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A. Normal Ovarian Function

  1. Normally, women are born with ~2 million oocytes
  2. Oocytes are lost through normal cycling with very few left by age 50 [2]
    1. Age at menses primarily determined by genetic factors (45-90%)
    2. Accelerated atresia of oocytes begins by age 37.5 years
    3. Median age of menopause 51.2 years (range 45-55)
  3. Definitions
    1. Menopause is cessation of menses due to loss of ovarian follicular function
    2. Perimenopause is a period of changing ovarian function, precedes final menses 2-8 years
    3. Postmenopausal period occurs after the last menses
    4. Clinical definition of menopause is absence of menses for 12 months
  4. The loss of oocytes leads to:
    1. Lost maturing follicles, which leads to:
    2. Decreased estradiol and inhibin secretion
    3. Ovaries normally produce >90% of all estrogens
    4. Gradual reduction in androgen levels
    5. Ovaries normally produce 25% of circulating testosterone, 60% of androstenedione
    6. Also normally produce about 20% of dehydroepiandrosterone (DHEA)
  5. Normally, estrogen produced by the ovary inhibits hypothalamic GnRH production [8]
    1. This feedback inhibition is lost at menopause
    2. Lack of inhibition at hypothalamus leads to increase in GnRH and pituitary hormones
    3. Both Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels increase
    4. Loss of LH surge is present in about 65% of women undergoing menopause
  6. Therefore, menopause can be diagnosed by changes in circulating hormone levels [8]
    1. These include increased FSH and LH and variable estradiol levels
    2. Oligomenorrhea then amenorrhea occurs in perimenopausal to postmenopausal transition
    3. About 30% women have very low estradiol levels in menopause
    4. About 65% of women have loss of LH surge in menopause
    5. Hypothalamic-pituitary insensitivity to estradiol appears to be most common mechanism
    6. Ovarian failure (lack of luteinization, lack of progesterone production) is always present
  7. In some situations, menopause is accelerated and/or with early onset
    1. Decreased number of ova at birth
    2. Ovarian failure = secondary amenorrhea with increased FSH occurring prior to age 50
    3. Anti-estrogens: tamoxifen (for breast carcinoma), raloxifene (osteoporosis)
  8. Menopausal Changes
    1. Most symptoms and signs of menopause are due to estrogen deficiency
    2. Androgen levels are reduced as well, with possible undesirable consequences
    3. Most menopause (~95%) occurs between ages of 40 and 55
    4. About 1% of women <40 years old will enter menopause
    5. About 5% of women enter menopause after age 55
    6. Perimenopausal hot flashes are associated primarily with reduced estrogen levels [8]

B. Functions of Key Hormones

  1. Estrogens
    1. Normal maturation of oocytes
    2. Normal maturation and function of certain uterine cells
    3. Inhibition of osteoclast function: net result is mainenance of bone mineral density (BMD)
    4. Reduction in LDL and increase in HDL cholesterol levels
    5. Increases in triglycerides
    6. Direct beneficial cardiac effects, possibly inotropic activity and vasodilation
    7. Possible maintenance of hypothalamic endogenous opioid production (see below)
    8. Mental functioning, including problem-solving abilities [16]
  2. Progestins
    1. Establishment and maintenance of normal endometrial cycling
    2. Little effect on cholesterol types or levels
  3. Androgens
    1. Include testosterone and its weakly active precursors DHEA, DHEA-sulfate
    2. Some positive effects on bone mass (reduction in calcium excretion)
    3. Possible detrimental effects on lipid (cholesterol) metaboism
    4. May increase insulin secretion, possibly with insulin resistance
    5. May play a role in enhancing stromal proliferation in breast cancer
    6. Supraphysiologic androgen treatment can enhance sexual arousal and libido
    7. Maintenance of normal urogenital physiology
    8. Hirsutism and acne can occur with androgen excess
  4. Menopause Transition
    1. Period which occurs several years before menopause
    2. Serum levels of FSH increase
    3. Ovarian follicles mature abnormally

