New combination in the market Z.Shahverdi M.D GynOncologist 17/02/2016
HRT was first available in the 1940s but became more widely used in the 1960s, creating a revolution in the management of the menopause Estrogen therapy in postmenopausal women relieves menopausal symptoms but has risks for some women, including breast cancer, coronary heart disease (CHD), stroke, and venous thromboembolism
Menopausal hormone therapy (MHT) is still a good option when used at low doses The benefit to risk relationship is especially favorable for women within 10 years of the onset of menopause or less than age 60 years
Estrogen is available in many forms: Systemic estrogens Oral Transdermal Topical (gels and lotions) Subcutaneous implant (In some countries) Vaginal estrogen Intravaginal creams and tablets Vaginal rings
For menopausal symptoms Systemic estrogen For Vulvovaginal atrophy Low-dose vaginal estrogen
Oral estrogen Estrogen administered orally has a greater effect on the liver due to the first-pass effect, and higher portal vein concentrations than transdermal administration Oral estrogen in compare with transdermal administration increases hepatic production of : Thyroxin-binding globulin Corticosteroid-binding globulin Sex hormone-binding globulin Triglycerides, high-density lipoprotein (HDL) cholesterol Clotting factors Saturation of bile with cholesterol
A number of oral estrogen preparations are available Conjugated equine estrogens Derived from pregnant mares' urine : Comprised mostly of estrone sulfate with small amounts of equilin sulfate, dihydroequilin sulfate, and many other estrogens Synthetic CEs are derived from a plant source : are similar but not identical to conjugated equine estrogens, as contain fewer forms of estrogen Oral micronized 17-beta estradiol structurally identical to the main product of the premenopausal ovary. Esterified estrogens Result in serum estradiol and estrone levels that are comparable to those seen with CE Estropipate A salt of estrone sulfate and piperazine Ethinyl estradiol (EE) Estrogen used in almost all oral contraceptive preparations EE is much more potent than the other estrogens used for MHT and, therefore, is used in very low doses (5 mcg) EE is used in at least one combined estrogen-progestin product that contains 2.5 to 5 mcg of EE with 0.5 or 1 mg norethindrone acetate
Transdermal estrogen Contains 17-beta estradiol range of dosing option from 14 mcg to 100 mcg/day Effective as oral estrogen for preserving bone density and treating menopausal symptoms A transdermal dose of 50 mcg/day is approximately equivalent to a 0.625 mg daily oral dose of CEs Transdermal 17-beta estradiol is associated with a lower risk of thromboembolism, stroke, and hypertriglyceridemia than oral estrogens Ultra-low doses of estrogen (transdermal estradiol 0.014 mg/day and oral micronized 17-beta estradiol 0.25 mg/day) also prevent bone loss
Estradiol patch 1- Lowest dose patch 0.014 mg of 17-beta estradiol is approved for prevention of osteoporosis and hot flash relief For women with a uterus, progestin is recommended, although the optimal interval for its administration is not known Many clinicians administer a 14-day cycle of oral progestin every 6 to 12 months, although this has not been well studied. 2- Combination patches 17-beta estradiol (0.05 mg/day) with norethindrone acetate (0.14 or 0.25 mg/day) applied twice weekly 17-beta estradiol (0.045 mg/day) with levonorgestrel (0.15 mg/day) and is applied once a week Relief of vasomotor flushes and prevention of endometrial hyperplasia
Topical estradiol All are effective for the treatment of vasomotor symptoms Lotion 3.48 g/day which delivers 0.05 mg estradiol/day, applied to the thighs or calves of each leg Gels available: 1- One gel is packaged in a non-aerosol Metered-dose pump, and is applied once daily on one arm (from wrist to shoulder) Recommended daily dose is 1.25 g, which delivers 0.75 mg estradiol/day 2- A second gel is supplied in foil packets Available in three doses: 0.25, 0.50, and 1.0 mg of estradiol 3- A third gel is administered via a pump In Two doses (0.87 g, which contains 0.52 mg of estradiol, and 1.7 g, which contains approximately 1 g of estradiol) Topical skin spray : Deliver 1.53mg of estradiol with each spray
Vaginal estrogens low doses is most commonly used in management of genitourinary syndrome of menopause (GSM) Estradiol tablet : Vagifem (10 mcg) Estradiol ring : Estring (7.5 mcg) Conjugated estrogen cream: Premarin( 1g=0.625mg) Estradiol cream: Estrace ( 1g = 100mcg estradiol) Higher doses can be used to treat vasomotor symptoms not suggested and a progestin needs to be added for women with a uterus
PROGESTIN PREPARATIONS Endometrial hyperplasia and cancer can occur after as little as 6 months of unopposed estrogen therapy Progestin should be added in women who have not had a hysterectomy
Available progestin preparations 1- Medroxyprogesterone acetate Most commonly prescribed progestin Given in a cyclic (5 to 10 mg/day) or continuous regimen (1.25 to 2.5 mg/day) MPA has proven efficacy for preventing endometrial hyperplasia, associated with an excess risk of breast cancer and possibly coronary heart disease (CHD) It Has unfavorable effects on lipids.
