1. Hot Flashes, Hormones, and Herbals
Tami Michele, DO, OB/GYN

2. Menopause Definition
Permanent cessation of menstruation following the loss of ovarian activity
Avg age is 51
Perimenopause lasts 2-8 yrs

3. Clinical Diagnosis Retrospective diagnosis
Amenorrhea for 12 months, over age 45, in absence of other causes
FSH and LH increases
Estrogen decreases after initial increase during the perimenopause phase

4. A Phenomenon of Modern Medicine
Life expectancy:
1000 B.C. = 18 yrs
100 B.C. = 25 yrs
= 49 yrs
= 84 yrs

5. Projected increased percentage of aging population, 1900-2050
CDC, U.S. Census Bureau

6. What does this mean to the clinician?
Women can expect to spend about 1/3 of their life postmenopausal.
Currently, about 37.5 million women
Changing the way we care for the patient

9. Disclaimer is on all products
“Consult your physician”

10. Perimenopausal Transition
2-8 yrs preceding menopause and one year after the last menstrual period
Normal ovulatory cycle interspersed with anovulatory (estrogen-only) cycles of varying length
Menses become irregular and heavy

11. Ovarian Function

12. Endogenous Estrogen Production
Ovary secretes mcg of Estradiol daily depending on phase of menstrual cycle

13. Measuring hormone levels for diagnostic purposes is not recommended

14. Abnormal Uterine Bleeding: Consider all causes
Pregnancy (uterine, ectopic, SAB)
Polyps/Fibroids
Endometrial hyperplasia/ Endometrial CA
Medications (Hormones, alternatives, anticoagulants)
Thyroid disorder
Speculum exam and pap
Orders: B-HCG, CBC, TSH, Endometrial BX, Pap, Sonohistogram; Consider US, Hysteroscopy D&C

15. Dysfunctional Uterine Bleeding: A Diagnosis of Exclusion
Treat with Progestin, medroxyprogesterone acetate (Provera) 5-10 mg po daily, either on days #16-25 of cycle, or if not cycling start and continue days to induce withdrawal bleed.
Treat with low-dose OCP if no contraindications
Mirena IUD

16. Urogenital Atrophy Estrogen effect Estrogen deficiency
pH < pH >4.5
Superficial epithelial basal cells
cells

17. Urogenital atrophy Dyspareunia Postcoital bleeding
Vaginal dryness, itching
Urethritis, incontinence, frequent UTIs

18. Topical Estrogen Treatments
Estradiol acetate vaginal ring (Femring) for systemic therapy
Placed in vagina and replaced every 90 days
Available as 0.05 and 0.1 mg/day rings
Estradiol vaginal ring (Estring) for local therapy
Available as 2 mg rings, delivers 6-9 mcg daily, progestin not required
Estradiol vaginal tablet (Vagifem)
Initial: One tablet intravaginally qd for 2 weeks
Later: One tablet intravaginally twice weekly
Available in 25 mcg tablets
Estrogen Cream (Premarin or Estrace creams)
Premarin applied 0.5 grams cream (0.3 mg) daily x 3 wks, then twice weekly
Estrace applied 0.5 grams (50 mcg) daily, then twice weekly

19. What is a hot flash?
Originates in hypothalamus, central noradrenergic system thermoregulatory dysfunction acting on the alpha-adrenergic receptors
Peripheral vasodilation, profuse perspiration followed by chills
Sudden onset, seconds to minutes
Recurs rarely to every few minutes
Frequent and severe at night, “Night Sweats”

20. Avoid hot flash “triggers”:
Alcohol
Caffeine
Hot or spicy foods
Stress
Hot drinks
Warm environment
smoking

21. Survival Tip for Patients
Dress in layers
Wear cotton
Avoid turtlenecks, wear open neck shirts
Keep ice water on hand
Use cotton sheets, sleep with fewer blankets
Take cool shower before bed
Eat smaller, more frequent meals
Limit caffeine and alcohol
Stop smoking

22. Internet shopping
Now, relief from “night sweats” without HRT

23. Differential Dx of Night Sweats
Estrogen deficiency can be documented by FSH
If clinical situation is not clear, also consider:
Pheochromocytoma
Carcinoid
Leukemias, Lymphoma
Tuberculosis
HIV
Pancreatic tumors
Thyroid disorder
Medication side effect, drug withdrawal