C. Symptoms of Menopause [29]

  1. Early
    1. Hot flashes, sweating
    2. Insomnia / other sleep disturbances
    3. Menstrual irregularity
    4. Psychological symptoms
    5. Vaginal dryness
  2. Intermediate
    1. Vaginal dryness / atrophy can cause dyspareunia
    2. Reduced sexual arousal, focus [34]
    3. Urge / Stress Incontinence or other urinary complaints [1]
    4. Skin atrophy
    5. Breast atrophy
  3. Later
    1. Osteoporosis
    2. Accelerated Atherosclerosis
  4. Osteoporosis
    1. Mainly trabecular bone loss
    2. Estrogen lowers Osteoclast and raises Osteoblast Activities
  5. Atherosclerosis (Coronary Artery Disease)
    1. Estrogen increases HDL and decreases LDL
    2. Estrogen also has similarity to digitalis and may have inotropic properties
  6. Physical activity reduces risk for death in post-menopausal women

D. Diagnosis

  1. Careful history for symptoms consistent with menopause
    1. Hot flashes
    2. Night sweats
    3. Vaginal dryness
    4. Self-assessment is not a reliable indicator
  2. Age is the most reliable risk factor for perimenopause
  3. Clinical definition of menopause is absence of menses for 12 months
  4. Increased levels of FSH and/or Inhibin B levels
    1. FSH levels >40 IU/L are highly specific but not sensitive
    2. FSH levels >23 IU/L are ~65% sensitive and 79% specific
    3. Inhibin B <30ng/L is ~46% sensitive and 78% specific
    4. Determination of LH levels are not necessary
    5. Determining FSH levels is not necessary, but can be confirmatory
  5. Pregnancy should be ruled out in sexually active women with short term amenorrhea
  6. Evaluation for secondary amenorrhea in women <40 years old

E. Hot Flashes (Hot Flushes) [17,22]

  1. Definition
    1. Sensation of warmth, usually with skin flushing and perspiration
    2. Chills may follow as core body temperature drops
    3. Over 50% of women have hot flashes in 2 years surrounding final menses
    4. Believed due to vasomotor instability (abnormal transient vasodilation)
  2. Etiology
    1. Appears to be related to endogenous opioid production in hypothalamus and brain stem
    2. Norepinephrine and serotonin both play a regulatory role as well
    3. Estrogen may maintain relatively high levels of endogenous opioid production
    4. Opioids depress noradrenergic activity locally in the brain
    5. Loss of estrogen at menopause (or with antagonists) leads to vasomotor hot flashes
    6. Tamoxifen and raloxifene (SERM) also cause hot flashes
    7. Androgens may play a role also as men with orchiectomy often have hot flashes
  3. Treatment [4,10,22,28,31]
    1. Hormonal and non-hormonal agents available for symptomatic benefit
    2. Estrogen replacement therapy (ERT) is mainstay and most effective agent (see below) [10]
    3. ERT/HRT improve quality of life and affect in women with menopausal flushing [19]
    4. Progestins, including megestrol acetate 20mg bid or norethisterone, are also effective [3]
    5. Progestins may not be contraindicated in women with history of breast cancer
    6. Tibolone (Livial®) - weak estrogenic activity, improves hot flashes and bone density [31]
    7. Gabapentin and venlafaxine are probably the most effective of the non-hormonal agents [10]
    8. Gabapentin (Neurontin®) 300mg po tid reduces hot flashes ~50% [32]
    9. Several SSRIs / SNRIs have shown activity
    10. Venlafaxine (Effexor® SR) 75mg qd, an SNRI, reduces hot flashes 30-60% for up to 12 weeks [18]
    11. Paroxetine controlled release (Paxil ® CR) effective for menopausal hot flashes [25]
    12. Fluoxetine (Prozac® and others) has also shown activity
    13. Clonidine (0.1mg/day) reduces tamoxifen induced hot flashes [14]
    14. Isoflavones (Promensil or Rimostil) had no significant effect on hot flashes [27]
    15. Methyldopa and bellergal may also be effective but should be avoided due to side effects
    16. Aspirin 81-162mg/d may be helpful and likely reduce cardiac risks
  4. Alternative Medicines [23]
    1. Black cohash ± other botanicals or soy had no benefit on vasomotor symptoms versus placebo in large randomized study
    2. No herbal supplement improved menopausal vasomotor symptoms
    3. Dong quai, primrose oil, vitamin E, acupuncture not effective

