 has 12 months of amenorrhea accompanied by menopausal symptoms and elevated FSH levels on two separate occasions.
The document discusses menopause and provides information about a fitness center for women experiencing menopause. It notes that menopause can cause both physical and psychological changes like anxiety and depression. The fitness center has various facilities like a swimming pool, yoga room, dance room, and chatting room. It also provides a weekly fitness schedule with classes like swimming, yoga, and dance held at different times and levels for beginners and intermediates.
This document discusses menopause and management options. It begins by defining menopause as the permanent cessation of menstruation resulting from loss of ovarian activity, typically between ages 45-55. It then outlines some of the main consequences of menopause like vasomotor symptoms, sexual dysfunction, osteoporosis, and cardiovascular risks. The document discusses treatment options like lifestyle changes, hormone replacement therapy, and alternative therapies. It provides details on hormone replacement regimens and duration of treatment for various symptoms and conditions.
This document discusses menopause and aging. It notes that midlife is between ages 45-65 and can be difficult. Menopause occurs when periods stop permanently, usually between ages 40-60, due to decreasing estrogen. During menopause, women experience changes like hot flashes and sleep issues. Medical options like hormone therapy help manage symptoms but also have risks. Aging well involves preventative measures like exercise, nutrition, and avoiding smoking. Support groups provide emotional support during this transition.
The document discusses menopause and the aging population. As life expectancy increases globally, societies must prepare to care for more older individuals. While medical advances have extended life, the last years are often still accompanied by illness and disability. Researchers and medical professionals should focus on promoting healthy aging for women by preventing issues and improving quality later in life through interventions like hormone replacement therapy and aspirin use. Providers must create awareness around preventive care and taking a holistic approach to menopause.
This document discusses several gynecological conditions including dysmenorrhoea (painful periods), premenstrual syndrome (PMS), amenorrhoea (absence of periods), polycystic ovarian syndrome (PCOS), and post-menopausal bleeding. It provides details on the definitions, causes, diagnostic approaches and treatment options for each condition. Key points include that dysmenorrhoea affects 45-95% of women and can be caused by endometriosis or adenomyosis; PMS involves physical and emotional symptoms before a woman's period; amenorrhoea can be primary or secondary; PCOS involves irregular periods, excess androgen levels and polycystic ovaries; and post
This document discusses various topics related to teen sexual health in the United States, including statistics on teen sexual activity, pregnancy rates, sexually transmitted infections, access to healthcare and contraception, and effectiveness of abstinence-only education programs. It provides perspectives from physicians advocating for comprehensive sex education and access to contraception to help improve sexual health outcomes for teens.
This document provides information on menopause and related topics. It discusses:
- The definition and causes of menopause, including natural menopause and premature menopause.
- Short, intermediate, and long term effects of menopause on a woman's health, including risks of osteoporosis, cardiovascular disease, and other conditions.
- Diagnosis of menopause and premature ovarian failure.
- Treatment options for menopausal symptoms including hormone replacement therapy and other medications, as well as their risks and benefits.
- Alternative and complementary therapies that can be used to treat menopausal symptoms.
This document discusses an alternative approach to treating menopausal syndrome that focuses on reducing inflammation. It notes that conventional treatments do not address the underlying inflammatory processes caused by hormonal changes. These inflammatory processes can lead to accelerated aging and increased risk of diseases. The alternative approach uses supplements, diet, and lifestyle changes to restore balance and reduce inflammation, with the goal of achieving dramatic results within three months and preventing long-term health issues. It is presented as a more holistic and effective method compared to conventional hormone replacement or prescription drugs.
The document discusses various women's reproductive disorders and the menstrual cycle. It describes the internal female genital organs and the two phases of the menstrual cycle. It then discusses menstrual disorders like amenorrhea, dysfunctional uterine bleeding, and dysmenorrhea. It provides information on the causes and treatments of these disorders. The document also covers other topics related to women's health issues like infertility, early pregnancy loss, menopause, and premenstrual syndrome.
This document discusses menopause and the female reproductive system. It explains that menopause occurs when the ovaries stop producing eggs and estrogen. During menopause, estrogen levels decline which can impact various parts of the body like increasing risks to the heart and bones. The stages of egg depletion from the ovaries are outlined, showing how the number of eggs decreases until menopause. Common symptoms of menopause like hot flashes and vaginal dryness are also described. The document concludes by presenting some solutions to help address the effects of declining estrogen levels during menopause.
This document discusses disorders of the menstrual cycle, specifically menorrhagia (heavy periods). It defines menorrhagia as blood loss greater than 80mL per period and notes it is extremely common. The document describes various treatments for menorrhagia including medications like NSAIDs, tranexamic acid, and hormonal contraceptives. It also discusses surgical treatments such as endometrial ablation and hysterectomy which are options when medical treatments fail.
This document discusses menopause, including its definition, stages, risk factors, signs and symptoms, and treatments. It defines menopause as the cessation of menstruation and reproductive ability in women. The presentation aims to describe menopause and its transitional stages, identify related risk factors, enumerate common signs and symptoms, and discuss treatment and nursing management.
This document summarizes the side effects of ovarian cancer treatment presented by Dr. Robert J. Morgan Jr. It discusses:
- Side effects of surgery depending on a woman's age, including immediate surgical menopause or menopausal symptoms.
- Menopausal symptoms like hot flashes, sleep issues, vaginal dryness, and mood changes.
- Treatment options for menopausal symptoms including hormones, lifestyle changes, and alternatives.
- Side effects of chemotherapy including nausea, fatigue, neuropathy, and myelosuppression. Ways to manage toxicities are discussed.
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Menopause is a biological stage in a woman's life that occurs when she stops menstruating and reaches the end of her natural reproductive life. This is not usually abrupt, but a gradual process during which women experience perimenopause before reaching post-menopause”
This document discusses hormonal replacement therapy (HRT). It begins by defining HRT as any medical treatment that replaces hormones the body can no longer produce on its own due to age or organ damage/failure. The main types of HRT are then listed, including various sex hormones. Effects of HRT for transgender individuals and testosterone replacement therapy are also outlined. The document concludes by discussing menopause, including its phases, causes, and physiological changes like hormonal and ovarian changes.
Here are the key considerations for this patient:
- She is postmenopausal based on her age
- With an intact uterus, estrogen-only hormone therapy would put her at increased risk for endometrial cancer
- As she is asymptomatic, hormone therapy may not be needed
- Screening for osteoporosis, cardiovascular risk, and breast cancer should be discussed based on risk factors
- Lifestyle modifications like calcium/vitamin D, exercise, not smoking can help prevent diseases of menopause
- Close monitoring without hormone therapy is a reasonable option given her age and lack of bothersome symptoms
The priorities would be assessing risk factors, discussing screening recommendations, and supporting lifestyle changes to promote health during men
This document discusses postmenopausal bleeding and provides information about menopause. It defines key terms like menopause, pathophysiology of menopause, and risk factors. It then describes postmenopausal bleeding including potential causes, clinical features, diagnosis, and management. Investigations for postmenopausal bleeding may include ultrasound, hysteroscopy, laparoscopy, and biopsy. Treatment involves addressing the underlying cause and patients may need to be observed during treatment.
Menopause typically occurs between ages 50-52 as ovaries stop producing eggs and estrogen levels decline. Symptoms include hot flashes, night sweats, and vaginal dryness. Management includes lifestyle changes and various hormonal and non-hormonal treatments to relieve symptoms and prevent long-term issues like osteoporosis and heart disease. Hormone replacement therapy (HRT) effectively treats short-term menopausal issues but carries risks if used long-term like an increased risk of breast cancer. Careful screening and use of the lowest effective dose for the shortest time is recommended for HRT.
This document provides an overview of menopause and related topics. It begins with definitions of key terms like pre-menopause, menopause, and climacteric. It then discusses the physiology and endocrinology of menopause, including how hormone levels fluctuate during the transition and after menopause. Signs and symptoms are outlined affecting various body systems like the brain, cardiovascular system, and bones. Finally, the document discusses diagnosis of menopause and treatment options involving hormone replacement therapy.
This document discusses the management of menopause. It begins with a case study of a 51-year-old woman experiencing less frequent periods, hot flashes, and vaginal dryness. It then covers how to diagnose menopause, differential diagnoses, common menopause problems like hot flashes and sleep issues, and treatment approaches. Non-hormonal treatments discussed include lifestyle changes, but evidence for supplements is inconsistent. Hormonal therapy is recommended for relieving menopausal symptoms in most women, though risks must be considered.
This document discusses male and female climacteric changes. It describes andropause or male menopause as age-related changes in men over 50 that involve a drop in testosterone levels and similar symptoms to hypogonadism. Common symptoms include low energy, depression, erectile dysfunction and reduced muscle mass. Diagnosis is based on history, exam and testosterone blood levels. Lifestyle changes and testosterone therapy are management options. Menopause in women occurs between 45-55 and involves stopping periods due to declining estrogen levels. Symptoms last 4 years and are managed with hormone replacement therapy, lifestyle changes or mindfulness.
This document discusses menopause and physical therapy approaches for related disorders. It begins by defining menopause and related terms. It then describes the endocrinological changes associated with menopause and how this impacts various body systems. Common clinical features of menopause are outlined including vasomotor symptoms, neurological/psychological symptoms, and increased risk of osteoporosis and cardiovascular disease due to estrogen deficiency. The document concludes by describing various physical therapy approaches that can be used to treat postural problems, osteoporosis, pelvic floor dysfunction, and other menopause-related conditions. Modalities discussed include resistance training, aerobic exercise, pulsed electromagnetic field therapy, and low-level laser therapy
Menopause is defined as the permanent cessation of menstruation and fertility, occurring naturally around age 45-55. It marks the end of the reproductive phase of a woman's life. There are typically four phases - pre-menopause, peri-menopause, menopausal, and post-menopausal. Common symptoms include hot flashes, night sweats, sleep issues, urinary problems, and mood changes. Hormone therapy can help treat symptoms but comes with some health risks, so lifestyle changes and non-hormonal options are usually recommended first.
This document provides an overview of controversies surrounding hormonal replacement therapy (HRT) and menopausal hormone therapy (MHT). It discusses the history of HRT, how the paradigm has shifted from viewing it as a preventative treatment to one focused on symptom relief. Key topics covered include the indications, contraindications and effects of HRT on breast cancer, endometrial cancer, osteoporosis and fractures. Routes of administration and precautions for prescribing HRT are also summarized.
Menopause is defined as the permanent cessation of menstruation resulting from loss of ovarian activity, occurring naturally or induced by surgery or medications. It typically occurs between ages 45-55. The document discusses the hypothalamic-pituitary-ovarian axis and changes that occur during perimenopause and menopause, including symptoms. Evaluation of menopausal women includes assessments of risk factors, symptoms, and quality of life to guide lifestyle and medical management options.
Menopause is defined as the permanent cessation of menstruation following the loss of ovarian activity, occurring after 12 consecutive months of amenorrhea. It marks the end of a woman's reproductive years. Common symptoms during perimenopause include hot flashes, night sweats, sleep disturbances, mood changes, and vaginal dryness. Lifestyle modifications like diet, exercise, and stress management can help alleviate symptoms. Hormone therapy is the most effective treatment for moderate to severe vasomotor symptoms, while SSRIs and other non-hormonal options show some efficacy. A comprehensive health evaluation at perimenopause involves screening for chronic conditions and assessing risk factors.
VASOMOTOR PROBLEMS IN MENOPAUSE BY DR SHASHWAT JANIDR SHASHWAT JANI
This document discusses vasomotor symptoms (VMS) associated with menopause. It provides details on:
- VMS affect most menopausal women and include hot flashes and night sweats. Symptoms typically last 5-7 years.
- VMS are caused by estrogen withdrawal and a narrowing of the body's thermoregulatory zone. Small temperature changes can trigger sweating or shivering responses.
- Management options include lifestyle changes, non-hormonal therapies like SSRIs, and hormone replacement therapy (HRT). HRT using the lowest effective dose of estrogen is the most effective treatment for reducing VMS.
Menopause is the permanent cessation of menstruation and fertility resulting from loss of ovarian follicular activity. It typically occurs naturally between ages 45-55. This document discusses the physiology and classification of menopause, including natural menopause, premature menopause, and induced menopause. It also outlines various causes of premature menopause such as genetic factors, metabolic disorders, and autoimmune conditions. The management of menopause symptoms and the importance of understanding menopause to alleviate women's fears are also covered.
Polycystic ovarian syndrome (PCOS) is the most common endocrine abnormality and cause of infertility in women of reproductive age. PCOS is characterized by oligomenorrhea/amenorrhea, hyperandrogenism, and polycystic ovaries on ultrasound. The pathophysiology involves an altered hypothalamic-pituitary feedback loop leading to excessive LH production and androgen excess from the ovaries. Insulin resistance also contributes to hyperandrogenism and anovulation. Labs used to diagnose PCOS show increased androgens, LH levels relative to FSH, and markers of insulin resistance. Differential diagnoses must be ruled out through appropriate testing.
Menopause is defined as the final menstrual period and results from loss of ovarian function. It occurs on average between ages 50-51 and can be influenced by various factors like smoking or surgery. Symptoms include hot flashes, sleep changes, mood changes and vaginal dryness. Hormone levels fluctuate during the menopausal transition and estrogen levels dramatically decline after menopause. Diagnosis is made after 12 months of no periods and confirmed by elevated FSH levels. Treatment options aim to relieve symptoms and prevent bone loss and include hormone therapy and non-hormonal therapies like SSRIs. HRT carries some health risks but may help vasomotor symptoms and prevent osteoporosis when used at lowest effective
PMS affects 40% of women and causes psychological and physical symptoms related to the menstrual cycle. The exact cause is unknown but likely involves sensitivity to hormone fluctuations. Diagnosis requires tracking symptoms over two cycles which improve after menstruation. Treatment depends on severity but may include lifestyle changes, SSRIs, COCPs, or suppressing ovulation. CBT and some supplements like Vitex and calcium can also help reduce symptoms.
The document discusses menopause, defining it as occurring after 12 months of amenorrhea and summarizing the stages of reproductive aging. It notes that menopause is caused by the programmed loss of ovarian follicles and describes changes in hormones like FSH and estradiol during the menopausal transition. Some key points covered include that the average age of menopause is 51.4 years, symptoms include hot flashes and vaginal dryness, and common therapies involve estrogen supplementation or behavioral changes.
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Mercurius is named after the roman god mercurius, the god of trade and science. The planet mercurius is named after the same god. Mercurius is sometimes called hydrargyrum, means ‘watery silver’. Its shine and colour are very similar to silver, but mercury is a fluid at room temperatures. The name quick silver is a translation of hydrargyrum, where the word quick describes its tendency to scatter away in all directions.
The droplets have a tendency to conglomerate to one big mass, but on being shaken they fall apart into countless little droplets again. It is used to ignite explosives, like mercury fulminate, the explosive character is one of its general themes.
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Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
5-hydroxytryptamine or 5-HT or Serotonin is a neurotransmitter that serves a range of roles in the human body. It is sometimes referred to as the happy chemical since it promotes overall well-being and happiness.
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3. ...