24. Night Sweats cause Sleep Deprivation
Irritability
Anxiety
Fatigue
Forgetfulness
Inability to concentrate

25. Benefits of Estrogen
#1 recommended tx for menopausal symptoms if not contraindicated
increases quality of life
 osteoporotic fractures
 colon cancer

26. Risks of Estrogen Replacement
N/V
water retention
vaginal bleeding
Venous thromboembolism (DVT, PE)
Stroke, MI
HTN
Gallblader disease/stones
Increased growth of uterine fibroids
Endometrial Hyperplasia/CA

27. If H/O irreg bleeding or exposure to unopposed estrogen (obesity, PCOS, menometrorrhagia, oligomenorrhea), endometrial biopsy will rule out hyperplasia or CA

28. Before Starting Hormone Replacement
Endometrial Bx
Pap
Mammogram
Lipid profile
Dexascan

29. Choosing a Hormone Treatment Oral, Transdermal, Vaginal
1st pass on liver
Acceptability of route of administration
Ease and convenience of use
Patient compliance
Side effects

30. Estrogen Receptors

32. Starting Estrogen
Acute onset (Oophorectomy) requires higher initial dose
Severe symptoms require higher dose
Then taper to lowest dose to relieve symptoms, and use for the shortest amount of time.

33. Types of Estrogen Conjugated equine estrogens (Premarin)
0.625 to 1.25 mg daily
Ethinyl estradiol (Femhrt, BCP)
5 to 10 mcg daily
Micronized 17B-estradiol (Estrace)
1 to 2 mg daily
Conjugated Plant estrogen (Cenestin)
0. 3 to 1.25 mg daily
Esterified estrogen (Menest)
0.3 to 2.5 mg daily

34. Conjugated Equine Estrogen
Mainly estrone with many other things
“conjugated” in the urine; polar, water soluble for easy absorption
$35.00 per 30

36. Conjugated Plant Estrogen
Cenestin
0.3 to 1.25 mg;
$41 – per 30
Contains 9 forms of estrogen
Synthetic, derived from plants

37. Ethinyl Estradiol Estinyl 0.02, 0.05 mg Used in Birth Control Pills
Compares to mcg pill
Alesse, Levlite, Loestrin = 20 mcg in combination with progestin
Potent synthethic estrogen, 10 mcg compares to 1 mg 17B-Estradiol in efficacy

38. Micronized 17 Beta Estradiol
Generic 1 mg $8.00/30
Estrace 1 mg $34.00/30
Gynodiol 1 mg $14.00/30
0.5 to 2 mg daily
Only one estrogen component
Estradiol is the primary human estrogen secreted prior to menopause, and is more potent than estrone and estriol at the receptor level

39. Esterified Estrogen Plant derived Menest 0.3 to 2.5 mg; $17-49.00/30
Priniciple component is estrone, but contains mixture of estrogenic substances

40. Transdermal Hormones Recommended for women with H/O:
Hypertriglyceridemia
Glucose intolerance
Gallbladder disease
Less likely to cause these adverse events than oral estrogens

41. Progestin Use with Estrogen in women with a Uterus
Medroxyprogesterone acetate (Provera)
Norethindrone acetate (Aygestin)
Micronized progesterone (Prometrium)
Megestrol acetate (Megace)
Levonorgestrel (Mirena)

42. Provera (medroxyprogesterone acetate)
2.5, 5, 10 mg
$21 – per 30
Available as generic; $9.00 per 30

43. Aygestin (Norethindrone)
5 mg
$65.00 per 30

44. Prometrium (micronized progesterone)
Contains peanut oil
Pregnancy category B, most compatible in women trying to achieve pregnancy
100 mg, 200 mg
$34 – per 30
Natural steroid hormone

45. Megace (megestrol acetate)
20-80 mg/day; $38.00 per 100
Antineoplastic effect on endometrium
a synthetic progestin hot flashes by 85%
Transient increase x 1-2 wks after initiation
Side effects:
Weight gain
Adrenal insufficiency possible after discontinuation

46. Mirena (levonorgestrel) IUD
Releases 20 mcg/day

47. Treatment Regimens: Cyclic vs. Continuous
Continuous combined estrogen and progestin avoid withdrawal bleeding and increases pt compliance.
Continuous estrogen-only for use in women after hysterectomy.
Cyclic, using progestin at beginning or end of the cycle.