F. Hormone Replacement Therapy (HRT) [3,4,5]

  1. HRT is no longer routinely recommended in healthy post-menopausal women [3,5,6]
  2. Effects of HRT
    1. Improves menopausal symptoms: hot flashes, atrophic vaginitis [7,19,34]
    2. BMD stabilized and osteoporosis and fractures reduced
    3. Discontinuation of ERT/HRT leads to rapid loss of BMD [9]
    4. HRT use over 4 years did not improve cognitive function in postmenopausal women with cardiovascular disease [26]
    5. May improve sexual dysfunction associated with menopause [12]
    6. In women without symptoms, HRT does not improve quality of life [7]
    7. Overall no effect on cardiovascular disease risk in prospective studies [20]
    8. Increased risk of symptomatic gallstones and venous thromboembolic disease [21]
    9. Increased risk ~1.6X for invasive breast cancer [6]
  3. Spontaneous resumption of menses may occur with certain regemins
    1. Estrogen-only (ERT) regimens should be restricted to subjects without a uterus
    2. Use of estrogen-only regiments with intact uterus increases risk of endometrial cancer
    3. Combination continuous estrogen-progestin daily therapy does not induce menses
    4. Daily estrogen with progestin used only on last 10 days of cycle can induce menses
  4. Dosing
    1. Typically give 0.31 -0.625 mg conjugated estrogens (such as Premarin®) daily
    2. Progestin should be given if the patient has a uterus (usually given daily)
    3. Estrogen can cause headaches, weight gain, bloating
    4. Estrogen patch should be considered in patients with hypertriglyceridemia
  5. Estrogens (incomplete listing) [5,11]
    1. Conjugated Estrogens (Premarin®) - 0.625mg x 28 days
    2. Plant-derived ("Phyto") Estrogen - estropipate (Ogen®) 0.625mg po qd
    3. Estradiol - usually 1mg
    4. Ethinyl estradiol - usually 5µg
  6. Progesterones
    1. Unopposed estrogen treatment leads to significant increase in endometrial cancer
    2. Progestin: given concommitantly or for the last 10-12d of the month (with estrogen)
    3. However, longer periods of progesterone, including daily (lower) doses, are acceptable
    4. Low dose megestrerol acetate can prevent hot flashes, is well tolerated
    5. Mildly reduces lipid-improving effects of estrogens (increases LDLs)
    6. Medroxyprogesterone (Provera®, Cycrin®) - 2.5mg x 28d; 5mg x 14d
    7. Dydrogesterone (Duphaston®, Teroulut®): 10-20mg/d cyclical only
    8. Norethrindrone (Micronor®, Nor-QD®) - 0.35mg x 28d or 0.7mg x 14d
    9. Drospirinone - 0.5mg qd
    10. Micronized progesterone (Prometrium®,Ultrogestan®): 100mg daily or 200mg cyclical
    11. Norethisterone (Micronor®, others): 0.35-0.5mg daily or 0.7-1.0mg cyclical
  7. Combinations [35]
    1. Prempro® (28d each): 0.3mg conjugated equine strogen/1.5mg medroxyprogesterone; also available as 0.45mg/1.5mg, 0.625/2.5 and 0.625/5
    2. Activella®: 1mg estradiol/0.5mg norethindrone; 0.5mg estradiol/0.1mg norethindrone
    3. Angeliq®: 1mg estradiol/0.5mg drospirenone
    4. FemHRT: 5µg ethinyl estradiol/1mg norethindrone acetate; also available 2.5µg/0.5mg
    5. Prefest®: 1mg estradiol/0.09mg norgestimate
    6. Combi-Patch®: 0.05 estradiol/0.14mg norethindrone; also available 0.05mg/0.25mg patch
    7. Climara Pro®: 0.045 estradiol/0.015 levonorgestrel patch
  8. Absolute Contraindications to HRT
    1. Pregnancy
    2. Unexplained vaginal bleeding
    3. Active or chronic liver disease
    4. History of endometrial cancer (consider raloxifene; see below)
    5. History of breast cancer (SERM should be used; see below)
    6. Recent vascular thrombosis
    7. Informed patient refusal
  9. Relative Contraindications
    1. Hypertriglyceridemia
    2. History of thromboembolic disease
    3. Gallbladder disease
    4. Migraine headaches
    5. Uterine leiomyoma
    6. Seizure disorder
  10. Atrophic Vaginitis Treatment
    1. Local application of vaginal estrogenic agents
    2. Vaginal tablets (Vagifem®)
    3. Vaginal cream (Vestine®, Synopause®)
    4. May improve sexual enjoyment as well [34]