• Average age of menopause : 51.5 y/o
• Influential factors:
• Smoking ( 2 years)
• Chemotherapy
• Pelvic radiation
• Ovarian surgery
4. Definition
• Menopause:
1 year after the cessation of menses
• POF:
cessation of menses before 40 and associated
with an ↑FSH
• Menopausal transition:
begins w/ menstrual irregularity and extend
to 1 year after permanent cessation of menses
6. Definition
• Early menopausal transition:
• Regular cycle
• Variable length (> 7days different from N)
• FSH ↑, E may ↑ in early follicular phase
• Normal ovulatory cycle may be interspersed
7. Definition
• Late menopausal transition:
• Irregular cycle
• ≥ 2 skipped menses and 1 interval of
amenorrhea (≥ 60 days)
9. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
12. The axis
• Arcuate nucleus release GnRH in a pulsatile
fashion
• GnRH binds to its receptors on the pituitary
• Stimulates cyclic LH and FSH release
• LH/FSH binds to receptors on ovaries
• Stimulates production of ovarian steroids:
Estrogen, progesterone, inhibin
20. The Axis
menopausal transition
• Level of FSH rise slightly ➔ ↑ovarian follicular response
• ↑ # follicles in the cohort ➔ Higher E level
• Accelerated loss of follicles ➔ ↓ quality and capability of
aging follicles to secrete inhibin ➔ rising FSH ➔ supply
follicle is depleted
21. The Axis
menopausal transition
• Ovarian steroids release ceases ➔ negative feedback loop
is open ➔ GnRH is release at maximal frequency &
amplitude
• FSH&LH ↑ up to 4 fold higher than in reproductive years
22. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
26. Ovarian changes
• From birth onward : primordial follicles are
continuously activated, mature partially and
then regress (independent of pituitary)
• More rapid deletion starts in late 30s early 40s
• Average women has ~ 400 ovulations in her
reproductive lifetime
27. Ovarian changes
• The process of atresia of the nondominant follicles
(independent of menstruation cyclicity) is the prime event
that leads to loss of ovarian activity and menopause
28. Adrenal steroids & SHBG
changes
Adrenal steroids level:
•↑ age = ↓ DHEAS, ↓ androstenedione
(regardless of menopausal status)
Sex-Hormone-binding globulin:
•SHBG ↓ after menopause ➔ ↑ free E, T
29. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
31. Endometrial changes
• Late menopausal transition : ↑ anovulation
• Endometrium display estrogen effect when
unopposed by progesterone
• Proliferative/disordered proliferative changes
are frequent findings on EMBx.
32. Menstrual disturbance
• Irregular cycle in > 50% of women in menopausal
transition
• DDx:
Anovulation (most common)
Endometrial hyperplasia
Endometrial polyp / fibroid (E-sensitive neoplasma)
Pregnancy
Infection
Endometrial CA
33. Endometrial Cancer
• Incidence:
• Menopausal transition : 0.1% per year
• Menopausal transition w/ AUB : 10%
• Malignant precursor are more prevalent:
• E.g. Complex Endometrial hyperplasia
(more common in menopausal transition)
34. Non cancerous
disordered proliferative changes of
endometrium
• From estrogen effects unopposed by
progesterone
• Premenopausal ➔ anovulation
• Postmenopausal ➔
• Extragonadal endogenous E production
(e.g. obesity)
• ↓ SHBG = ↑ unbound hormones
• Unopposed estrogen administration
35. Evaluation of AUB
Ultrasound: (endometrial thickness)
• Can be use to avoid EMBx
• EMBx not required if < 5mm (Speroff)
EMBx:
• Can be done in office vs D&C in OR
• <10% postmenopausal pt can’t be done in office most
often 2° to stenotic Cx
• Misoprostol 100 mcv PO night before or morning of
36. Evaluation of AUB
Hysterocopy and D&C
• Can be Dx and treatment
• Allows evaluation of focal lesions
• Misoprostol 100 mcv PO night before or morning
of
37. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
40. Central thermoregulation
Incidence :
• Most common complaint of perimenopausal pt:
Hot flushes/flashes & night sweats (60-80%)
• Hot flashes : (↓ with time)
• start 2y before FMP
• 85% of pt who experienced it will do for >1y
• 25-50% will experienced them for 5 years
• 15% may experienced them for >15 years
41. Hot Flushes
• Wave of heat over the body
• Last 1 to 5 minutes
• ↑ skin T° b/c peripheral vasodilatation
• Sweat primarily on the upper body
• ↑ systolic BP, ↑ HR (7-15 bmp)
• Skin temperature gradually return to N
• Significant contributor to sleep disturbance
42. Risk factors
• Surgical menopause (90% probability during 1st
year)
• Race/ethnicity ➔ black > white > asian
• BMI ? (SOGC obesity / Williams thinner lady)
• Early menopause
• Smoking
• SERMs
• Exposed to high ambient T°, hot drinks, R-OH
43. Pathophysiology
• Dysfunction of central thermoregulation
centers in the hypothalamus (narrowing of this
“thermoneutral zone” )
• Small changes in T° can evoke regulatory
response of sweating or shivering
44. Pathophysiology: Estrogen
• Play a vital role in the development of hot flashes.
Different hypothesis:
• ? Estrogen withdrawal
• ? Rapid fluctuation
• Not related to low level estrogen:
• Supported by: pt w/ Turner (lack N estrogen level)
don’t have hot flushes unless Tx and then withdrawn
50. Treatment
• Estrogen is the most effective (see HRT section)
• ↓ by 75% hot flashes compared to placebo
• Transdermal patch : avoid first liver passage
• Progestin alone (see HRT section)
• Mild reduction in hot flashes (use when E contraindicated)
• Nonhormonal options that have shown some efficacy:
(but they have their own side effects…)
• Bellergal
• Clonidine
• SNRIs
• Gapapentin
• Zopiclone (sleep aids)
• Complementary and Alternative Medecine (acupuncture, naturopathy,etc.)
53. Treatment:
Non-Hormonal : SSRI
• Effexor, Prozac, Paxil, Pristiq : modest improvement in RCT compare to
placebo
• ↓ hot flashes:
• Effexor 37.5 mg/d ➔ 37%
• Effexor 75 mg/d ➔ 61%
• Effexor 150mg/d ➔ 61%
• Placebo ➔ 27%
• Paxil and Prozac also had ↓ in hot flashes
• When translated by event ➔ ↓ of ~1-2 hot flashes/d compare to
placebo.
• Need to balance against s/e : n°,d°,h/a,insomnia,fatigue,sexual dysfct
54. Treatment:
Non-Hormonal: clonidine
• Centrally active α2-adrenergic receptor agonist
• One study (1987)
Clonidine 0.1 mg/d transdermally x 8w
• 12/15 had ↓ vasomotor Sx vs 5/14 in placebo
group
• s/e : dry mouth, hypotension, dizziness,
constipation, sedation
• Low-dose clonidine is ineffective for many
women, and higher dose would magnify the s/e.
56. Treatment:
N n-Ho rm o na l : αlp ha -m e thy ld o p a
o
• NOT recommended ➔
significant s/e and modest improvement
• Aldomet 500-1000 mg/d ➔ 2x more effective than placebo
• S/e: dizziness, nausea, fatigue, dry mouth, ↓BP
57. Treatment:
Non-Hormonal : Bellergal
• NOT recommended : limited efficacy & significant s/e
• Sedative
• contains:
phenobarbital, ergotamine tartrate and belladonna
alkaloid
• RCT : modest to no reduction in Sx vs placebo
• >30% pt withdrew b/c of side effect and ineffectiveness
• Barbiturate are addictive and not recommended for longterm use
59. Treatment:
• Acupuncture:
• RCT — multicenter, perimenopausal and postmenopausal
• Tx groups (10 or 12 sessions) vs control group.
• Significant ↓ hot flash frequency & intensity. BUT: Small study groups and had
data from only short-term therapy and follow-up.
• Adiposity
• 2 hypothesis:
• 1- aromatization of A ➔ E in body fat should lead to ↓ hot flash frequency.
• 2- High body fat should be associated with ↑ hot flashes from insulating effects.
• Thurston and colleagues (2008) found that ↑ abdominal adiposity was associated
with ↑ odds of hot flashes. Their suggestion is that fat loss and aerobic exercise
may improve the severity of hot flashes.
60. Treatment: Phytoestrogen
(isoflavone)
• Plant-derived compound that binds to ER —agonist & antagonist effect
• Found in soy product & Red clover
• Small studies evaluating their effectiveness for the Tx of hot flashes have noted no
efficacy or mixed results (Krebs, 2004).
• Soy product:
• Genistein & daidzein (isoflavone)
• Assumed to bound to ER ➔ shouldn’t assume that these dietary supplements are safe
for women w/ E-dependant cancer
• Albertazzi & col (1998) : 76 mg of isoflavone ↓45% hot flashes vs 30% w/ placebo
• Cheng & ass (2007) 60 mg of isoflavone daily x 3 months (↓57%)
• Levis & col (2011) Double-blind clinical trial w/ breast Ca survivor ➔ higher rate of
hot flashes compare to placebo
• Effect of soy protein in various food aren't bioequivalent.
Eg. processing in manufacture of tofu and soy milk remove the biologically active form.
61. Treatment: Phytoestrogen
(isoflavone)
• FLAXSEED
• (Linum usitatissimum) is rich in -linolenic acid, (omega-3 fatty acid)
• Use to ↓ inflam°, bone turnover, ♥ disease, cancer, DM, and cholesterol levels.
• For perimenopausal women, it also is purported to protect against breast cancer, hot flashes, and mood
disturbances.
• Data regarding efficacy for Tx of hot flashes are limited.
• Lewis and coworkers (2006)
• Double-blinded, RCT (87 pt in 3 group : soy, flaxseed, wheat).
• No significant difference in vasomotor symptoms among the three groups.
• Lemay and associates (2002) found 40 g of flaxseed as effective as 0.625 mg of CEE for the Tx of mild
menopausal symptoms in a randomized cross-over study comparing the two.
• RED CLOVER
• Trifolium pratense is a member of the legume family. Contains at least 4 estrogenic isoflavones a
• Several studies have failed to demonstrate an effect over placebo in the Tx of menopausal symptoms
• RCT: placebo over red clover : No significant change in hot flash frequency was reported (Tice, 2003).
62. Treatment: Phytoestrogen
(isoflavone)
• DONG QUAI
• Chinese herbal medicine (root of Angelica sinensis) and is the most commonly prescribed Chinese herbal
medicine for "female problems."
• Most herbal practitioners seem to agree that it is contraindicated during pregnancy and lactation.
• 1997 Hirata and coll. ➔ Double-blinded controlled clinical trial (daily dong quai dose of 4.5 g)
• Tx group and placebo group both reported a ↓ hot flashes (25%).
• Critics of the study have noted that the dose of dong quai was lower than that often used i
• Potentially toxic: conntains numerous coumarin-like derivatives (↑ bleeding or interactions with other
anticoagulants)
• Contains psoralens and is potentially photosensitizing, which ↑ concerns of sun exposure-related skin
cancers.
• BLACK COHOSH
• 2x RCT: did not ↓ frequency of vasomotor symptoms compared with placebo (Geller, 2009; Krebs, 2004).
• Few adverse effects have been reported BUT the long-term safety of these products is unknown.
•
.
63. Treatment:
phytoprogestin
• Extracts, tablets, and creams derived from yams are claimed to be
progesterone substitutes and are frequently sell as a natural source of DHEA.
• Sterol structures from the plant do not have inherent biologic activity.
• Plant sterol dioscorea CAN’T be converted in the body into progesterone.
• There is no human biochemical pathway for bioconversion of dioscorea to
progesterone or DHEA in vivo.
• Oral ingestion does not produce serum levels.
• Lack of bioavailability ➔ not to be expected to have efficacy.
• Wild yam extracts are neither estrogenic nor progestational,
• There are no published reports demonstrating the effectiveness of wild yam
cream for postmenopausal symptoms.
64. Treatment:
• Vitamin E :
(Barton 1998) 125 pt with a Hx of breast Ca
• ↓ 25% hot flashes vs ↓ 22% w/ placebo.
• ↓ one hot flash per person per day
• Environmental & life style:
• Fan, dressing in layer, cool shower temporarily help
• Relaxation techniques/meditation can ↓ Sx
• stop smoking, weight loss
65. 1.Lifestyle modifications: ↓ core body T°, regular exercise, wgt management, smoking cessation, and avoidance of known
triggers such as hot drinks and R-OH may be recommended to ↓ mild vasomotor symptoms. (IC)
2.MD should offer HT (E alone or EPT) as the most effective therapy for the medical management of menopausal Sx. (IA)
3.Progestins alone or low-dose OCP can be offered as alternatives for the relief of menopausal Sx during perimenopause
(IA)
4.Nonhormonal Rx, including Tx w/ certain antidepressant agents, gabapentin, clonidine, and bellergal, may afford some
relief from hot flashes but have their own s/e. These alternatives can be considered when HT is CI or not desired. (IB)
5.Limited evidence of benefit for most complementary approaches foe hot flashes. W/o good evidence for effectiveness, and
in the face of minimal data on safety, these approaches should be advised with caution. Most approaches have not been
rigorously tested for the Tx of moderate to severe hot flashes, and many lack evidence of efficacy and safety. (IB)
6.Any unexpected PVB that occurs after menopause is considered PMB and should be investigated. (IA)
7.HT should be offered to pt with POF or early menopause (IA) and it can be use until the age of natural menopause (IIIC)
8.Estrogen therapy can be offered to pt who have undergone surgical menopause for the Tx of endometriosis. (IA)
66. Sleep Dysfunction
• Difficulty in sleep onset and maintenance are
common
• Sleep fragmentation is commonly associated
with hot flushes ➔ daytime fatigue, mood
lability, irritability, problem with short-term
memory
• As women age ➔ more likely to experience
lighter sleep
67. Sleep Dysfunction
• Lead to fatigue, irritability, depressive Sx and
cognitive dysfunction
• Relationship between vasomotor Sx and
impaired sleep (Hollander 2001)
• ↑ hot flushes = ↑ sleep disturbance
• Fatigue 2° to vasomotor Sx, difficulty sleeping
or independent risk factors (unresolved)
68. Fatigue prevention
instructions
• Obtain adequate sleep every night
• Exercise regularly to ↓ stress
• Avoid long work hour, maintain your personal schedule
• If stress is environmental :switch job, take vacation,etc.
• Limit intake of R-OH, drug and nicotine
• Eat healthy and well-balanced diet
• Drink adequate amount of water
(8-10 glasses in the early part of the day)
• Menopausal medecine
69. Treatment:
Sleep medication
• Indication : night sweats and sleep disruption
• Antihistamine, diphenhydramine
hydrochloride (cheap, over-the-counter)
• Insomnia Tx : Zopiclone ➔ improve sleep
and positively affect mood, QOL, next day
functioning, menopause-related Sx
— RCT 2006 (Soares)
70.
71. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
73. Bone metabolism change
• Peak bone mass is influenced by heredity and
endocrine factors
• Almost all bone mass in hip and vertebral bodies
is accumulated in young women by late
adolescence (peak)
• Bone reposition is couple with bone formation
(positive bone balance until bone maturity 25-35 y/o
• Thereafter : steady ↓ bone mass (0.4% year)
• ↓ ↓ during menopause
(2-5% per year for the first 5-10y then 1% per year)
74. Osteoporosis sequelae
• Fx are the most debilitating and $$ consequences
• Spine, hip and wrist are the most common
• Associated with significant M&M:
• Mortality hip Fx : 30%
• Only 40% of pt w/ hip Fx go back to their prefracture
level of independence
75. Osteoporosis
• Definition: impairment in bone strength due to an
abnormal quantity or quality of bone, or both
• Quantity:
determined by BMD
• Quality:
determined by several factors; degree of
mineralization, connectivity of the bony
trabeculae, quality of the collagen fibres, and
health of the bone ¢
76. pathophysiology
• Primary osteoporosis:
• Bone loss associated w/ aging and
menopausal estrogen deficiency
• As E ↓ bone resorption ↑
(most rapid in early postmenopausal)
• Secondary osteoporosis:
• Caused by disease or medication
77. PTH response
• ↓ Ca intake or gut absorption ➔ low [ca] serum
• ↓ [Ca] ➔ ↑ production of PTH
• ↑ PTH = ↑ bone resorption to ↑ [Ca]
• Premenopausal pt : after ↑ in Ca, PTH quickly
return to N
• Postmenopausal pt : greater response to PTH *
78.
79. Osteoporosis
risk factors
• Low BMD
• Fragility Fx :
• prior vertebral vex ↑ 4x risk of an other Fx
• 20% of pt have a second vertebral Fx in the following year
• Aging:
• ↑ 8x risk of Fx (from 45 to 85y/o)
• Race: Most common in caucasian
• Genetic: Maternal Hx of hip Fx is a key risk factor
• Risk of fall: ➔ reduce muscle strength, balance, visual acuity,R-OH,Rx
• Glucocorticoid: daily dose ≥ 7.5mg
80. Osteoporosis
risk factors
Osteoporosis risk factors
Major risk factor
Minor risk factors
> 65 y/o
RA
Vertebral compression Fx
PMHx hyperT4
Fragility Fx > 40 y/o
Chronic anticonvulsant Tx
Systemic glucocorticoid Tx >3months
Low diet Ca intake
Malabsorption syndrome
Smoking
Primary hyperPTH
Excess R-OH
Propensity to fall
Excessive caffeine
Osteopenia apparent x-ray
Weight less 57kg
Hypogonadism
> 10% wgt loss at 25 y/o
Early menopause (<45y/o)
Chronic heparin therapy
81. Screening (BMD)
• Women ≥ 65 y/o
• Women with 1 or more major risk factor
• Women with 2 minor risk factors
• Women who sustain fractures
• Women on treatment
82. Osteoporosis Dx
• BMD is the standard (reported in T-score)
• DEXA of lumbar spine, radius and hip
• Lumbar spine :
• Trabecular bone ➔ less dense, rapid remodeling
• Early rapid bone loss can be evaluate there
• Greater trochanter/femoral neck:
• Cortical bone ➔ more dense and compact
• Ideal for assessment of hip fracture risk
83. Osteoporosis Dx
BMD and T-scores:
• Reported and standard deviation : variance of an
individual’s BMD from that expected for a person of
the same sex at peak bone mass (25-30 y/o)
• Normal BMD: T-score between +2.5 and -1.0
• Osteopenia: T-score between -1.0 and -2.5
• Osteoporosis: T-score lower than -2.5
85. Osteoporosis Dx
• 10 year Fracture Risk Assessment Tool & FRAX gives you
a percentage:
• High : >20%
• Moderate: 20-10%
• Low: <10%
• The additional effect of a pre-existing fragility Fx or glucocorticoid
use moves the patient 1 risk category higher
• Very high risk: Fx during antiresorptive Tx or significant bone loss
during Tx
86. Who needs treatment?
• High risk ➔ treatment (Raloxifene or biphosphonate PO or IV)
• Moderate risk ➔ management decision should be individualized
• Low risk ➔ r/o 2° causes and implement prevention strategies
VitD & Calcium
Exercise
↓R-OH (<2/d), ↓coffee (<4/d)
Smoking cessation
Biphosphonate : shown prevent bone loss in postmenopausal women with
osteopenia
HRT (if postmenopausal Sx) protect against OP and Fx
• Very high risk: should be considered for Tx with an anabolic agent ; ensure there
is no 2° causes and the patient is compliant.
87. Treatment
• Antiresorptive (anticatabolic):
• Inhibit osteoclast activity / ↓bone turnover ➔ ↓ Fx by 30-50%
• Act most quickly on bone w/ high trabecular content (rapid turnover) like vertebrae vs
hip (which is 50% cortical, 50% trabecular)
• Biphosphonates : ↓bone turnover/modest ↑ BMD
• Estrogen: link to E receptor , block the RANKL-induced osteoclast differentiation.
• Raloxifen (SERM): ↓ bone remodeling
• Calcitonin: inhibit osteoclastic bone resorption
• Vitamin D
• Anabolic therapy:
• ↑ production of bone matrix / enhance osteoblastic function
• ↓ Fx by 65% after 18 months Tx in Post-menopausal women w/ OP
• Teriparatide (recombinant PTH)
• ? Strontium ranelate
88. Treatment
Calcium/Vitamin D:
• WHI : 1000mg Calcium, 400UI vit D
•
29% reduction in hip Fx risk among the women taking 80% or more of their
calcium and vitamin D supplements.
•
A small, but significant, 17% ↑ in the risk of renal stones. So ensure that pts
aren’t using excessive calcium supplementation
• Not sufficient by itself for Tx of OP, it is recommended
as a mandatory adjunct to Rx
• Vit. D 800 IU daily or 10 000 IU weekly
• Calcium : 31-50y/o 1000g daily, >50y/o 1200 mg daily
(williams)
89. Treatment
HRT
• Estrogen:
• Block the RANKL/RANK interaction required for osteoclast recruitment and
activation ➔ ↓ bone loss ➔ ↑ BMD
• WHI : ↓ 30-39% Fx (E arm)
• Effect loss rapidly following discontinuation of HT
• Combined Estrogen&Progesterone:
• WHI: ↑hip BMD, ↓34% hip&vertebral Fx
• Low, ultralow dose HRT:
• Linear dose response of the skeleton
• RCTs: low dosage can prevent OP in postmenopaisal
• No Fx trial
90. Treatment
SERM
• Tissue-specific estrogen-agonist/antagonist effects
• Raloxifen is the only one approved for OP
• Most appropriate for Tx of vertebral disease
• MORE trial: Raloxifen 60-120mg daily x 4 y : ↓35-45% Vertebral Fx. Also
2° outcome : ↓ 65% RR breast Cancer. No ↑ CHD.
• STAR trial: ~20 000 pt at ↑risk breast CA : raloxifen 60mg = Tamoxifen
20mg daily. Both drugs ↓ breast CA by 50% but raloxifen had 36% less
uterine CA and 29% less DVT.
• S/E : (1) hot flushes (low incidente) and (2) ↑ VTE RR 1.78
91. Treatment
Biphosphonate
• Nitrogen containing biphosphonate (Alendronate, Risedronate,
zoledronic acid)
• Antiresorptive effect :
• Binds to hydroxyapatite crystal at site of bone resorption (where
bone matrix is expose).
• Biphosphonate is buried under newly form bone, where it lies
inert w/o skeletal effect.
• When there is bone resorption, the Rx is released and ingested
by osteoclast leading to their deactivation and apoptosis.
• Result in ↓ bone turnover and enhanced bone mineralization
• Compliance is necessary to achieve a ↓in Fx risk.
92. Treatment
Biphosphonate
• Advantage:
• Ease of administration and tolerability
• IV Rx have less frequent dosing, less GI s/e
• Disadvantage:
• Most common s/e : abdominal pain and dysphagia (but RCT doesn’t support
that)
• c/o : upper GI inflam°, ulceration, bleeding
• (Rare) Osteonecrosis of the jaw (ONJ) : limited mostly to oncology pt
• avascular bone necrosis
• most of the reports have been associated with frequent high-dose iv
• Many of these pt had risk factor: CxTx, RxTx
93. Treatment
Biphosphonate
• Alendronate:
• ↓risk of vertebral Fx in post-menopausal pt
(regardless of Hx of previous Fx)
Prevention of OP:
1)5mg daily
Treatment of OP:
1)10 mg daily
2)70 mg weekly
• ↓bone resorption and improve BMD
• ↑ BMD at the lumbar spine and hip continue through 10 years of Tx
• Risedronate:
• Maintain bone mass and preserve bone microarchitecture
• ↓ vertebral and non vertebral Fx
• 5 mg daily :
• ↓new Fx within 6 months, ↓ vertebral Fx within 1y
• ↑BMD at lumbar spine by >5% during 2y of Tx
• ↓ in vertebral Fx risk are independent of ↑ in BMD
Prevention&Tx of OP:
1) 5mg daily
2) 35mg weekly
3) 75mg x2d q month
94. Treatment
Biphosphonate
• Zoledronic acid:
• Most potent biphosphonate available
• 4mg IV doses : approved for prevention&Tx of
metastatic bone disease and hyperCa++ 2° malignant
disease
• 5mg IV annualy ➔ Tx Paget’s disease and
postmenopausal OP
• ↓ risk of vertebral Fx (3y) by 70% and hip Fx by 41%
• Improvement BMD and ↓ height loss
95. Treatment:
Clinical capsule
Biphosphonate
• Poor bioavailability ➔ should be taken on a
empty stomach w/ adequate water for
proper dissolution and absorption
• Take in the morning with water
• No other intake for 30 minutes
• Remain upright (sit/stand) for 30 minutes
96. Treatment
Calcitonine
• Produced in thyroid gland
• Inhibit osteoclastic bone resorption
• Poor GI absorption ➔ subcutaneous or nasal
• 200 IU daily by nasal spray is approved for Tx
• BMD stabilizes at the lumbar spine and hip
• ↓ 21% vertebral Fx (failed to prove ↓ non vertebral Fx)
• Have analgesic effect ➔ useful in managing the pain of
acute vertebral compression Fx.
• s/e : 3% rhinitis, 8-10% nausea or gastric discomfort
97. Treatment
Denosumab (Prolia)
• Human monoclonal Ab against RANKL
• Prevent osteoclast activation (↓ bone resorption)
• Subcutaneous injection twice a year
• FREEDOM trial : ↓68% vertebral Fx, ↓ 40% hip Fx.
• ↓ bone turnover and ↑ BMD in OP and cancer pt
• Seem to be as effective as Forteo or Zolendronate and is
perhaps more effective than oral biphosphonate
• Because it’s an antibody ➔ its potential to affect the immune
system requires assessment
98. Treatment
Anabolic agent
• Teriparatide (PTH): - Forteo
• 20 mg SC x 21 months ➔ 9% ↑ in lumbar spine BMD and improved femoral-neck
and whole-body BMD.
• ↑ osteoblast # and activity.
• ↓ Risks for vertebral Fx (65%) and nonvertebral Fx (53%)
• Dramatic ↑thickness, density, # of trabeculae and ↑ cortical thickness & bone size.
• ↓ back pain has also been noted with teriparatide use.
• Well tolerated, with only minor s/e: n°, h/a, mild hyperCa++, leg cramp
• ATTENTION: dose & duration-dependent relationship between teriparatide and
osteosarcoma
• Osteosarcoma has not been seen in humans or in studies with monkeys. To date,
about 300 000 people have been treated with teriparatide, and 1 case of osteosarcoma
has occurred, which is comparable to the background incidence of osteosarcoma of 1
in 250 000.
99. Treatment
Anabolic agent
• Strontium ranelate
• antiresorptive effects + anabolic properties.
• Not associated with an ↑ risk of osteosarcoma.
• 9% ↓ new vertebral fractures at 1 year (2 g daily)
• 16% ↓ nonvertebral fractures
• 36% ↓ hip fracture
• S/e: n°, d°
100. Treatment
• Exercise ➔ small but statistically
significant ↑ BMD in pt doing aerobic
exercise and resistance training
• Fall prevention strategy
• ↓ caffein intake & sodium intake
101. Recommendation:
1. The goals of OP management include assessment of Fx risk and prevention of Fx and
height loss. (1B)
2. A stable or ↑ BMD = response to therapy in the absence of low trauma fracture or
height loss. Progressive ↓ in BMD, with the magnitude of bone loss being greater than
the precision error of the bone densitometer = lack of response to current therapy.
Management should be reviewed and modified appropriately. (1A)
3. MD should identify the absolute Fx risk in postmenopausal pt by integrating the key
risk factors for Fx; namely, age, BMD, prior fracture, and glucocorticoid use. (1B)
4. MD should be aware that a prevalent vertebral or nonvertebral fragility Fx markedly ↑
risk of a future fracture and confirms the Dx of OP irrespective of the results of the
bone density assessment. (1A)
5. Tx should be initiated according to the results of the 10-year absolute fracture risk
assessment. (1B)
102. Calcium and vitamin D
1. Adequate calcium and vitamin D supplementation is key to
ensuring prevention of progressive bone loss. For
postmenopausal pt (recommendation): (IB)
1. Total intake of 1500 mg/day of Ca2+ (food and suppl.)
2. Supplementation of 800 IU/d of vitamin D
2. Calcium and vitamin D suppl. alone is insufficient to prevent
Fx in pt with OP; however, it is an important adjunct to
pharmacologic intervention with antiresorptive and anabolic
drugs. (1B)
103. Hormone therapy
1. Usual-dosage HT should be prescribed for symptomatic postmenopausal women
as the most effective therapy for menopausal symptom relief (1A) and a reasonable
choice for the prevention of bone loss and fracture. (1A)
2. MD may recommend low- and ultralow-dosage E therapy to symptomatic women
for relief of menopausal symptoms (1A) but should inform their patients that
despite the fact that such therapy has demonstrated a beneficial effect in OP
prevention (1A), no data are yet available on reduction of Fx risk.
Biphosphonate
3. Should be considered to ↓ risk of vertebral, nonvertebral, and hip Fx (IA)
4. Etidronate is a weak antiresorptive agent and may be effective in ↓ risk of vertebral
fracture in those at high risk. (1B)
104. SERM
1. Tx with raloxifene should be considered to ↓risk of vertebral Fx.
(1A)
Calcitonin
2. Tx with calcitonin can be considered to ↓ the risk of vertebral Fx and
to ↓ pain associated with acute vertebral Fx. (1B)
PTH
3. Tx with teriparatide should be considered to ↓risk of vertebral and
nonvertebral Fx in postmenopausal women with severe OP. (1A)
105. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
109. INTERHEART
study (RCT)
• Examining modifiable risk factor
• 94% of CVD is attributed to modifiable RF
•
Current smoking (OR 2.87)
•
Psychosocial stress (OR 2.67)
•
DM (OR 2.37)
•
HTN (OR 1.91)
•
Abdominal obesity (OR 1.62)
110. Effect of hormones on
cardiovascular function
1. Effect on lipid
2. Effect on hemostasis
3. Effect on carbohydrate metabolism
4. Modulation of blood vessel reactivity
(short-term - nongenomic)
5. Vascular structural remodeling (long term - genomic)
111. ? HTR Cardioprotection
HERS:
• No benefit + early adverse events in pt w/ know CDV
who were randomly assigned to receive CEE & MPA.
Angiographic study :
• HT fails to delay the progression of CVD
112. ? HRT Cardioprotection
Epidemiological and observational studies, clinical trials :
• Suggest possibility of a role for E in primary prevention of CVD
WHI (2002)
• EPT :↑ risk of MI/stroke
WHI (adjudicated findings)
• EPT : No statistically significant ↑ in CVD/death
• EPT : significant ↑ CV events in 1st year but not thereafter ( risk 21 /10 000) w/o ↑ in
CVD mortality
In the EPT arm of the WHI trial the RR for CAD was 1.68 in the first 2 years after the start of HT, 1.25
in years 2 to 5, and 0.66 beyond 5 years.