48. Intractable Hot Flashes despite adequate dose of estrogen
Consider:
Drugs
Decrease the absorption (antibiotics)
Increase hepatic enzyme activity (barbiturates, anticonvulsants, tranquilizers)
Change route (oral to transdermal)
Stop estrogen for 1-2 wks, then restart to compare hot flashes on and off estrogen

49. Discontinuing hormones
Use the shortest amt of time (6 mos to 5 yrs), and taper slowly to discontinue
Progestin can be stopped abruptly w/o negative consequences, but can also be tapered
Decrease Estrogen by one pill per week (6 wks), but may see less SE if tapered over 12 weeks

50. Other conventional treatments:
Effexor (venlafaxine) a serotonin and norepinephrine reuptake inhibitor,37.5 to 75 mg daily.
Paxil CR (Paroxetine) 25 mg daily
Effective in hot flashes by 61-65%
SSRIs also treat depression/mood disorders associated with menopause

51. Progestins
Megestrol acetate (Megace), a synthetic progestin hot flashes by 85%
Transient increase x 1-2 wks after initiation
Side effects:
Weight gain
Adrenal insufficiency possible after discontinuation
Norethindrone acetate (Aygestin)
Medroxyprogesterone acetate (Provera)
Progestins also control irreg perimenopausal bleeding

52. Clonidine Clonidine (Catapres) alpha adrenergic agonist
Blocks noradrenergic neuron activity assoc with rapid changes in skin temp
Oral 0.1 to 0.4 daily
Transdermally 0.1 mg/day q weekly patch
If Pt also has HTN, consider as 1st line tx.

53. Gabapentin Gabapentin (Neurontin) hot flashes 45% vs 29% in placebo
300 mg at bedtime relieves hot flashes that awaken pt from sleep

54. Bioidentical hormones
Safety concerns following the report of the WHI reflect increased interest in “natural” or “bioidentical” hormone treatment.
Definitions:
1. Plant-derived and similar to those produced by the ovary.
2. Compounded formulation of hormones according to individual specifications based on salivary hormone concentrations.

56. “Bioidentical” Has no scientific meaning
Term created by marketers, implies an advantage over pharmaceuticals
Consumers rarely question its origin
Comparable to “hypoallergenic” used by the cosmetic industry

57. Compounded Hormones 1% of all RX in US
30 million prescriptions per year

58. Compounding Ingredients
Source of active ingredients same as pharmaceuticals
Bulk ingredients from overseas
Loyd V. Allen, Jr., PhD, RPh, 17th Annual Meeting of The North American Menopause Society 2006
James A. Simon, MD, 17th Annual Meeting of The North American Menopause Society 2006

59. Compounded Products Prescription only No package insert
Not approved by FDA
Risks/Warnings not given
Dosage and Potency varies
Claims of increased efficacy or safety is not supported by evidence
Internet is not regulated, and is dominated by vendors of natural products

60. Saliva Testing Experimental Marketing Tool
In theory, saliva is an ultrafiltrate of the blood and may have “free” (unbound) concentrations of hormones.
Large within-patient variation
Salivary hormones vary by time of day, day of cycle, diet, and other variables.
One study showed some value only in testing women on ET
Prog Neuropsychopharmacol Biol Psychiatry Jun;29(5): Saliva versus serum estradiol: implications for research studies using postmenopausal women. T ivis LJ, Richardson MD, Peddi E, Arjmandi B. CONCLUSIONS: These data suggest that saliva E2 may be a fairly robust predictor of serum E2, but only among postmenopausal women who use ET.

61. Research is minimal Compare to Cortisol research Levels affected by:
Medications (insulin, BCPs, barbiturates, phenytoin, steroids, niacin)
Body weight, malnutrition
Alcohol, alcohol abuse
Albumin and binding proteins

62. Feedback System
Do not use FSH as a guide to manage estrogen therapy, FSH is regulated by inhibin.

63. Treat Symptoms, Not Levels

64. Compounded Hormones
Examples of individually prepared natural estrogens include Biest, a combination estrogen preparation of 20% estradiol and 80% estriol, and triestrogen (Triest) containing 10% estradiol, 10% estrone, and 80% estriol.
Estriol is not commercially marketed for oral use in the United States, either as a single entity or in combination with other ingredients.

