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

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

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

A Phenomenon of Modern Medicine Life expectancy: 1000 B.C. = 18 yrs 100 B.C. = 25 yrs 1900 = 49 yrs 2006 = 84 yrs

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

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

Disclaimer is on all products “Consult your physician”

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

Ovarian Function

Endogenous Estrogen Production Ovary secretes 70-500 mcg of Estradiol daily depending on phase of menstrual cycle

Measuring hormone levels for diagnostic purposes is not recommended

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

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 10-14 days to induce withdrawal bleed. Treat with low-dose OCP if no contraindications Mirena IUD

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

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

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

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”

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

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

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

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

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

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

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

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

Before Starting Hormone Replacement Endometrial Bx Pap Mammogram Lipid profile Dexascan

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

Estrogen Receptors

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.

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

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

Conjugated Plant Estrogen Cenestin 0.3 to 1.25 mg; $41 – 37.00 per 30 Contains 9 forms of estrogen Synthetic, derived from plants

Ethinyl Estradiol Estinyl 0.02, 0.05 mg Used in Birth Control Pills Compares to 20-50 mcg pill Alesse, Levlite, Loestrin = 20 mcg in combination with progestin Potent synthethic estrogen, 10 mcg compares to 1 mg 17B-Estradiol in efficacy

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

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

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

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

Provera (medroxyprogesterone acetate) 2.5, 5, 10 mg $21 – 41.00 per 30 Available as generic; $9.00 per 30

Aygestin (Norethindrone) 5 mg $65.00 per 30

Prometrium (micronized progesterone) Contains peanut oil Pregnancy category B, most compatible in women trying to achieve pregnancy 100 mg, 200 mg $34 – 68.00 per 30 Natural steroid hormone

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

Mirena (levonorgestrel) IUD Releases 20 mcg/day

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.

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

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

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

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

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.

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

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.

“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

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

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

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

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. 2005 Jun;29(5):727-32. 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.

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

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

Treat Symptoms, Not Levels

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.

“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.

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

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

Alternative Treatments Placebo effect 30% in randomized trials Study: 40-60 yo, botanical dietary supplements used by 79%, 48% used 3 or more types. 70% of the women were not informing their physicians of use.

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

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.

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.

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.

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

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”

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

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

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

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

Wild Yam 600 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

Soy Phytoestrogen Soy protein 60 mg BID comparable to Premarin 0.625 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 40-80 mg/day

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

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