• E : no evidence of risk nor benefit ➔ suggestion of ↓CVD in pt aged 50-59 at baseline
(HR 0.63) & mortality (HR 0.70)
(*subgroup analysis)
113. ? Cardioprotection
• Why does WHI have different result than clinical
trial ?
• ? Pt who seeks HT are better educated, higher SES; greater
access to health care (Tx for DM, HTN, etc.)
• ? Adhere to HT for disease prevention so they are more
likely to adhere to exercise program, be leaner, drink more
R-OH (affords a degree of ♥ protection)
• ? When they get sick they stop their HT so there is more
death in nonuser than current user of HT
114. ? Cardioprotection
• Why does clinical trial have different result than WHI? Why are
WHI results challenged?
• Greater age of participant & time since menopause onset (loss of
ovarian E production)➔ Average 13y
• Time since menopause correlate w/ extent of subclinical atherosclerosis
• INTERHEARt risk factors were identified in their population
• 70% of women in WHI were > 60 y/o @ enrollment
• Likely that substantial proportion had subclinical CVD
• The ↑ in CVD event during first year is similar to the effect of HT
started in older women in the HERS
115. ? HRT Cardioprotection
WHI (adjudicated findings)
• EPT : significant ↑ CV events in 1st year but not
thereafter ( risk 21 /10 000) w/o ↑ in CVD mortality
Lobo et al. (2 pivotal clinical trial, 4065 young health
menopause patients)
• No ↑ incidence of MI/stroke in the year after
initiation of Tx
• Not followed for long enough to determine whether
there might be longer=term benefit
117. ? HRT Cardioprotection
«Critical-window» hypothesis
• Dichotomous effect of HT :
HT at onset of menopause is cardioprotective whereas later
initiation could cause CV events
• 27-hydroxycholesterol (abundant in atherosclerotic lesion) acts as a competitive
antagonist of E receptor.
• Would account for loss of cardiovascular protection from vascular disease in older
women
Saltpeter et al. (meta-analysis w/ 23 RCT)
• HT significantly ↓CHD events in younger (OR 0.68) but not older (OR 1.03)
Saltpeter et al. (meta-analysis w/ 30 RCT)
• HT ↓ mortality when stated in younger group, but not in older group
118. «Critical-window» hypothesis
Summary
• Saltpeter et al, Nurses’Health Study :
↓ incidence of CHD event when initiated younger
• Saltpeter et al, HERS, WHI:
Initiation of HT in older women is associated with ↑
incidence of adverse CHD in the first year only
• Rossouw et al. (2° analysis of WHI):
Didn’t identify any subgroup w/ ↓risk of CHD but
mortality was ↓ in 50 to 59 y/o group
119. «Critical-window» hypothesis
Summary
• Carotid artery progression study:
↓ incidence of CHD event when initiated younger
• Carotid IMT has been followed as an early marker of
atherosclerotic disease
• Women who underwent H-BSO menopause had significantly ↑
IMT after 1 year compare to pt with just hysterectomy
• IMT ↑ among E nonuser and ↓ among E user in early menopause.
No benefit on progression in pt more remote from menopause
120. • Evidences that HT has no role in ↓ future risks
of CVD events in pt with established CAD.
• The absence of excess absolute risk of CHD
and the suggestion of reduced total mortality
in younger women offers some reassurance
that hormones remain a reasonable option for
the short-term treatment of menopausal
symptoms.”
121. Premature loss of ovarian
function
• Pt who had BSO had a ↑ risk for CAD
• WHI : pt who didn’t receive HT had 2x risk of
coronary artery calcium compare to pt who
received HT within 5 years of their Sx.
• Supports the need for E following premature
loss of ovarian function at least until the
natural age of menopause if estrogen is not CI
for other reasons
122. Stroke
Nurses’ Health Study: (observational)
• Dose–response relationship between the use of E and stroke
• Found an association between the use of P and stroke.
Lobo et al.
• No ↑ risk of stroke (4065 newly menopausal started HT : CEE w/ or w/o progestin
in 2 pivotal clinical trials)
WHI (2002)
• ↑ ischemic stroke across all age group
• E only : stroke risk appeared lower in 50-59 y/o then 60-69
• Conclusion cant be reached b/c of the small numbers in the younger group
WISDOM
• No excess incidence of CVA in women with EPT vs Placebo at 1 year
123. Stroke
• Absolute level of risk of ischemic stroke in
younger menopausal women is low
• Additional risk conferred by HTR : (WHI)
• 8/10 000 ( EPT)
• 13/10 000 (E)
124. Metabolic syndrome
• The results of large RCTs have suggested that HT ↓ incidence of
new-onset DM
• WHI : ↓ 21%
• HERS: similar ↓ than WHI
• Meta-analysis: 107 trials examining components of the metabolic
syndrome concluded that HT ↓: (in women w/o DM)
• Abdominal obesity
• Insulin resistance, new-onset diabetes
• Lipid levels
• Blood pressure in women without diabetes
• ***↓ insulin resistance and fasting glucose levels in pt w/ DM
125. DVT
• Oral HRT ↑ risk of VTE (greater in the first years)
• WHI: risk 4.0 (@1y) ↓ 1.04 (@6y)
• Data from WHI analyzed: other factors contribute
• 60-69 y/o had 2x risk of 50-59y/o
• 70-79 y/o had 4x risk of 50-59y/o
• Overweight (2x) obesity (3x)
• Highest risk: women who carries Leifen factor V
126. DVT
• Greatest risk factor : AGE
• Absolute incidence 2-3/10 000 at 50-54
• Absolute incidence 20-30/10 000 at 80
• ? Risk lower with Estrogen alone
• ? HT not synergistic with obesity and age
• ESTHER study : (case ctrl, multicentre)
risk of VTE ↑ with oral vs transdermal
127. Protection for CVD
• Premenopausal protection: Estrogen ➔ ↑ HDL
• This benefit disappear after menopause
• Risk of CVD ↑ exponentially for women as
they enter menopause and ↓ E
129. Lipid profil
• ↑ total cholesterol
• Low HDL is a strong predictor for CVD
• Total cholesterol and LDL level can be
favorably reduced by :
• Diet modification
• Estrogen treatment*
• Lipid lowering Rx
130. Coagulation
• Change in clotting parameters occur w/ age:
• ↑ fibrinogen
• ↑ plasminogen activator-1
• ↑ factor VII
• Cause relatively hypercoagulable state
131. Summary cardiovascular
• First decade after menopause: cardiovascular risks from initiating
HT for distressing vasomotor symptoms are very small.
• Uncertainty remains about whether early initiation of estrogen
may even afford protection from atherosclerosis.
• HT should not be used for primary or secondary cardioprotection.
• Available evidence demonstrates that: initiation of HT should be
done with caution in women who are more than a decade after
menopause b/c it may be associated with an ↑ risk of adverse
cardiac events
• HT appears to slightly ↑ the risk of ischemic stroke
132. 1.MD should not initiate or continue HT for the sole purpose of preventing CVD (IA)
2.MD should abstain from prescribing HT in women at high risk for VTE disease. (IA)
3.MD should initiate other evidence-based therapies and interventions to effectively reduce the risk of CVD
events in pt w/ or w/o vascular disease. (IA)
4.Risk factors for stroke (obesity, HTN, and smoking) should be addressed in all post-menopausal women. (IA)
5.If prescribing HT to older postmenopausal women, MD should address cardiovascular risk factors; low- or
ultralow-dose estrogen therapy is preferred. (IB)
6.MD providers may prescribe HT to diabetic women for the relief of menopausal symptoms. (IA)
133. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
135. Weight gain
• ↑ age = ↓ metabolism = ↓ caloric requirement
• In exercise and diet don’t change = ↑ weight
• Weight gain is not an effect of hormonal changes
• Estrogen therapy doesn’t cause weight gain
(clinical trial and epidemiological studies)
136. ↑ weight and its risk...
• Weight gain in menopause = ↑ abdominal fat
deposition = ↑ risk insulin resistance = ↑ risk of
DM and CVD
137. Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes
140. Dental changes
• Buccal epithelium undergoes atrophy due to ↓
E ➔ ↓ saliva and sensation
• Bad taste in the mouth
• ↑ cavity
• ↑ tooth loss
•
Strongly correlated to smoking and hygiene
•
Correlated to osteoporosis
141. Breast changes
• ↓ E and P = reduction in breast proliferation
• ↓ in volume and % of dense tissue ➔ these
areas become replaced w/ adipose tissue
142. Treatment
• Skin aging:
• Avoid UV light
• Avoid tobacco
• Lmitation of R-OH intake
• ACOG : "there is insufficient evidence to
recommend estrogen treatment to increase skin
thickness and collagen content and thereby decrease
wrinkling in sun-exposed areas such as the face and
forearms."
143. Overview
• Hypothalamus-pituitary-ovarian axis change
• Ovarian changes
• Endometrial changes
• Central thermoregulation changes
• Bone metabolism and structures changes
• Cardiovascular changes
• Weight gain and fat distribution changes
• Dermatologic, dental and breast changes
• CNS changes
• Psychosocial changes
• Libido changes
• Lower reproductive tract changes
145. CNS changes
• Memory decreases with advancing age
• No direct effect of lowered E on memory and cognition has been
determined yet
• High suspicion that there is a relationship
• Study 1995 (Hallbreich):
• Cognitive fct assessment in women in their forties vs
postmenopausal
• 40s: less likely to experienced cognitive decline
• Risk factor for ↓ perfusion and thinning of gray and white matter:
• TIAs, DLPD,HTN,smoking,excessive R-OH, male gender (?lack of
E)
146. Mood
• Evidence that depression can occur in the absence of
vasomotor symptoms and sleep disturbance.
• Recent systematic review of cohort studies failed to
detect a link between the menopausal transition and
new-onset depression
• They found contributory factors in additional to stage
of menopause that figure into the development of
perimenopausal depression (vasomotor symptoms, life
stress, Hx of depression in a family member,
postpartum blues, a high BMI, and sexual abuse)
147. Mood
• Limited clinical-trial data :
• Transdermal estrogen may be effective for Tx
major depressive episodes in perimenopausal
women, but not postmenopausal women.
• Psychotherapy and judicious use of
antidepressants will remain the mainstay of Tx
for depression; however, in cases of resistant
depression at the onset of menopause, HT may
be appropriate.
148. Memory
• Epidemiologic studies:
unable to document cognitive decline in women
throughout the menopausal transition.
• Spatial and semantic memory seem to be relatively
unaffected, whereas episodic memory and, in
particular, verbal fluency may show deterioration.
• having difficulties with word finding and recall.
• General lack of discernible cognitive impairment is
important and reassuring to women
149. Memory
• The WHIMS trials of EPT and E alone were 2 large RCTs
conducted in older postmenopausal women:
• HTR ↑ risk of cognitive decline.
• Various explanations:
(1) theory that memory is related to cardiovascular health and
that the cognitive decline mirrors the ↑ risk of CVA observed in
older postmenopausal women in the WHI.
(2) there may exist a critical window for neuroprotection.
• The clinical importance of these studies is that they showed no
benefit, and the potential for harm, in administering HT to older
postmenopausal women.
150. Memory
• Henderson et al (2007) reanalyzed data from the
WHIMS trial:
• All-cause dementia was significantly less likely to
develop in women reporting prior HT
• Women’s Estrogen for Stroke Trial Estrogen
administrated for troke prevention
• No impact of E Tx, except in women with normal
function at baseline, who had less decline in
cognitive domains (RR, 0.46 [95% CI, 0.24 to 0.87])
151. Memory
• RCT(recent) for prevention of osteoporosis:
• Women randomized to HT had a ↓ risk of cognitive impairment
than those receiving placebo.
• Bagger et al.:
• Early administration of E was associated with significantly
improved performance in cognitive testing 5, 11, and 15 years
later; this study was limited by the absence of baseline cognitive
testing.
• Case-control studies:
• Women who underwent oophorectomy before menopause have
recently shown a small increase in the risk of dementia
152. What does it mean for our
patient?
• Women experiencing verbal memory changes at menopause can be
advised that there is no apparent association between verbal memory
change and global cognitive decline.
• For best preservation of memory and cognition: good overall health,
good cardiac and vascular health, exercise,maintenance of an active
mind, avoidance of excessive alcohol consumption, and measures to
reduce the risk of diabetes and hypertension.
• HT is not indicated for neuroprotection.
• Two clinical trials in progress may shed additional light on this question.
• Clinical studies support basic science research suggesting that ultralowdosage estrogen therapy may be sufficient for neuroprotection.
153. Recommendation:
1. Estrogen alone may be offered as an effective Tx for depressive disorders in
perimenopausal women and may augment the clinical response to
antidepressant, specifically with SSRIs (IB). The use of antidepressant
however, is supported by most research evidence (IA).
2. Estrogen can be prescribed to enhance mood in women with depressive
symptoms. The effect appears to be greater for perimenopausal symptomatic
women than for postmenopausal women. (IA)
3. Estrogen is not currently recommended for ↓ risk of dementia developing in
postmenopausal women or for retarding the progression of Dx Alzheimer’s
disease, although limited data suggest that early use of HT in the
menopause may be associated with ↓ risk of later dementia. (IB)
154. Overview
• Hypothalamus-pituitary-ovarian axis change
• Ovarian changes
• Endometrial changes
• Central thermoregulation changes
• Bone metabolism and structures changes
• Cardiovascular changes
• Weight gain and fat distribution changes
• Dermatologic, dental and breast changes
• CNS changes
• Psychosocial changes
• Libido changes
• Lower reproductive tract changes
156. Psychological changes
• Psychosocial and cognitive symptoms may
develop during menopausal transition and
include:
•
Depression
•
Mood changes
•
Poor concentration
•
Impaired memory
157. Psychological changes
• Psychosocial factors may contribute:
•
Emotional stress from adolescents
•
Onset of major illness
•
Caring for aging parent
•
Career change
•
Retirement
158. Psychological changes
• Hormonal fluctuation during early menopausal
transition are responsible for this affective instability
• Surgical menopause induces mood changes because of
the rapid hormonal loss at this time
• One placebo-controlled study w/ CEE 0.625mg per day
and it improved significantly sleep and hostility
159. Treatment
• First line treatment for menopausal women
presenting with depression would be a traditional
antidepressant e.g. SSRI.
• Tx with estrogen for pt with mild to moderate
depression may be an alternative
• Consideration to add HT to a fail response to SSRI
160. Overview
• Hypothalamus-pituitary-ovarian axis change
• Ovarian changes
• Endometrial changes
• Central thermoregulation changes
• Bone metabolism and structures changes
• Cardiovascular changes
• Weight gain and fat distribution changes
• Dermatologic, dental and breast changes
• CNS changes
• Psychosocial changes
• Libido changes
• Lower reproductive tract changes
162. Libido
• Definitive data are lacking in regards of the
relationship between circulating hormones and
libido
•
Avis and co. (2000) study 200 women, postmenopausal status was
significantly related to a ↓ in sexual interest. However, after adjustment for
physical&mental health, smoking and marital satisfaction, menopause wasn’t
significantly related to ↓ libido.