G. Selective Estrogen Receptor Modulators

  1. These agents are called SERMS
  2. They have mixed agonist/antagonist activities
  3. Indications
    1. In patients at high risk for breast cancer, these SERM agents should be considered instead of ERT or HRT agents
    2. Excellent lipid lowering and bone enhancing activities
    3. May reduce risk of breast cancer 45-55% after 3-5 years
    4. Raloxifene may be used safely in women with an intact uterus
  4. Agents generally worsen hot flashes
    1. Tamoxifen (Nolvadex®)
    2. Raloxifene (Evista®)
  5. Tamoxifen
    1. Antagonist on breast tissue only
    2. Agonist activity in uterus and bone
    3. Tamoxifen is approved for reduction (~45%) of breast cancer risk in high risk patients
  6. Raloxifene
    1. Approved for post-menopausal osteoporosis risk reduction and treatment
    2. Antagonist on breast tissue
    3. Neutral uterine effects - can be used without endometrial biopsy
    4. Has shown >55% reduction in risk of breast cancer in high risk patients
    5. Reduction in new breast cancer >50% in post-menopausal women with osteoporosis
  7. Hot flashes will generally worsen with SERMs and must be managed with other agents
  8. SERMs appear to have a risk of venous thrombosis similar to that of HRT

H. Androgens [12]

  1. Androgen Levels and Sexual Function [30]
    1. No single androgen level is predictive of low female sexual function
    2. Low serum DHEA-S levels are best correlated with reduced arousal, responsiveness, pleasure, and organism but not desire or self image
    3. Levels of testosterone and androstenedione do not correlate well with sexual function
  2. Testosterone Replacement [1,12,15]
    1. May improve sexual arousal and libido
    2. Concern for undesirable effects of androgens are significant (see above)
    3. May be most appropriate in women undergoing bilateral oophorectomy
    4. Physiologic doses should be used, and levels may be monitored
    5. Low dose methyltestosterone (1.25-2.5mg/d) appears safe and may be effective
    6. Daily 90µL trasdermal testosterone improved sexual satisfuaction in premenopausal women with reduced libido and low serum-free testosterone levels [36]
    7. High doses can cause liver dysfunction
    8. Liver function tests (LFTs) should be monitored
    9. Transdermal testosterone patch (150-300µg/d) improves sexual function, well being [15]
    10. Testosterone patch has no hepatic or lipid effects compared with placebo [15]
    11. The overall long-term risks are not well understood at this time
  3. DHEA Therapy
    1. DHEA is an androgenic steroid normally made by the adrenals
    2. DHEA increases serum insulin-like growth fractor 1 (IGF-1) levels
    3. DHEA is converted to androstenedione and testosterone
    4. Low DHEA sulfate (DHEA-S) levels in blood correlate with reduced sexual function [30]
    5. May reduce HDL levels slightly when given to women with adrenal insufficiency
    6. Increases well being, sexual interest and thoughts in women with adrenal insufficiency
    7. Reduces feelings of anxiety and depression in women with adrenal insufficiency
    8. Dose is 50mg/day or 50mg qod po
    9. No benefit on body composition, physical performance, insulin sensitivity, or quality of life in elderly women (or in elderly men) [33]

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