65. “Bioidentical” Hormones
Not approved by FDA, but should be considered to have the same safety issues as other hormone therapy.
May have additional risks intrinsic to compounding.
Not typically reimbursed by insurance.

66. Bioidentical Compounded Hormones: ACOG Summary
There is no scientific evidence to support claims of increased efficacy or safety for individualized estrogen or progesterone regimens.
ACOG Committee Opinion Nov 2005

67. Also not supported by: North American Menopause Society
The Endocrine Society
FDA

68. Alternative Treatments
Placebo effect 30% in randomized trials
Study: yo, botanical dietary supplements used by 79%, 48% used 3 or more types.
70% of the women were not informing their physicians of use.

69. Homeopathic Remedies Like treats like
Greater dilution = greater effect (??)
Treatments based on symptom picture
University of Michigan 1875
Homeopathic Medical College of Missouri

70. Belladonna
This remedy can be useful if flushes of heat during menopause are very sudden and intense. Pulsation or throbbing may be felt in the head, or any part of the body. A heavy flow of blood that feels very hot appears with some periods. Although the woman may be fairly stable emotionally, short bursts of anger can occur during headaches or in stressful situations. Migraines, blood pressure fluctuations, and a craving for lemons or lemonade are often seen when this remedy is needed.

71. Sepia (Squid Ink)
This remedy can be helpful if a woman’s periods are sometimes late and scanty, but heavy and flooding at other times. Her pelvic organs can feel weak and sagging, and she may have a craving for vinegar or sour foods. Women who need this remedy usually feel dragged-out and weary, with an irritable detachment regarding family members, and a loss of interest in daily tasks.

72. Staphysagria (Delphinium)
A person who needs this remedy usually seems mild-mannered, shy, and accommodating, but has many suppressed emotions. Women around the time of menopause may become depressed, or have outbursts of unaccustomed rage (even throwing or breaking things). Many people needing Staphysagria have deferred to a spouse for many years, or have experienced abuse in childhood.

73. Black Cohosh Cimicifuga racemosa
Used by native americans,
introduced to europeans
Used in Germany since
1950s for menopause
Comparable to transdermal and conjugated estrogens in some studies
Monitor liver enzymes
No toxicity reported,
Probably safe

75. Results of Study
After 16 wks of treatment, symptoms decreased by 50% in treatment group compared with 19.6% in placebo group.
No difference in adverse events
Conclusion: “the combination of black cohosh and St. John’s Wort has been shown to be very effective”

76. Red Clover Trifolium pratense
Isoflavone class of phytoestrogens
Affinity for beta recepter
Anticoagulant effect
Likely safe
Effectiveness not proven

77. Dong Quai Angelica sinensis
Traditional Chinese medicine
Coumadin-like property
Used in formulas
Not recommended

78. Evening Primrose Oil Oenothera biennis
Gamma linolenic acid, essential fatty acids
May lower seizure threshold
Anticoagulant properties
Precursor to prostaglandin E1
No proven benefit for hot flashes

79. DHEA: dehydroepiandrosterone
Endogenously produced in adrenal gland
Synthetically manufactured from soy and wild yam
Metabolized to androgens and estrogens
“Potent estrogen receptor agonist”, avoid if hormone sensitive conditions like breast CA
May worsen PCOS and cause androgenic effects
Increased psychiatric adverse events if h/o depression or bipolar
Possibly safe & effective in short term tx
Banned by NCAA for use in athletes

80. Wild Yam species
Diosgenin is precursor in commercial chemical synthesis of hormones and DHEA
Is not converted in vivo
May have estrogenic effect, do not use in hormone sensitive conditions like breast CA
May increase risk of thrombosis

81. Soy
Phytoestrogen
Soy protein 60 mg BID comparable to Premarin QD, but may take 8 wks for effect.
Structurally similar to SERMs (selective estrogen-receptor modulators)
May Breast CA
8 clinical trials and numerous pharmacological investigations have not found evidence of endometrial hyperplasia after treatment with soy isoflavones and/or soy protein.
In presence of estrogen is anti-estrogenic
In absence of estrogen, is weakly estrogenic
Recommended dose is mg/day

82. Summary Listen to Women Educate Women Evaluate Abnormal Bleeding
Treat symptoms, not lab levels
Lowest dose for shortest duration
Know alternatives

83. The End