•
Tungphasial (1991) study 100 naturally menopause women: ↓ sexual
thought, ↓ sexual activity compared to premenopausal status. They reported ↓
libido, dyspareunia and orgasme dysfunction (86% reporting no orgasms)
163. Treatment
• Estrogen replacement :
• RCT : significant positive effect of E on mood and
sexuality
• Testosterone:
• Controversial
• Study demonstrate effectiveness however very strong
placebo effect
• Off-label use ➔ s/e hirsutism, acne, △ lipid profile
• improve bone mass, muscle mass and ↓ hor flashes
164. Overview
• Hypothalamus-pituitary-ovarian axis change
• Ovarian changes
• Endometrial changes
• Central thermoregulation changes
• Bone metabolism and structures changes
• Cardiovascular changes
• Weight gain and fat distribution changes
• Dermatologic, dental and breast changes
• CNS changes
• Psychosocial changes
• Libido changes
• Lower reproductive tract changes
166. Lower reproductive tract
changes
• ↓ E ➔ vaginal loss of collagen, adipose tissues and
ability to retain water
• Vaginal walls shrinks, rugae flatten and vagina looks :
flat-walled, pale-pink
• Surface epithelium thins ➔ surface is friable and prone
to bleeding with minimal trauma
• Glandular secretions ↓
• The prepuce of the clitoris atrophies, exposing the gland
to irritation from clothing, prolonged sitting,etc.
167. Vaginal dryness
• Vaginal dryness ↑ progressively as women
approached and passed through menopause:
• 3% in premenopause
• 25% by 1 year
• 47% by 3 years after menopause
• Women who smoke have higher rates
168. Vaginal dryness : Treatment
• Local lubricants can alleviate dryness and discomfort but do not
reverse the histologic ∆.
• E.g. polycarbophil-based gel Replens ➔
- more sustained correction of vaginal dryness
- acidity of the gel lower vaginal pH to premenopausal level
• Intravaginal estrogen Tx can be used for vaginal dryness either alone
or in addition to systemic estrogen HRT.
• Cream, ring, tablet are all comparable
• Vagifem had less endometrial proliferation than CEE cream
• Vagifem and ring were more acceptable than cream
• Up to 40% of women receiving systemic Tx do not get an adequate
effect of estrogen on the vaginal mucosa.
169. Urogenital Treatment
• PV estrogen can have systemic effects if given
in sufficient quantity.
• In a low dose it may be transiently absorbed in
the first 7 to 14 days b/c the thinned
epithelium of the hypoestrogenic vagina
presents a minimal barrier to absorption.
• Generally after Tx for 1 to2 weeks the systemic
level of estrogen is once again at the
pretreatment level.
170. Urogenital Tx and Breast
Cancer
• Recent evidence: women with breast CA who have
endogenous E levels suppressed by use of an aromatase
inhibitor, systemic absorption of vaginal E, even though very
low, can be detected with conventional assays.
• Data on this finding are very limited at present.
• A large cohort study demonstrated no difference in the
outcome of breast CA for women choosing to receive local
vaginal estrogen therapy, although it is likely that few
women in this study were receiving aromatase inhibitors.
• This suggests caution in prescribing these products if the
intent of aromatase therapy is to completely suppress
endogenous estrogen.
171. Urinary incontinence
• Urgency incontinence affects:
• 10% of women by age 50
• 15% by age 60
• 25% by age 70
• 35% after age 80.1
172. Urinary incontinence
• HERS trial: 4.2 years of HRT vs Placebo
• 64% of women assigned to HT vs 49% of those assigned to placebo reported
weekly incontinence (P < 0.001)
• Four years of HT caused an excess risk of 12% for weekly urge incontinence
and 16% for weekly stress incontinence.
• WHI :
• UI developed at a significantly higher rate among continent women taking
CEE alone or with MPA than among continent women taking a placebo.
• UI worsened in women taking CEE alone or with MPA compared with those
taking a placebo.
• Conclude: oral estrogen formulations used in the study ↑ risk of UI and
therefore should not be used to treat it.
173. Urinary incontinence
• Basic science in this area is limited:
• Randomized clinical trial :
Pt receiving 2 mg of estradiol valerate PO x 6 months showed significant ↓ in total
periurethral collagen
• According to the authors, connective tissue is crucial to:
• the integrated action of the suburethral vaginal wall,
• the pubourethral ligaments,
• the pubococcygeus muscles
• the paraurethral connective tissues;
• consequently, its degradation contribute to the development of urethral hypermobility,
intrinsic urethral sphincter dysfunction, or both, thus setting the stage for stress urinary
incontinence.
• However, there is conflicting evidence:
Using Doppler imaging,they found that HT for 3 months improved periurethral vessel
number and blood flow, therefor improving urethral sphincter function and promote
continence, not worsen it.
174. Urinary incontinence:
Role of estrogen Tx
• Cochrane Review (2003):
15 small trials evaluating the role of E vs
placebo for the Tx of all UI.
• ~ 50% of the E-Tx women reported
improvement or cure compared with 25% of
those who received placebo.
• The effect was largest in the women with
pure urge incontinence.
175. Urinary incontinence
• Basically :
• the influence of hormone factors on urethral and bladder
function is still poorly understood
• Data are conflicting
• unlikely that estrogen Tx has a significant role to play in the
treatment of UI
• Aim to optimize risk factors : obesity, amount and type of fluid
intake, smoking, major depression, and the use of certain Rx
• ↓ of 5% in BMI showed an improvement in symptoms
176. Recurrent UTI
• Recurrent UTI and vaginal infections are more
likely in estrogen-deficient women.
• Both systemic and local estrogen Tx will
correct vaginal health, but only local Tx ↓
frequency of recurrent UTI
177. Urogenital concerns:
1. Conjugated estrogen cream, intravaginal estradiol ring, or estradiol vaginal
tablets are recommended as effective Tx for vaginal atrophy. (IA
2. Routine progestin cotherapy is not required for endometrial protection in pt
receiving vaginal E (N dose) (IIIC)
3. Vaginal lubricants may be recommended for subjective symptom
improvement of dyspareunia. (IIIC)
4. MD can offer polycarbophil gel (a vaginal moisturizer) as an effective Tx for
symptoms of vaginal atrophy, including dryness and dyspareunia. (IA)
5. As part of management of USI, pt should try nonsurgical optionsuch as
↓weight, pelvic floor physic (±biofeedback), weighted vaginal cones,
functional electrical stimulation, and/or vaginal pessary (II-1B)
178. Urogenital concerns:
5. Lifestyle modification, bladder drill (II-1B), and anti-muscarinic Tx
(IA) are recommended for the Tx of urge UI
6. Estrogen therapy should not be recommended for the Tx of
postmenopausal urge or USI but may be recommended before
corrective surgery (IA)
7. Vaginal estrogen therapy can be recommended for the prevention of
recurrent UTI in postmenopausal women. (IA)
8. Following treatment of adenocarcinoma of the endometrium (stage
1) estrogen therapy may be offered to women distressed by
moderate to severe menopausal symptoms. (IB)
179. Sexual concerns:
10.A biopsychosexual assessment of preferably both partners (when appropriate),
identifying intrapersonal, contextual, interpersonal, and biological factors, is
recommended prior to Tx of women’s sexual problems. (IIIA)
11.Routine evaluation of sex hormone levels in post-menopausal women with
sexual problems is not recommended. Available androgen assays neither reflect
total androgen activity, nor correlate with sexual function. (IIIA)
12.Testosterone therapy when included in the management of selected women
with acquired sexual desire disorder should only be initiated by clinicians
experienced in women’s sexual dysfunction and with informed consent from
the woman. The lack of long-term safety data and the need for concomitant
estrogen therapy mandate careful follow-up. (IC)
180. Overview
• Hypothalamus-pituitary-ovarian axis change
• Ovarian changes
• Endometrial changes
• Central thermoregulation changes
• Bone metabolism and structures changes
• Cardiovascular changes
• Weight gain and fat distribution changes
• Dermatologic, dental and breast changes
• CNS changes
• Psychosocial changes
• Libido changes
• Lower reproductive tract changes
182. Herbal remedies
• WHI 2002 ➔ MD abandoned prescription of HT for
vasomotor Sx
• Pt have turned to unproven and untested complementary
therapies
• Multi-billion $ business and only a few have met rigorous
testing criteria required of pharmaceutical products by US
FDA.
• Pharmaceutical regulatory requirement : pt in study
must have average of 7 hot flashes/d or 50/week,
• Most reported study of hebal product: open label and in
women with as few as 1 or 2 hot flashes per day.
183. Herbal remedies
• Caution about potential adverse safety profiles
• Cautions about interaction w/ pharmaceutical &
anesthetic agents
• New canadian legislation : January 2004
• Removed herbal product from food category
and placed them into a special drug category
(to allow regulation of manufacturing, labeling
and indications)
• Very few accomplished in the regulation so far
184. Herbal remedies
• Several systematic review :
• No single complementary therapy have been
proven efficacious for moderate to severe
hot flashes
• Same efficacy than placebo
• Direct head-to-dead : HT vs black cohosh,
soy or multibotanical showed only HT to be
more efficacious than placebo.
187. PEPI
Postmenopausal E/P interventions trial
• 1980s E were prescribed not only for vasomotor Sx but also for prevention of
other condition
• PEPI : ~900 pt, Mean age 56 y/o and 5 group, x 3 years
(1)
Placebo
(2)
E
(3)
E + cyclic MDPA
(4)
E + micronized progesterone
(5)
E + continuous MDPA
• 1995 PEPI trial results were published:
• LDL ↓ & HDL ↑ in group 2-5
• Fibrinogen was ↑ in placebo group
• no difference in systolic BP and glucose intolerance
• clinical event : 2 x MI, 1x cardiac arrest, 2 x strokes (all in HRT groups)
188. Hers
• Published in 1998
• 2800 patients w/ pre-existing ♥ disease receiving E
as secondary prevention Vs placebo group
• 1st year: ↑MI in pt EPT
• After 4y: no difference between the groups OR 0.99
• Started to question the cardioprotective effect of
HRT
• June 2002 ➔ HERS II : Showed that HT wasn’t
beneficial in secondary prevention of heart disease
after 6.8 years
189. WHI
• Before the result of PEPI & HERS
• WHI was launch in 1993
• Compare EPT vs Placebo in ~16 000 healthy postmenopausal
women aged 50-79. Outcomes:
• Coronary heart disease
• Breast CA
• VTE
• Colon CA
• Bone Fx
• Concurrently they had a E only arm (pt w/o uterus) vs Placebo
190. WHI
• After 5.2 y the EPT arm was halted b/c risk exceeded benefits
• July 2002 ➔ result released to media prior to publication of the data and education to health care
provider
• 2007 (Rossouw & Colleague) did secondary analysis go WHI data
• Pt started HRT closer to menopause had ↓ risk of CHD vs pt more distant from menopause
• < 10 y from menopause : OR 0.76
• 10-20y from menopause: OR 1.10
• >20y from menopause : OR 1.28
• Pt younger at start of HRT had lower risk of CHD
• 50-59y/o : OR 0.93 (↓ 2/10 000)
• 60-69 y/o : OR 0.98 (↓1/10 000)
• 70-79 y/o : OR 1.26 (↑19/10 000)
• HRT ↑ risk of stroke (OR 1.32) and it didn't vary by age or time since menopause
• WISDOM trial (started 1999) was halted after the WHI result ➔ data collected showed ↑ risk of
CHD & VTE when started many years after menopause
192. Summary risks
• ↑ risk of CHD in older menopausal women
• ↑ risk Breast Ca ( w/ >5y use)
• ↑ Stroke
• ↑ VTE
• ↑ cholescystitis
• ↑ Ovarian Ca (w/ > 10y use)
• 2 studies showed that (Danforth 2007, Lacey 2006)
• Other studies haven’t confirmed this
193. Summary benefits
• ↑ BMD
• ↓ rate of Fx
• ↓ colorectal Ca
• Effect on mortality (metanalysis OR 0.98)
• HRT ↓ mortality in <60y/o (OR 0.61) vs
> 60 (OR 1.03)
• Suggest: once CHD is establish, HRT has
no effect in reversing progression
194. Summary of indications
• Tx of vasomotor Sx & vaginal atrophy
• Tx or prevention of osteoporosis
• Re-evaluation of the need of HRT q 6-12months
• Prescribed in lowest dose for the shortest period
• Bone specific agent would be more appropriate for long-term OP
prevention or Tx
• Use continuous or cyclic progestin (cyclic is useful while in
transition)
• Mirena can be use for progestin
• Low-dose OCP can be useful in transitional period (younger
patient, provide contraception for the occasional ovulation)
195. Summary of contraindication
• Contraindicated:
� Known/suspected/Hx Breast CA
� Known/suspected/Hx E-dependant CA
� Undiagnose AUB
� Known or suspected pregnancy
� Active/Hx of VTE
� Active or recent (<1y) MI or stroke (Arterial thromboembolic)
� Liver disease
� Known allergy to any component
• Used with caution:
� Dementia
� Gallbladder disease
� Hypertriglyceridemia
� Prior cholestatic jaundice
197. SOGC’s Canadian Consensus
Conference on Menopause (2006) :
• ↑risk of breast CA detection after 5 years of EPT, with
an RR ~ 1.3 over many clinical trials
• Unopposed E appears to be slightly lower than that
after EPT
• Most women using HT for symptomatic relief use it for
< 5 years
• Risk of breast CA returns to N shortly after d/c of HT
Consensus has been that short-term use of HT for relief of disruptive
vasomotor symptoms carries little appreciable risk for the average woman
entering menopause. Longer-term is a matter for discussion w/ the pt.
198. WHI
• Women w/ prior HRT had ↑ risk after 3y EPT
• Women w/o use of HRT had no ↑ during the 5 y
• No ↑ risk of invasive breast CA up to 2.4y after WHI
• The ↑ risk of breast CA detection reported for combined
HT in the WHI : HR, 1.24
• The 24% ↑ risk of breast CA translated into an absolute ↑
risk of only 8 additional cases/10 000 hormone users
per year in the older age-mix of the WHI.
199. WHI
• Factors that modify breast CA risk to a similar/greater degree:
(all HR ~ 1.3)
• Early menarche
• Late menopause
• Post-menopausal obesity
• Delaying pregnancy until after 30
• No breastfeeding
• No exercise
• Consuming excessive amounts of alcohol
• Shift work*(not 1.3)
200. WHI
• Major risk factor:
• Positive family history (HR 3)
• Past breast Bx with atypic (HR 5)
• Premenopausal women w/ BRCA mutation (HR 200)
201. WHI
• E only arm : no ↑ in breast CA
but population mostly overweight, and pt obese have an ↑
risk of breast CA so it’s a possibility that there were only a
little added risk when exposed to HT.
202. Other research
• Other research supports the fact that the effect of
estrogen alone on breast cancer is small and is
usually undetectable with short-term exposure:
• Finish study:
• E for > 4 years resulted in 2 to 3 extra cases of breast
CA per 1000 women followed over 10 years
• No ↑ if treated for less than 5 y
• Harvard’s Women Health study:
• No ↑ in women using CEE after a mean of 10y
203. 2 meta-analasis post-WHI
• Strong statistical evidence that EPT
carries a statistically significant risk for
breast cancer greater than the risk
attributable to estrogen alone
204. The Million Women Study
• 1 084 110 women (1996 and 2001)
• No ↑ breast CA in past user, regardless
of time since discontinuation and
duration of use
• Current HTR showed ↑RR 1.3 (E) and
↑RR 2.0 (EPT)
• Consistent with WHI
205. Facilitated detection vs de
novo breast tumor
• Is HTR facilitating the detection of pre-existing small
carcinomas b/c of a more rapid growth ?
