Menopause

=Objectives= These objectives are purely student created.

Definitions
Natural/Spontaneous menopause: Final menstrual period (FNP), confirmed after 12 consecutive months of amennorhea with no obvious pathologic cause.

Induced menopause: Permanent cessation of menstruation after bilateral oophorectomy or iatrogenic ablation of ovarian function.

Perimenopause/menopause transition: Span of time when menstrual cycle and endocrine changes occur a few years before and 12 months after FMP resulting from natural menopause.

Premature menopause: Menopause reached before age 40, whether natural or induced.

Premature ovarian insufficiency: Ovarian insufficiency experienced under age 40, leading to permanent or transient amenorrhea.

Early menopause: Natural or induced menopause that occurs well before the average age of natural menopause (51yrs), less than age 45

Early postmenopause: The time period within 5 years after the FMP resulting from natural or induced menopause.

Define the process of menopause
The transition from normal menstrual cycles to menopause is known as perimenopause, in which there is a decline in oocyte quality and number. Symptoms include variation in menstrual cycles (usually prolongation of cycles), changes in quality of bleeding (heavier or lighter than usual), and chaotic hormone production. The onset of these changes up until 12 months after the last menstrual period is regarded as perimenopause, which is 4 years on average. She emphasized that it is a clinical diagnosis and that there are no reliable tests to determine perimenopause.

The granulosa cell product inhibin‐B decreases over time, which removes the suppression of FSH. FSH elevation triggers accelerated follicular development which increases estrogen levels, but this is only temporary. Eventually, FSH levels continue to rise without the corresponding rise in estrogen release from granulosa cells. A persistent FSH level > 20 is diagnostic of menopause, which occurs at an average of 51 and is a natural consequence of aging. Menopause is defined as no menstrual periods for one year as a result of follicular depletion or “surgical menopause” with the removal of the ovaries.

Discuss the physiologic changes associated with menopause
During menopause, there is a depletion of ovarian granulosa cells and eventually a decline in estrogen levels, which releases another negative feedback regulator on FSH, allowing it to rise. LH will rise too, with no more surges. Obese women who have substantial adipose tissue will have corresponding longer lasting estrone production however. Although controversial, menopause is also associated with a decline in androgen production, as women with bilateral oophorectomy have lower levels of androstenedione and testosterone. Since estrogen had several functions, the loss of estrogen causes a cascade of physiologic effects.

Recall the various functions of estrogen, which we’ve seen so many times throughout this course: • growth of follicle • endometrial proliferation, myometrial excitability • genitalia development • stromal breast tissue development • female fat distribution • hepatic synthesis of transport proteins • feedback inhibition of FSH • LH surge (estrogen feedback on LH secretion switches to positive from negative just before LH surge)

Hot flashes and night sweats (both vasomotor symptoms) occur early in estrogen deficiency, but the exact physiologic mechanism is unknown. Lack of estrogen causes several health risks, including osteoporosis because there is insufficient estrogen to bind the estrogen receptor which would reduce osteoclast activity and may also suppress cytokines that promote bone resorption (IL-­‐1, TNF-­‐a, IL-­‐6). This decrease in bone mineral density is rapid at 3% per year for the first five years, and 1-­‐2% per year beyond. Loss of trabecular bone (spine) and cortical bone (femoral neck) is associated with an increased risk of fracture, which is also dependent on other variables such as family history, genetics, nutrition, and exercise.

Urogenital (vaginal) atrophy occurs because without estrogen, parabasal cells increase, superficial cells decrease, and the vaginal pH increases. Tissues are more fragile, susceptible to trauma and infection, and there is increased risk of dyspareunia and risk of stress incontinence. SERMs like tamoxifene and raloxifene have anti-­‐ estrogen effects at the level of the vagina, so do not improve symptoms of vaginal atrophy.