2- Natural progesterone Micronized progesterone suggested as first-line progestin Natural oral micronized progesterone, protects endometrium and has little impact upon serum lipids and does not appear to increase the risk of either breast cancer or CHD (data are limited) Usual dose is 200 mg/day (12days) or 100 mg/day continuously 3- Intravaginal progesterone Suggested for menopausal women taking estrogen who cannot tolerate oral progestin
Levonorgestrel-releasing intrauterine device (LNG-IUS) - Contraceptive agents that are effective and approved for endometrial protection for menopausal women taking estrogen who cannot tolerate oral progestins - Two doses of levonorgestrel-releasing intrauterine devices (IUDs) are available: One contains 52 mg initially releasing 20 mcg/day (LNG-20) Other contains 13.5 mg initially releasing 14 mcg/day (LNG-14) The lower dose has been available in many countries, but was not approved in the United States until 2013 Two meta-analyses of trials in women using LNG-20 combined with estrogen therapy reported that the IUD was as good or better than estrogen combined with systemic progestins for preventing endometrial hyperplasia
Other proginestin There are menopausal hormone preparations that contain progestins derived from testosterone (19-nortestestosterone), such as norethindrone and norethindrone acetate Activella (Estradiol/Norethindrone Acetate) Approved April 2000 Angeliq (drospirenone and estradiol) First approved September 28th, 2005 A newer progestin,drospirenone (DRSP), is derived from 17 alpha-spironolactone and has progestogenic, antiandrogenic, and antimineralocorticoid activity DRSP preparations for MHT: In Europe Estradiol 1 mg / 2 mgdrsp In The united states Estradiol1 mg /0.5 mg DRSP Estradiol0.5 mg /0.25 mg DRSP
In a trial of 1142 postmenopausal women receive oral estradiol alone (1 mg/day) or in combination with DRSP 0.5, 1, 2, or 3 mg/day for 13 months All of estradiol/drsp regimens decreased risk of endometrial hyperplasia Hyperkalemia was not observed in any patient Decreases in serum total cholesterol, triglycerides, LDL concentrations, and increases in serum HDL
Tibolone Synthetic steroid whose metabolites have estrogenic, androgenic, and progestogenic properties Reduces vasomotor symptoms Beneficial effect on bone mineral density and modest effect for symptoms of sexual dysfunction Not approved by FDA due to concern about risk of breast and endometrial cancer and stroke In women with a personal history of breast cancer, Tibolone may increase the risk of recurrence.
New Medication
Selective Estrogen Receptor Modulators(SERM) 2013 Ospemifene is: A SERM that acts as an estrogen agonist in the vagina and appears to have no clinically significant estrogenic effect on the endometrium or breast 60mg oral/daily approved by FDA in February, 2013 for treatment of moderate to severe dyspareunia caused by vulvovaginal atrophy Used for those who cannot (severe arthritis, obesity, vulvodynia) or prefer not to use a vaginal product A potential benefit is a reduction in bone turnover Have a favorable endometrial safety profile Disadvantages are daily use and systemic side effects (hot flashes, potential risk of thromboembolism) Safety has not been demonstrated in women with a prior history or an increased risk of breast cancer or thromboembolism
Brisdelle (low-dose paroxetine mesylate) Approved July 2013 Brisdelle is A low-dose formulation of paroxetine mesylate, a selective serotonin reuptake inhibitor. It is not an estrogen, and its mechanism of action for the treatment of VMS is unknown. Specifically indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause. Supplied as a capsule for oral administration. The recommended dose is 7.5 mg once daily, at bedtime, with or without food.
Oral Conjugated estrogen/bazedoxifene (2014) Combination of CEE with a selective estrogen receptor modulator bazedoxifene(serm BZA)(0.45mg/20mg ) is available for treatment of menopausal vasomotor symptoms and osteoporosis prevention SERM BZA prevents estrogen-induced endometrial hyperplasia so that administering a progestin is not necessary. BZA/CE is a progestin-free MHT for women with a uterus. It is useful for moderate-to-severe hot flashes and breast tenderness with standard estrogen-progestin therapy and who cannot tolerate any type of progestin therapy because of side effects. The effect od bazodexofene/cee on breast and ovarian cancer risk is un known. Like other SERMs, the risk of VTE is increased with bazedoxifene. To date, no additive effect on VTE has been observed with the combination bazedoxifene-conjugated estrogen, but longer studies are needed to fully address this risk.
Intravaginal DHEA Eases Postmenopausal Vaginal Dryness, Pain Marcia Frellick January 06, 2016 Intravaginal dehydroepiandrosterone (DHEA) administration may be a novel therapy for postmenopausal women with atrophic vaginitis and sexual dysfunction. DHEA may be a viable alternative to intravaginal estrogen in combatting dryness and painful sex after menopause. In a trial of postmenopausal women with symptomatic vaginal atrophy, 12 weeks of intravaginal daily 0.5% DHEA (6.5 mg) suppositories corrected signs and symptoms of atrophy, appeared to improve some measures of sexual function. No significant increases in serum DHEA or estrogen concentrations were seen. This agent is not commercially available
New Options for Treating Menopause Mood and Symptoms Vyvanse (lisdexamfetamine) Low estrogen levels in menopause can cause a drop in serotonin and dopamine levels, leading to severe mood and cognitive changes HRT can help with memory and mood issues. But some women may not want to take HRT because of potential health risks Preliminary clinical studies point to a role for attention deficit hyperactivity disorder (ADHD) drugs in treating menopause. Research suggests ADHD treatment can be effective for cognitive symptoms.
Once a decision has been made to treat a woman with menopausal hormone therapy (MHT), consideration should be given to: Type of estrogen and the route by which it is to be given Need for progestin and the most appropriate progestin regimen
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