• Is HTR causing the development of new malignant
breast tumors by an ↑ frequency of initiating mutation?
• Studies that report the rapid appearance of breast CA
after initiation of HTR ➔ support the hypothesis that
HTR is speeding up the growth and detection of preexisting tumors.
• In support of this hypothesis are data indicating better
outcomes for women whose cancers were detected while
on HTR.
206. Return to Breast CA risk
shortly after d/c
• Return of the breast CA risk to baseline
shortly after d/c HTR has been
consistently reported in observational
studies
207. Difference between
progestins
• Many studies have been unable to distinguish
between the progestins used (b/c of low
numbers of users of products different than
MPA)
• E3N cohort study (France): 80 377 pt
• Incidence of breast CA wasn’t ↑ in pt taking E
and progesterone (OR, 1.0)
• Incidence of breast CA was ↑ in pt taking E and
other progestogens (OR, 1.69)
208. Breast density
• ↑ breast density is an independent risk
factor for breast CA. However, even though
breast density can be ↑ by the use of E with a
progestin, it has never been shown that an
acquired ↑ density (2° hormonal Tx) ↑ breast
cancer risk.
• Estrogen alone and low-dose or transdermal
combination therapy appear to have a lesser
impact on breast density.
209. Random
• There is no consistent evidence to favor
either continuous or cyclic sequential
regimens for estrogen and progestin.
• Women using EPT had an 11% greater risk
of an abnormal mammogram after 5 years
• There remains no consensus on whether
cancers detected in women using HT are
more or less advanced.(WHI had
contradictory findings)
210. Random
• Pt choosing to use HT for relief of symptoms need
to understand that short-term HTR use is unlikely
to appreciably alter their personal risk of breast
cancer
• The risk of breast CA appears to be : EPT > E alone.
• Insufficient evidence to support progesterone over
various progestogens, but there is both clinical and
basic science evidence accumulating to suggest it.
• Risk of breast cancer has been found to return to
baseline after cessation of HTR
211. Random
• Singletary:
• HT had about the same risk as early
menarche, late menopause, excessive
alcohol consumption and failure to
exercise.
212. HTR IN WOMEN
WITH A PFHx OF BREAST CANCER
• Pt w/ a single 1stdegree relative (mother, sister, or
daughter) in whom breast CA was Dx > 50y have little ↑
in risk over the approximately 12% risk of the general
population
• Pt w/ two 1stdegree relative doubles a woman’s lifetime
risk (to approximately 24%).
• Pt w/a single 1stdegree relative in whom breast CA was
Dx <50y have a risk of 24%.
• Pt w/ two 1stdegree relative doubles a woman’s lifetime
risk (to approximately 48%).
213. HTR IN WOMEN
WITH A PFHx OF BREAST CANCER
• One study: HTR in pt w/ positive family hx didn’t
have any ↑ in the overall risk but ↓mortality
• Similar conclusion with a collaborative reanalysis
• Why ? The influence of genetic is so important that
it generally overshadows any small potential
increment resulting from lifestyle or HRT.
214. HRT IN BREAST CA SURVIVORS
WITH VASOMOTOR SYMPTOMS
• The HABITS trial found that women who used HT after a
Dx of breast CA had a ↑ ↑ recurrence risk than did pt w/
placebo.
• Owing to the adverse findings in the HABITS trial the
Stockholm Trial was prematurely closed, even though it
had failed to find any adverse effect of HT
• Possible explanations for the discrepant findings of these
2 RCTs include the fact that more node-positive tumours
were evident in the HABITS trial, more women in the
Stockholm Trial were treated with tamoxifen, and
different progestin regimens were used in the 2 trials.
215. HRT IN BREAST CA SURVIVORS
WITH VASOMOTOR SYMPTOMS
• What should we say to the patient?
• Women who wish to consider HT for improved
quality of life after a Dx of breast CA should
understand that a definitive answer to the question
of when HT will influence Px is lacking. The results
of observational studies, which are fraught with
potential biases, have been reassuring; however, a
single RCT suggested that HT had an adverse effect
on recurrence rates.
216. SERM AND BREAST CA
• Raloxifene : Tx and prevention of osteoporosis
+ approved in US to prevent breast CA
• MORE trial : pt on raloxifene had ↓72% risk of
breast CA at 4 years.
• STAR trial: raloxifene was as effective as
tamoxifen in reducing risk of invasive breast
CA. Raloxifen has ↓risk of VTE
217. 1. MD should periodically review the risks and benefits of
prescribing HT to a menopausal woman in light of the
association between duration of use and breast cancer risk.
(IA)
2. MD may prescribe HT for menopausal symptoms in
women at increased risk of breast cancer with appropriate
counseling and surveillance. (IA)
3. MD should clearly discuss the uncertainty of risks
associated with HT after a diagnosis of breast cancer in
women seeking treatment for distressing symptoms. (IB)
218.
219. Progestin preparation
Trade name
Strength
Apo-Medroxy
2.5, 5, 10
Gen-Medroxy
2.5, 5, 10
Medroxy 2.5
2.5
Medroxy 5
5
Novo-Medrone
2.5, 5, 10
PMS-Medroxyprogesterone
2.5, 5, 10
Ratio-MPA
2.5, 5, 10
Provera
2.5, 5, 10, 100
Provera Pak
5, 10
Comment
Oral (mg)
Medroxyprogesterone acetate
Provera Pak 5 mg contains 14 tablets
Provera Pak 10 mg contains 10 tablets
Megestrol
40, 160
Nu-Megestrol
40, 160
Linmegestrol
40, 160
Megace
40, 160
Megace OS
40 per mL (liquid)
Prometrium
100
Micronor
0.35
Norlutate
Norethindrone
40, 160
Megestrol-40 Megestrol-160
Micronized progesterone
Apo-Megestrol
5
Depo-Provera
50 per mL (5 mL)
Injectable
Medroxyprogesterone acetate
150 per mL (1 mL)
Progesterone
Progesterone Injection
50 per mL (10 mL)
Implanon
40 g/d
Minera Intrauterine
System (IUS)
52 mg per IUS
Implant
Progestogen
Intrauterine
Levonorgestrel
Approval pending
220.
221. Nonhormonal osteoporosis medications
Regimen
Treatment
Alendronate (Fosamax)
10 mg daily
70 mg once weekly
Cyclical etidronate* (Didrocal)
400 mg daily for 2 weeks followed by 500 mg
calcium daily for 76 days in a 3-month kit (Didrocal)
Fosavance 70/2800
70 mg/2800 IU vitamin D3
Fosavance 70/5600
70 mg/5600 IU vitamin D3
Nasal calcitonin (Miacalcin NS)
200 IU daily, intranasally via alternating nostrils
Parathyroid hormone
20 µg subcutaneously daily
Raloxifene ( Evista)
60 mg daily
Risedronate (Actonel)
5 mg daily
35 mg once weekly
Risedronate plus Calcium carbonate
(Actonel plus calcium)
35 mg once-a-week + 1250 mg calcium carbonate
Teriparatide (Forteo)
20 µg injectable daily
Prevention
Alendronate (Fosamax)
5 mg daily
Cyclical etidronate* (Didrocal)
400 mg daily for 2 weeks followed by 500 mg
calcium daily for 76 days in a 3-month kit (Didrocal)
Raloxifene ( Evista)
60 mg daily
Risedronate (Actonel)
5 mg daily
*Etidronate alone (Didronel) is only available as a 200 mg tablet.
222.
223. FDA approved product
• Definition: therapy similar in chemical
composition to that made in human
body ➔ 17-E2 and/or progesterone
• Products are regulated and monitored
by the FDA. They have proven efficacy
at relieving menopausal symptoms and
have published endometrial safety
profiles ➔ See next slides table
224.
225.
226. Non-FDA approved
• Topical regimens (estrogen) :
• Tri-est (80 % estriol, 10 % estrone, 10 % estradiol) ➔ 1.25 to 2.5 mg
• Bi-est (estriol 80 % & estradiol 20 %) ➔ 1.25 to 2.5 mg
• These estrogens are compounded w/ micronized progesterone:
• Dermabase ➔ 10 to 50 mg daily,
• Eucerin➔ 10 to 50 mg daily
• Some pharmacy individualized to pt based on salivary hormone testing
• Lack of correlation w/ serum hormone level
• Not undergone rigorous RCT for safety and efficacy
• Educate patient regarding potential risks & benefit
• FDA : "Other doses of CEE and MPA, and other combinations and dosage forms of estrogens and
progestins were not studied in the WHI clinical trials, and in the absence of comparable data, these
risks should be assumed to be similar.”
• Compounded hormone can’t assumed to be safer than conventional E and progestin and it is very
important that adequate endometria protection is provided if compounded E are prescribed.
Editor's Notes
In williams gyne 2007
The straw report divides reproductive and postreproductive life into several stages
GnRH neurons develop in the olfactory placed ➔ migrate through the forbrain to the arcuate nucleus of the hypothalamus by 11 wGA ➔ form axon that extend to the pituitary portal plexus in which they release GnRH (pulsatile fashion)
Decreasing levels of estradiol and progesterone from the regressing corpus luteum of the preceding cycle initiate an increase in FSH by a negative feedback mechanism, which stimulates follicular growth and estradiol secretion. A major characteristic of follicular growth and estradiol secretion is explained by the two-gonadotropin (LH and FSH), two-cell (theca cell and granulosa cell) theory of ovarian follicular development. According to this theory, there are separate cellular functions in the ovarian follicle wherein LH stimulates the theca cells to produce androgens (androstenedione and testosterone) and FSH then stimulates the granulosa cells to convert these androgens into estrogens (androstenedione to estrone and testosterone to estradiol), as depicted in Figure 4-3. Initially, at lower levels of estradiol, there is a negative feedback effect on the ready-release form of LH from the pool of gonadotropins in the pituitary gonadotrophs. As estradiol levels rise later in the follicular phase, there is a positive feedback on the release of storage gonadotropins, resulting in the LH surge and ovulation. The latter occurs 36 to 44 hours after the onset of this midcycle LH surge. With pharmacologic doses of progestins contained in contraceptive pills, there is a profound negative feedback effect on gonadotropin-releasing hormone (GnRH) so that none of the gonadotropin pool (ready-release or storage) is released. Hence, ovulation is (generally) blocked (see Chapter 26).
During the luteal phase, both LH and FSH are significantly suppressed through the negative feedback effect of elevated circulating estradiol and progesterone. This inhibition persists until progesterone and estradiol levels decline near the end of the luteal phase as a result of corpus luteal regression, should pregnancy fail to occur. The net effect is a slight rise in serum FSH, which initiates new follicular growth for the next cycle. The duration of the corpus luteum's functional regression is such that menstruation generally occurs 14 days after the LH surge in the absence of pregnancy.
HYPOTHALAMUS
Five different small peptides or biogenic amines that affect the reproductive cycle have been isolated from the hypothalamus. All exert specific effects on the hormonal secretion of the anterior pituitary gland. They are GnRH, thyrotropin-releasing hormone (TRH), somatotropin release-inhibiting factor (SRIF) or somatostatin, corticotropin-releasing factor (CRF), and prolactin release-inhibiting factor (PIF). Only GnRH and PIF are discussed in this chapter.
Figure 4-3 The two-gonadotropin (LH and FSH), two-cell (theca cell on top and granulosa cell below) theory of follicular development. Each cell is theorized to perform separate functions; LH stimulates the production of androgens (androstenedione and testosterone) in the theca cell, and FSH stimulates the aromatization of these androgens to estrogens, estrone, and estradiol in the granulosa cell.
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GnRH is a decapeptide that is synthesized primarily in the arcuate nucleus. It is responsible for the synthesis and release of both LH and FSH. Because it usually causes the release of more LH than FSH, it is less commonly called LH-releasing hormone (LH-RH) or LH-releasing factor (LRF). Both FSH and LH appear to be present in two different forms within the pituitary gonadotrophs. One is a releasable form and the other a storage form. GnRH reaches the anterior pituitary through the hypophyseal portal vessels and stimulates the synthesis of both FSH and LH, which are stored within gonadotrophs. Subsequently, GnRH activates and transforms these molecules into releasable forms. GnRH can also induce immediate release of both LH and FSH into the circulation. Some recent research that found receptors for GnRH in other tissues including the ovary suggests that GnRH may have a direct effect on ovarian function as well.
GnRH is secreted in a pulsatile fashion throughout the menstrual cycle as depicted in Figure 4-4. The frequency of GnRH release, as assessed indirectly by measurement of LH pulses, varies from about every 90 minutes in the early follicular phase to every 60 to 70 minutes in the immediate preovulatory period. During the luteal phase, pulse frequency decreases while pulse amplitude increases. A considerable variation among individuals has been identified.
Intravenous and subcutaneous administration of exogenous pulsatile GnRH has been used to induce ovulation in selected women who are not ovulating as a result of hypothalamic dysfunction. A continuous (nonpulsatile) infusion of GnRH results in a reversible inhibition of gonadotropin secretion through a process of "downregulation" or desensitization of pituitary gonadotrophs. This represents the basic mechanism of action for the GnRH agonists (nonapeptides, containing only nine amino acids) that have been successfully used in the therapy of such ovarian hormone-dependent disorders as endometriosis, leiomyomas, hirsutism, and precocious puberty.
Several mechanisms control the secretion of GnRH. Estradiol appears to enhance hypothalamic release of GnRH and may help induce the midcycle LH surge by increasing GnRH release or by enhancing pituitary responsiveness to the decapeptide. Gonadotropins have an inhibitory effect on GnRH release. Catecholamines may play a major regulatory role as well. Dopamine is synthesized in the arcuate and periventricular nuclei and may have a direct inhibitory effect on GnRH secretion through the tuberoinfundibular tract that projects onto the median eminence. Serotonin also appears to inhibit GnRH pulsatile release, whereas norepinephrine stimulates it. Endogenous opioids suppress release of GnRH from the hypothalamus in a manner that may be partially regulated by ovarian steroids.
Estrogen give a negative feedback except at ovulation
Inhibin : negative feedback for FSH
6-7 millions oocyte present at 20th week gestation
1 million at birth
At birth FSH LH rise abruptly 2° to the fall of estrogen produced by placenta and gradually declined within the first few months of life to reach prepubertal level by age 1 to 4.
During childhood the ovary increases in size and undergoes active follicular growth and atresia
By puberty you have 300 000 - 500 000 follicles
The principal sex steroids, estradiol and testosterone curculate in the blood bound to a glycoprotein carrier produced in the liver.
In all women, regardless of menopausal status, the etiology of abnormal bleeding should be determnes
Should be suspected in any pt with AUB in menopausal transition
<5mm not required because the risk of cancer is low
There is no evidence about that for premenopausal women ➔ Bx required if a clinical history ssuggest long-term unopposed estrogen exposure even if endometrial thickness is normal (5-12mm)
<5mm not required because the risk of cancer is low
There is no evidence about that for premenopausal women ➔ Bx required if a clinical history ssuggest long-term unopposed estrogen exposure even if endometrial thickness is normal (5-12mm)
FMP final menstrual period
Skin temperature can take up to 30 minutes to go back to normal
BMI some say that thinner is more common to have hot flashes other says ↑ BMI ↑ risk
Not clearly understood but…
Although estrogen withdrawal clearly has a significant impact on hot flush development, recent research has demonstrated that other factors are involved.