Menopause doesn’t cause depression, but it is more likely to reappear in women who have a history of depression (i.e. post-­‐partum depression). It isn’t known whether a change of libido is due to physiologic mechanisms, or outside influences because many life stressors are also occurring during this time. However, the decline in estrogen certainly is associated with vaginal tissue thinning which can cause pain during intercourse or even on speculum insertion for pap smears. Other symptoms include breast tenderness, bloating (some women have these symptoms when estrogen is present, others have them when estrogen is absent), worsening of pre-­‐existing medical problems (migraines, diabetes), and skin dryness.

Discuss the potential long-­term complications of menopause
In short, think about: hot flashes, vaginal atrophy, osteoporosis, and coronary heart disease. Please refer to question 2 and 5, for a more complete summary. Cardiovascular effects are unclear, although our current understanding suggests that estrogen has no benefit in either primary or secondary prevention of heart disease, but rather, it increases the risk for women who have established disease. On the other hand, the Framingham Study suggested that estrogen has cardioprotective effects since the post-­‐ menopausal women had four-­‐fold more cardiovascular disease than age controlled perimenopausal women. This may be due to favorable changes in lipids and lipoproteins, coagulations changes, vessel effects, and other metabolic effects. Some of the confusion about the use of estrogen stems from the WHI and HERS trial, explained below.

What is hormone therapy used for?

 * Treatment of moderate to severe vasomotor symptoms (hot flashes, night sweats) is the primary indication
 * Proven to reduce postmenopausal osteoporosis-related fractures
 * Approved for this
 * Optimal time is early years after menopause
 * It is the most effective therapy for moderate to severe vaginal and vulvar atrophy, often used as local application
 * Treatment of moderate to severe vaginal atrophy can relieve dyspareunia (painful sexual intercourse)
 * One systemic ET approved for this
 * Not recommended as sole treatment of other sexual problems (libido, etc.)
 * Reduced new diabetes mellitus onset
 * Inadequate evidence though to suggest as sole or primary prevention
 * ET may benefit some women with urge incontinence who have vaginal atrophy
 * Unclear if effective for overactive bladder
 * Controversial if can help stress incontinence
 * May reduce mortality in women who start before age 30
 * Local therapy may reduce risk of recurrent UTI, but none approved for this indication
 * May reduce CHD risk when initiated in younger and more recently postmenopausal women
 * Short term use may increases CHD risk in women farther from menopause at time of initiation
 * Long term use associated with less coronary artery calcium
 * Not currently recommended as sole or primary indication for prevention of CHD in women of any age
 * Not shown to affect BMI and weight gain
 * Can improve health related quality of life through mood elevation and decreased menopause symptoms, but not indicated for this

Hormone Therapy Risks/Adverse Effects

 * Both ET and EPT appear to increase ischemic stroke
 * Has no effect on hemorrhagic stroke in postmenopausal women
 * Oral ET increases VTE risk in postmenopausal women
 * Unopposed estrogen associated with increased risk of endometrial cancer related to dose and duration of use
 * Adequate concommitant progresterone therapy suggested for women with intact uterus
 * Note recommended if endometrial cancer history
 * Breast cancer risk increases with EPT use beyond 3-5 years
 * Viewed as "rare"
 * Basically, this is a problematic and uncertain area
 * Data on HT and ovarian cancer are conflicting
 * May promote growth of existing lung cancer
 * Does not decrease dementia, and may contribute to it in some studies


 * Risk emerges soon after initiation
 * Risks fall into the "rare" category

Discuss the risks and benefits of hormone replacement therapy for menopause
Unfortunately, data isn’t consistent. The Women’s Health Initiative (WHI) assessed the absolute and relative risks/benefits of HRT, and found an increase in heart attacks, strokes, breast cancer, and venous thrombotic events and a decrease in colorectal cancer and hip fractures for those on HRT. The cohort was older (average age of 63). The WHI didn’t evaluate for symptomatic relief (hot flashes, night sweats, decreasing bone mineral densities), which is the reason most women take HRT. According to the HERS trial, estrogen replacement causes increased risk of cardiovascular events in the first year of treatment, but no difference overall during the four year follow up period. This may have been due to the older cohort of women (average was 67 years) who had significant cardiovascular disease. Main message from the evaluation of data was that HRT does not have a huge increase in absolute risk of these pathologies, but an increase is nonetheless present. Don’t give HRT therapy (estrogen plus MPA) to older women with pre-­‐existing cardiovascular disease, and instead consult with them other methods of CVD prevention (-­‐lifestyle changes, cholesterol and BP lowering drugs).