Change in NT may contribute pt hotflushes
Although estrogen withdrawal clearly has a significant impact on hot flush development, recent research has demonstrated that other factors are involved.
Change in NT may contribute pt hotflushes
The Medical Letter in 2004 and another systematic review of estrogen versus placebo in the treatment of hot flashes con- cluded that no therapeutic agent was as effective as estro- gen.18,19 MPA and estrogen were shown to have comparable efficacy in a 1-year randomized double-blind trial.20 Nonhormonal options that have shown some efficacy for relief of vasomotor symptoms include bellergal,21 clonidine,22 SNRIs23 or their active metabolites such as desvenlafaxine succinate,24 and gabapentin.25,26
They reported that 12 of 15 women noted a decrease in vasomotor symptoms compared with 5 of 14 receiving placebo. However, hypotension, dry mouth, dizziness, constipation, and sedation have limited its use. For many women, low-dose clonidine is ineffective, and thus adequate therapy may require substantially higher doses that may magnify side effects.
Also, the prescription insomnia treatment eszopiclone (Lunesta) significantly improved sleep and positively affected mood, quality of life, next-day functioning, and menopause-related symptoms in a double-blind, placebo-controlled study of perimenopausal and postmenopausal women (Soares, 2006). A list of available sleep aids is found in (Table 1-24).
Normal bone is a dynamic, living tissue that is in a continuous process of destruction and rebuilding. The born turnover allows adaptation to mechanical changes in wgt bearing and other physical activities.
Osteoclast and osteoblast
ADD secondary OP causes table
For any level of PTH there is more calcum removed from bone
Reduce muscle strength (ask pt to get up w/o using arm rest
Dual energy x-ray absorptiometry
There is also the Z-score : average bone mass for a pt with the same age and wright.
Z-score lower than -2.0 require Dx evaluation for secondary osteoporosis
In 2005, Osteoporosis Canada recommended identifying absolute fracture risk by integrating the key risk factors for fracture; namely, age, BMD, prior fracture, and glucocorticoid use.2
articularly if fractures have occurred during antiresorptive therapy or if significant bone loss has occurred despite antiresorptive therapy
AACE ➔ Tx women with T-score - 2.0 w/o risk factor and -1.5 if risk factor
Antiresorptive (anticatabolic) agents inhibit osteoclast activity and reduce bone turnover.4,5 The various agents have different mechanisms of action. Bisphosphonates reduce the rate of bone turnover, providing a longer time for bone to mineralize. Bisphosphonate therapy is thus associated with modest increases in BMD. Estrogen acts through the estrogen receptors on both osteoblasts and osteoclasts, suppressing receptor activator of nuclear factor B ligand (RANKL)-induced osteoclast differentiation and thereby decreasing bone remodeling.6 Raloxifene, a SERM, can bind to estrogen receptors, with tissue-specific agonist or antagonist effects. Raloxifene decreases bone remodel- ling in addition to its extraskeletal effects. Osteoclastic bone resorption is also inhibited by calcitonin acting on calcitonin receptors.
These antiresorptive agents are effective in reducing fracture risk by approximately 30% to 50% in postmenopausal women. However, fractures still occur, and more effective options are desirable, particularly for severe disease states. Anabolic therapy can make major improvements in the quality and quantity of bone and are therefore a welcome addition to the antiresorptive options currently available.
Although it might not be sufficient as the sole means of therapy for osteoporosis, routine supplementation with calcium (1000 mg/d) and vitamin D3 (800 IU/d) is still recommended as a mandatory adjunct to the main pharmacologic agents (antiresorptive and anabolic drugs). Vitamin D in doses of 800 IU daily has been shown to be effective in reducing the risk of falls by 49% over a 12-week period of therapy.9 (Vitamin D supplementation at a dose of 10 000 IU once weekly has been suggested for women unable to take daily supplements of vitamin D in areas where such a preparation is available. Doses of 100 000 IU of vitamin D3 given orally every 4 months have been shown to be effective in reducing the risk of osteoporotic fractures.10
A major advantage of oral bisphosphonate therapy is ease of administration and excellent tolerability. The most com- mon side effects are abdominal pain and dysphagia. How- ever, in the RCTs conducted to date, the incidence rates of upper gastrointestinal side effects of both alendronate and risedronate have been comparable to those of placebo.
Zoledronic acid
Zoledronic acid is the most potent bisphosphonate avail- able.40,41 It contains 2 nitrogen atoms in the R2 side chain. The intravenous administration of 4-mg doses has been approved for the prevention and treatment of metastatic bone disease and hypercalcemia related to malignant dis- ease. Zoledronic acid, 5 mg intravenously on an annual basis, has been approved in Canada for the treatment for Paget’s disease and postmenopausal osteoporosis.
Compared with placebo, zoledronic acid reduced the 3-year risk of vertebral fracture by 70% (RR, 0.30 [95% CI, 0.24 to 0.38]) and the 3-year risk of hip fracture by 41% (HR, 0.59 [95% CI, 0.42 to 0.83]). Increases in BMD were significantly greater and height loss reduced in the group receiving zoledronic acid.
roduced in the thyroid gland, inhibits osteoclastic bone resorption. Its poor oral absorp- tion necessitates either subcutaneous or intranasal adminis- tration. Administration of 200 IU by nasal spray is approved for the treatment of postmenopausal osteoporosis. With this treatment, BMD stabilizes at the lumbar spine and at the hip
RR reduc- tion of 21% (P = 0.05) for vertebral fractures but not for nonvertebral fractures (P = 0.12)
Calcium and vitamin D
Adequate calcium and vitamin D supplementation is key to ensuring prevention of progressive bone loss. For postmenopausal women a total intake of 1500 mg of ele- mental calcium from dietary and supplemental sources and supplementation with 800 IU/d of vitamin D are recommended. Calcium and vitamin D supplementation alone is insufficient to prevent fracture in those with osteoporosis; however, it is an important adjunct to pharmacologic intervention with antiresorptive and anabolic drugs. (1B)
The INTERHEART study, an RCT examining modifiable risk factors across many populations, determined that the main risks for CVD are modifiable and that for women 94% of CVD risk could be attributed to modifiable factors.2 Factors identified in that study as contributing to increased CVD risk included diabetes mellitus (OR, 2.37), hyperten- sion (OR,1.91), abdominal obesity (OR, 1.62), current smoking (OR, 2.87), and psychosocial stress (OR, 2.67). Each of these substantial risks can be reduced through appropriate choices, interventions, or both.
The structural remodelling of the blood vessels includes changes in the lumen, overall diameter, and relative intimal and medial areas of smooth muscle. These changes arise from hypertrophy and hyperplasia of the vascular cells and increased synthesis of the extracellular matrix. Estrogen has both rapid (nongenomic) and longer-term (genomic) effects on the blood vessel wall. Both types of effects are estrogen- receptor-mediated, although only the genomic effects result from alterations in gene expression.4,5 Recently obtained in vitro evidence suggests that a cholesterol metabolite (27-hydroxycholesterol) may compete for the estrogen receptor in blood vessels and negate or neutralize certain receptor-mediated actions of estrogen.6 The development of atherosclerosis and thrombosis is a complex process, now thought to include inflammation within the arterial wall. Oral, but not transdermal, estrogen has been shown to increase the plasma concentration of CRP, a marker of inflammation, which points to the complexity required in any model designed to explain the actions of estrogen on the cardiovascular system.7–9
The HERS secondary prevention trial demonstrated no benefit and an increased risk of early adverse cardiac events in women with known CVD who were randomly assigned to receive CEE and MPA.10 Other research in women with angiographically proven CAD has confirmed that HT fails to delay the progression of disease.11–13
The data on the role of HT for primary prevention of CVD have been the primary reason for the ongoing debate. Whereas data from a variety of sources (epidemiologic stud- ies, observational studies, and clinical trials examining sur- rogate endpoints) suggested a possible cardioprotective role for estrogen,14,15 the WHI cast doubt on the value of HT in this situation. The first publication from the WHI reported that combined estrogen/progestin therapy increased the risk of myocardial infarction and stroke.16 The subsequently published “adjudicated” findings showed no statistically significant overall increase in the incidence of coronary events or death among users of the combination of CEE and MPA (EPT).17 There was, however, a significant eleva- tion in the incidence of cardiovascular events in EPT users compared with women receiving a placebo in the first year of therapy but not thereafter: in year 1 the attributable risk of nonfatal myocardial infarction was 21 per 10 000 woman-years. The estrogen-only arm of the trial demon- strated no evidence of coronary artery benefit or risk, although the authors concluded that “there was a sugges- tion of lower coronary heart disease risk in women aged 50–59 at baseline” (HR, 0.63 [95% CI, 0.36 to 1.08]).18,19 This finding was evident only in a subgroup analysis and therefore should be considered only “hypothesis-generating.” Subsequent subgroup analysis demonstrated a reduction in the total mortality rate in the age group 50 to 59 years (HR, 0.70 [95% CI, 0.51 to 0.96]).20
The data on the role of HT for primary prevention of CVD have been the primary reason for the ongoing debate. Whereas data from a variety of sources (epidemiologic stud- ies, observational studies, and clinical trials examining sur- rogate endpoints) suggested a possible cardioprotective role for estrogen,14,15 the WHI cast doubt on the value of HT in this situation.
The first publication from the WHI reported that combined estrogen/progestin therapy increased the risk of myocardial infarction and stroke.16
The subsequently published “adjudicated” findings showed no statistically significant overall increase in the incidence of coronary events or death among users of the combination of CEE and MPA (EPT).17 There was, however, a significant eleva- tion in the incidence of cardiovascular events in EPT users compared with women receiving a placebo in the first year of therapy but not thereafter: in year 1 the attributable risk of nonfatal myocardial infarction was 21 per 10 000 woman-years.
The estrogen-only arm of the trial demon- strated no evidence of coronary artery benefit or risk, although the authors concluded that “there was a sugges- tion of lower coronary heart disease risk in women aged 50–59 at baseline” (HR, 0.63 [95% CI, 0.36 to 1.08]).18,19 This finding was evident only in a subgroup analysis and therefore should be considered only “hypothesis-generating.” Subsequent subgroup analysis demonstrated a reduction in the total mortality rate in the age group 50 to 59 years (HR, 0.70 [95% CI, 0.51 to 0.96]).20
However, while acknowledging the potential for bias in observational studies, many within the scientific commu- nity point out that there are still not RCT data available that refute the preponderance of experimental and clinical trial data suggesting cardioprotective benefits for HT when started early in postmenopausal women.
Conclusions about the role of HT for primary cardioprevention based on the WHI findings have been challenged because of the greater ages of the participants and the time since loss of ovarian estrogen production (an average of 13 years).23 Time since menopause has been shown to correlate with extent of subclinical atherosclerosis as determined by carotid IMT in populations of women with natural and surgical menopause.24 WHI subsamples were weighted heavily in favour of the inclusion of minority women to strengthen the study of intervention effects on certain intermediate effects, and many of the modifiable risks for CVD identified in the INTERHEART study were present in such women. With close to 70% of women in the WHI over the age of 60 years at enrolment, it seems likely that a substantial proportion of the WHI population would have had subclinical CVD.
The early increase in the incidence of cardiac events reported in the EPT arm of the WHI, with no overall difference in the cardiovascular mor-tality rate, is similar to the effect of HT started in older women in the HERS secondary prevention trial.10 In the EPT arm of the WHI trial the RR for CAD was 1.68 in the first 2 years after the start of HT, 1.25 in years 2 to 5, and 0.66 beyond 5 years.
Lobo et al25 looked elsewhere for data on immediate cardio- vascular risks of HT when started in newly menopausal women. Using data from 2 pivotal clinical trials in which all adverse events were recorded for 4065 young, healthy postmenopausal women started on HT, these investigators found no increase in the incidence of either myocardial infarction or stroke in the year after initiation of therapy. These women were not followed for long enough to deter- mine whether there might be longer-term benefit or risk.
A “critical-window” or “critical-timing” hypothesis was subsequently advanced as a way to try to explain how the use of HT at the onset of menopause could be cardioprotective whereas later initiation could cause adverse coronary events as seen in the WHI.26–29 This theory suggests that the prothrombotic or plaque-destabilizing effects of HT in women with established CAD may account for an initial increase in the incidence of coronary artery events in older women but that the healthy coronary arteries of younger women benefit from the anti-atherogenic effects of estrogen. Recently a contributory mechanism for this dichotomous effect of HT has been postulated with the discovery that 27-hydroxycholesterol, an abundant cholesterol metabolite found in atherosclerotic lesions, acts as a competitive antagonist of estrogen receptor action in the vasculature. According to this theory, 27-hydroxycholesterol accumulations in atherosclerotic lesions might account for the loss of estrogen protection from vascular disease in older women.6
To further explore the critical-timing hypothesis, Salpeter et al30 performed a meta-analysis of 23 RCTs with 39 049 women followed for 191 340 woman-years to assess the effect of HT for at least 6 months on the incidence of CHD events including myocardial infarction and death in younger and older postmenopausal women. They found that HT significantly reduced the incidence of CHD events when initiated in younger (OR, 0.68 [95% CI, 0.48 to 0.96]) but not older (OR, 1.03 [95% CI, 0.91 t01.16]) menopausal women.
In another meta-analysis of RCTs, Salpeter et al31 examined the effects of HT on mortality in 30 trials and 26 708 women. They found an overall OR for total mortality asso- ciated with HT of 0.98 (95% CI, 0.87 to 1.12). Hormone replacement reduced the mortality rate in the younger group (OR, 0.61 [95% CI, 0.39 to 0.95]) but not in the older group (OR, 1.03 [95% CI, 0.90 to 1.18]).
is of 23 RCTs with 39 049 women followed for 191 340 woman-years to assess the effect of HT for at least 6 months on the incidence of CHD events including myocardial infarction and death in younger and older postmenopausal women. They found that HT significantly reduced the incidence of CHD events when initiated in younger (OR, 0.68 [95% CI, 0.48 to 0.96]) but not older (OR, 1.03 [95% CI, 0.91 t01.16]) menopausal women. The authors concluded that the reduced cardiac event rate for younger women seen in this meta-analysis of RCTs paralleled that seen in the observational Nurses’ Health Study, which followed a cohort of 120 000 women below the age of 55 years. After adjustment for potential confounding variables, such as age, cardiovascular risk fac- tors, and socioeconomic status, HT use was found to be associated with a 40% reduction in the incidence of CHD events.14 Similarly, the findings in older women paralleled those of the HERS10 and WHI16 trials, in which initiation of HT in older women was associated with an increase in the incidence of adverse CHD events in the first year only.