Hormone replacement therapy consists an estrogen and a progestin, because unopposed estrogen causes endometrial hyperplasia and the risk of cancer. Both medroxyprogesterone acetate (MPA) and 19-­‐nortestosterone derivatives can markedly reduce these risks. The estrogen only arm of the WHI had a decrease in hip fractures, no decrease in coronary heart disease, no increase in breast cancer (or colon cancer), and an increase risk in stroke. This doesn’t imply that progesterone is responsible for the increased relative risk of breast cancer, however, just that there may be still a lot we don’t know. Despite the potential increased risk of breast cancer with HRT, breast cancer mortality has not been shown to increase. In fact, women with breast cancer are more likely to have well differentiated, localized and early disease if they are taking estrogen at the time of the diagnosis. Definitive conclusions about the relationship with HRT and breast cancer remain controversial.

Pretreatment Evaluation

 * Comprehensive history and physical evaluation essential
 * Mammography within the 12 months before HT initiation
 * Other special exams on a case-by-case basis

Discuss alternatives to hormone replacement therapy
Nonpharmacologic management includes decreasing saturated fat, caffeine and alcohol which increases frequency of hot flashes. Weight has an insulation effect, so women may also feel warmer even though those with more adipose tissue have more residual estrogen. Smoking increases the risk of hot flashes as well as their severity, so smoking cessation would help. Supplements of calcium and vitamin D are recommended to combat osteoporosis.

Alternative treatments have little proven benefits, but patients will be taking them. Soy isoflavones are phytoestrogens, along with black cohosh, red clover, can help with some hot flashes. Black cohosh is largely used in Europe, but it doesn’t have established safety and has been reported to cause liver failure necessitating liver transplant. There are other adverse effects of these alternative treatments: dong quai (increased bleeding when taken with warfarin), ginseng (post-­‐menopausal bleeding), licorice (hypokalemia)… Go to the NCCAM website for more info: http://nccam.nih.gov/

Since HRT is not recommended to prevent heart disease, patients should try to lower their lipid profiles and some need the help of statin drugs. Statins are useful in primary and secondary prevention of cardiovascular events. Of the pharmacologic management of osteoporosis, which we’ll be discussing more in tomorrow’s lecture, she mentioned bisphosphonates (i.e. alendronate) which has some GI side effects and also calcitonin, which only has little effect in increasing bone mineral density.

SERMs (selective estrogen receptor modulators) are so named because they possess tissue-­‐selective estrogen agonist and antagonist properties.

Tamoxifen has antiestrogen effect in breast tissue but pro-­‐estrogen effects on the uterus, so it can increase risk of endometrial disease. It has variable agonist effects in bone and liver, but is antagonistic in vagina and certain brain regions. It may be somewhat protective against osteoporosis, but is associated with an increased risk of venous thrombosis and does not control hot flashes. One of its main uses is to reduce the risk of recurrence or death among women with ER-­‐positive breast cancer, when given as adjuvant therapy. It can also provide palliation for those with metastatic disease. Tamoxifene is also used as prevention of breast cancer in those at high risk. Raloxifene is helpful in menopausal women to prevent or treat osteoporosis, as it has been shown to reduce fractures. (Recommended to try alendronate first.) Although raloxifene lowers LDL and TG’s, it does not increase HDL and has not yet shown to reduce coronary heart disease. It doesn’t reduce hot flashes nor is it beneficial for vaginal atrophy. It also has an increased risk of VTE as does with tamoxifen, but raloxifene does not increase risk of endometrial disease.