NURSES HEALTH STUDY : ↓ incidence CHD for both ARMS E and EPT
Rossouw et al20 performed a secondary analysis of the WHI data to determine the impact of years since menopause and age at the time of HT initiation on cardiovascular outcomes. The HR for adverse cardiovascular outcomes was 0.76 in women starting HT less than 10 years after menopause, 1.10 for women starting 10 to 20 years since menopause, and 1.28 for women starting more than 20 years after meno- pause (P for trend, 0.02). The HR for total mortality among the women aged 50 to 59 years who were randomly assigned to HT was significantly reduced, at 0.76 (95% CI, 0.51 to 0.96). In their concluding remarks the authors stated: “We did not identify any subgroup with reduced risk of CHD, although total mortality was reduced among women aged 50 to 59 years. The absence of excess absolute risk of CHD and the suggestion of reduced total mortality in younger women offers some reassurance that hormones remain a reasonable option for the short-term treatment of menopausal symptoms.”
oth arms of the WHI reported an increased risk of ischemic stroke across all age groups (HR, 1.44 [95% CI, 1.09 to 1.90] for the EPT trial and 1.55 [95% CI, 1.19 to 2.01] for the estrogen arm).56 In the estrogen arm the stroke risk appeared to be lower in women aged 50 to 59 years (HR, 1.09) than in women 60 to 69 years (HR, 1.72) or 70 to 79 years (HR, 1.52), but because of the small numbers in the youngest subgroup definitive conclusions could not be reached. In the EPT arm the HR was actually greatest in the youngest group. The increased risk of stroke was restricted to the ischemic variety. Among the various racial and ethnic groups, black women had the highest risk of stroke (HR, 2.52 [CI, 1.05 to 6.08]). In the WISDOM trial58 there was no excess incidence of cerebrovascular accidents among 2196 women randomly assigned to EPT compared with 2189 randomly assigned to placebo therapy, with an average of 1 year of follow-up. A meta-analysis of RCTs performed before the WISDOM trial found an HR of 1.30 (95% CI, 1.13 to 1.47) for total stroke.59
It is important to note that the absolute level of risk of ischemic stroke due to HT in younger menopausal women is low. The additional risk conferred by the use of HT was
S14 JANUARY JOGC JANVIER 2009
CHAPTER 3: Cardiovascular Disease
found to be 8/10 000 woman-years in the EPT arm of the WHI56 and 13/10 000 woman-years in the estrogen arm.60
Clearly risk factors for stroke should be addressed in all menopausal women and particularly in those seeking HT for distressing vasomotor symptoms. There is no evidence that HT has any role in the treatment or the primary or secondary prevention of stroke.
A meta-analysis of 107 trials examining components of the metabolic syndrome concluded that HT reduced abdomi- nal obesity, insulin resistance, new-onset diabetes, lipid lev- els, and blood pressure in women without diabetes and reduced insulin resistance and fasting glucose levels in women with diabetes.6
Oral HT results in an increased risk of venous thromboembolism that is greatest in the first few years after the start of therapy. In the WHI the HR was 4.0 in year 1 and fell to 1.04 by year 6.64,65 Analysis of the WHI data confirmed other factors that contribute to the risk of venous thromboembolism. Compared with women aged 50 to 59 years, those aged 60 to 69 years had a doubling of risk (HR, 2.03; 95% CI, 1.43 to 2.88), and those aged 70 to 79 years had an almost 4-fold increase in risk (HR, 3.72; 95% CI, 2.57 to 5.36). Being overweight doubled the risk (HR, 1.96; 95% CI, 1.33 to 2.88), and obesity tripled it (HR, 3.09; 95% CI, 2.13 to 4.49). Although the highest risks were in women who were carriers of the Leiden factor V gene defect, screening is not recommended for this condition on the basis of low cost-effectiveness. Calculations suggest that screening of 795 women would be required to prevent 1 episode of venous thromboembolism in 5 years.66
The greatest risk factor for venous thromboembolism is advancing age: a large population study revealed that the absolute incidence is 2 to 3/10 000 for women aged 50 to 54 years and increases to 20 to 30/10 000 at age 80.67 In the EPT arm of the WHI the absolute incidence of venous thromboembolism among hormone users was 8/10 000 for those aged 50 to 59 years and of normal weight; in compari- son, the incidence was 89/10 000 woman-years among obese women aged 70 to 79 years.64 The incidence in the placebo users in the estrogen arm of the WHI was higher than the incidence in placebo users in the EPT arm. The investigators attributed this difference to greater age and more obesity in the population under study. The overall risk was lower with estrogen therapy alone (HR, 1.32 [95% CI, 0.99 to 1.75]) than with EPT (HR, 2.06 [95% CI, 1.57 to 2.70]). The risk attributable to HT was not synergistic with the other risk factors of obesity or advancing age.65
The Estrogen and Thromboembolism Risk (ESTHER) Study, a multicentre case–control evaluation of the risk of thromboembolism in postmenopausal estrogen users, reported more risk associated with oral than with trans- dermal estrogen therapy.68 Differences in lipid and coagula- tion responses to oral and transdermal routes have led to the suggestion that the route of HT might be selected on the basis of individual risk profiles.6
Oral HT results in an increased risk of venous thromboembolism that is greatest in the first few years after the start of therapy. In the WHI the HR was 4.0 in year 1 and fell to 1.04 by year 6.64,65 Analysis of the WHI data confirmed other factors that contribute to the risk of venous thromboembolism. Compared with women aged 50 to 59 years, those aged 60 to 69 years had a doubling of risk (HR, 2.03; 95% CI, 1.43 to 2.88), and those aged 70 to 79 years had an almost 4-fold increase in risk (HR, 3.72; 95% CI, 2.57 to 5.36). Being overweight doubled the risk (HR, 1.96; 95% CI, 1.33 to 2.88), and obesity tripled it (HR, 3.09; 95% CI, 2.13 to 4.49). Although the highest risks were in women who were carriers of the Leiden factor V gene defect, screening is not recommended for this condition on the basis of low cost-effectiveness. Calculations suggest that screening of 795 women would be required to prevent 1 episode of venous thromboembolism in 5 years.66
The greatest risk factor for venous thromboembolism is advancing age: a large population study revealed that the absolute incidence is 2 to 3/10 000 for women aged 50 to 54 years and increases to 20 to 30/10 000 at age 80.67 In the EPT arm of the WHI the absolute incidence of venous thromboembolism among hormone users was 8/10 000 for those aged 50 to 59 years and of normal weight; in comparison, the incidence was 89/10 000 woman-years among obese women aged 70 to 79 years.64 The incidence in the placebo users in the estrogen arm of the WHI was higher than the incidence in placebo users in the EPT arm. The investigators attributed this difference to greater age and more obesity in the population under study. The overall risk was lower with estrogen therapy alone (HR, 1.32 [95% CI, 0.99 to 1.75]) than with EPT (HR, 2.06 [95% CI, 1.57 to 2.70]). The risk attributable to HT was not synergistic with the other risk factors of obesity or advancing age.65
The Estrogen and Thromboembolism Risk (ESTHER) Study, a multicentre case–control evaluation of the risk of thromboembolism in postmenopausal estrogen users, reported more risk associated with oral than with trans- dermal estrogen therapy.68 Differences in lipid and coagula- tion responses to oral and transdermal routes have led to the suggestion that the route of HT might be selected on the basis of individual risk profiles.6
Ring (2mg estradiol) x 90d
tab 10 mcg PV daily x 2 w then twice a week
Since the report about risks associated with HT from the WHI in 2002, many physicians have abandoned the pre- scription of HT for vasomotor symptoms in favour of rec- ommending lifestyle changes and cooling devices that can be purchased through the Internet. Unfortunately, many women find that these approaches afford little relief and have turned to unproven and often untested complemen- tary and alternative therapies.
Herbal remedies have become a multi-billion-dollar busi- ness in North America,6 yet few of those promoted for vasomotor symptoms have met the rigorous testing criteria required of pharmaceutical products by the US Food and Drug Administration. The current regulatory requirement for pharmaceutical products with purported benefit for hotflashes is that participants in clinical trials must experience on average 7 hot flashes per day or 50 per week. Most reported studies of herbal products have been open label and conducted in women with as few as 1 or 2 hot flashes per day.
Recent reports caution about potential adverse safety pro- files of marketed herbal products, and cautions have appeared about interactions of natural health products (NHPs) with pharmaceutical and anesthetic agents.7–9 New Canadian legislation in January 2004 removed NHPs from the food category and placed them into a special drug cate- gory to allow regulation of manufacturing, labelling, and indications for use.10 To date, little appears to have been accomplished in the regulation of NHPs in Canada.
Several recent systematic reviews have examined options for treatment of moderate to severe vasomotor symp- toms.11–16 None of these found any single complementary therapy to have proven efficacy for moderate to severe hot flashes, and the most recent review15 concluded by stating that “although individual trials suggest benefits from certain therapies, data are insufficient to support the effectiveness of any complementary and alternative therapy in this review for the management of menopausal symptoms.” A direct head-to-head comparison of HT versus black cohosh, soy, or multibotanicals showed only the HT to have an effect greater than that of placebo.17
Although women with prior hormone use enrolled in the WHI showed an increase in risk after 3 years of EPT, women who had not used HT before enrolment showed no increase in the risk of breast cancer during the 5 years of the study.
Many other factors modify breast cancer risk to a similar or greater extent. For example, early menarche, late meno- pause, postmenopausal obesity, and certain lifestyle choices such as delaying first pregnancy until after age 30, choosing not to breastfeed, failing to exercise regularly, and consum- ing excessive amounts of alcohol all carry similar risks, with HRs around 1.3.9 Accumulating evidence suggests that shift work resulting in light exposure at night may be another lifestyle factor that increases breast cancer risk.10 Although these risks are statistically significant, clinically significant RRs in epidemiologic terms are generally considered those that are greater than 3. Major risk factors for breast cancer have risk estimates that range from 3 for some instances of positive family history to 5 for women with past breast biopsy findings of atypia and to 200 for premenopausal women with a mutation in a BRCA gene.9 A recent compre- hensive analysis of breast cancer articles in the media found that news articles were much more likely to focus narrowly on pharmaceutical products, such as hormones, with little if any coverage of other equally important risk factors or pre- ventive strategies related to lifestyle.11
Major risk factors for breast cancer have risk estimates that range from 3 for some instances of positive family history to 5 for women with past breast biopsy findings of atypia and to 200 for premenopausal women with a mutation in a BRCA gene.9 A recent compre- hensive analysis of breast cancer articles in the media found that news articles were much more likely to focus narrowly on pharmaceutical products, such as hormones, with little if any coverage of other equally important risk factors or pre- ventive strategies related to lifestyle.11
The estrogen-only arm of the WHI did not show an increased risk of breast cancer; in fact, there was a nonsignificant decrease in the risk of breast cancer among women using estrogen alone for the 7.2 years (HR, 0.82 [95% CI, 0.65 to 1.04]). Many of the women in the estrogen-only arm were overweight: 45% had a BMI greater than 30, and 36% had a BMI between 25 and 30. The facts that obese women have an increased risk of breast cancer and show little added risk when exposed to exogenous HT4,12 might account, in part, for the fact that no increase in breast cancer risk was observed in this population.
Harvard Women’s Health Study and reported that consistent current users of conjugated estrogen com- pared with “never users” showed no significant increase in breast cancer risk after a mean of 10 years of follow-up (HR, 1.13 [95% CI, 0.77 to 1.64]). Similarly, Li et al,15 in a population-based case–control study, found no increase in the risk of breast cancer in women who had used unop- posed estrogen for up to 25 years.
Two meta-analyses subsequent to the WHI, looking at both cohort and controlled trial data, have provided strong statis- tical evidence that EPT carries a statistically significant risk for breast cancer that is greater than the risk attributable to estrogen therapy alone.2
The Million Women Study recruited 1 084 110 women between 1996 and 2001 from those invited by the British National Health Service Breast Screening Programme to have screening mammography every 3 years; about half had ever used postmenopausal HT.26 The study data were recorded from questionnaires returned before mammogra- phy, and the women were followed to determine cancer incidence and death rates. The study is noteworthy for its large numbers and adjustments for the well-recognized fac- tors associated with risk of breast cancer. Data on breast cancer were analyzed for 828 923 women. No increase in risk of breast cancer was found in past users of any hor- mone preparation, regardless of time since discontinua- tion, from less than 5 years to 10 or more years, and regardless of duration of use. Current HT use was reported to increase the RR of incident breast cancer in estrogen- only users to 1.3 and in EPT users to 2.0. The finding of a greater risk with EPT than with estrogen alone is consistent with the WHI findings.
The most surprising findings in the Million Women Study were the timelines reported from HT initiation until breast cancer detection and death from breast cancer: a mean of 1.2 years from recruitment to diagnosis and 2.4 years from recruitment to death.26 An understanding of tumour growth rates based on the concept of tumour doubling time suggests that for a breast cancer each doubling would take 50 to 100 days27 and that 30 to 35 doublings are required for a tumour size of 1 cm.28 In other words, 5 to 10 years is required for a cancerous breast cell to grow to a tumour of detectable size. Both the collaborative reanalysis4 and the WHI5 detected no increase in the risk of breast cancer with HT for less than 5 years. The unusually rapid appearance of tumours attributed to HT and other methodologic issues in data collection and analysis in the Million Women Study have led some epidemiologists to question this study’s conclusions.29–31
Although estrogen and progesterone have been targeted as responsible for breast cancer, there is in fact considerable debate as to whether the apparent associations between HT and breast cancer are due to the facilitated detection of pre-existing small carcinomas because of more rapid growth under HT stimulation or to de novo development of malignant breast tumours brought about by an increased frequency of initiating mutations.2
out by an increased frequency of initiating mutations.29 There is no question that estrogen and progesterone have a role in the cell divi- sion and replication that lead to the development of mature breast tissue.
Progestins are currently class-labelled according to their effect on the endometrium. There are considerable differ- ences between progestins. Although many studies have been unable to distinguish between the progestins used, often because of relatively low numbers of users of prod- ucts other than MPA, the E3N cohort study in France,52 following 80 377 women for 12 years, found that risk varied between the progestins used. The incidence of breast cancer was not increased in users of estrogen and progesterone (OR, 1.00 [95% CI, 0.83to 1.22]) but was increased in users of estrogen with a variety of other progestogens (OR, 1.69 [95% CI, 1.50 to 1.91]).
In a study designed to address the safety of HT in women with a positive family history, the use of hormones was found not to be associated with an increase in the overall risk of breast cancer, yet was associated with a reduced overall mortality rate.76 Similar conclusions were drawn from the collaborative reanalysis.4 This is hardly surprising, since the influence of genetic factors is so large that it gener- ally overshadows any small potential increment resulting from lifestyle or hormonal exposure.
HORMONE THERAPY IN BREAST CANCER SURVIVORS WITH VASOMOTOR SYMPTOMS
Raloxifene has been approved in the United States for both the treatment and the prevention of osteoporosis. In the pivotal osteoporosis prevention trial MORE, women assigned to raloxifene rather than to placebo demonstrated a 72% reduction in the incidence rate of invasive breast cancer at 4 years.82 The MORE trial was not designed to measure the reduction in breast cancer incidence in women at increased risk, so in 1999 the National Surgical Adjuvant Breast and Bowel Project initiated the STAR trial. In this study, postmenopausal women aged at least 35 years and at increased risk for breast cancer were randomly assigned to either tamoxifen or raloxifene for 5 years and were required to complete follow-up examinations for at least 7 years. The STAR trial found that raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer and was associated with a lower risk of thromboembolic events and cataracts but a higher, though not statistically signifi- cant, risk of noninvasive breast cancer.83 The risk of other cancers, fractures, ischemic heart disease, and stroke was similar for the 2 drugs.22 Raloxifene has now been approved in the United States for use in preventing breast cancer in women at high risk.
Thus, compounded hormones cannot be assumed to be safer than conventional pharmaceutical estrogen or progestins. Importantly, adequate endometrial protection is needed if compounded estrogens are prescribed (Pinkerton, 2009).