In 1997, Dr. Behram A described the Three Stages Of Menopause to understand the duration and events of menopause. The also guides us in managing the menopausal woman
The Regimes and dosages used depend upon the need of the woman.
Women need to be counseled about the risk and benefit of HT.
Estrogen – emerging role in women’s healthcare
Estrogen – Role in women’s reproductive process Inadequate endometrial preparation affecting fertility How adequate endometrial preparation increase the success rate of pregnancy Consequences of natural estrogen deprivation – Menopause Menopause – As an opportunity in preventive healthcare Therapeutic options for menopausal symptoms Estradiol valerate – Pharmacological profile Estradiol valerate - Various indications and dosage regime ERT – Fear and realities (benefits outweigh the risk) Superiority of estradiol valerate over other estrogen preparation
All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it. All steroid hormones are lipid soluble Androgens are precursors of estrogens.
Are not packaged, but synthesized and immediately released Enzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ER The rate-limiting step is transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR).
Steroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins. Sex steroid binding globulin carries testosterone and estradiol In some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain
The Two-Cell Theory of Estrogen Production in the Ovary • Numerous studies have now shown that the androgens required for aromatization come from the neighboring theca cells: LH FSH LH receptor cholesterol estradiol aromatase androgens androgens theca cell granulosa cell
Estrogens are group of steroid compounds that are mainly present in female, and comprises of estrone, estradiol, and estriol. During reproductive years, the main type of estrogen produced is estradiol. Enzymatic actions produce estradiol from androgens and testosterone, while estrone is made from androstenedione Estradiol is stronger in action as compared to estrone From menarche to menopause, primary estrogen is estradiol, while after menopause it is estrone
Estrogen is an essential part of a woman’s reproductive processes Contributes to the development of secondary sex characteristics in females Regulates menstrual cycle and prepares the uterus for pregnancy by enriching and thickening the endometrium Mostly produced in ovaries, also produced by the corpus luteum, placenta, adrenal glands, etc. At menopause, woman experiences reduction in estrogen that leads to hot flashes, sleep disturbances, mood swings, vaginal dryness, etc.
Estrogen has significant effect on the fertility of the female as it helps in the proliferation of endometrium and hence, implantation. deficiency of estrogen- inadequate endometrial thickness - implantation failure. E supplemented for endometrial preparation Endometrial preparation - essential for successful implantation and establishment of pregnancy as it increases the receptivity for implantation.
Maximum distance between the Echogenic Interfaces of the Myometrium and the Endometrium Endometrium grows at the rate of 0.5mm /day in Proliferative phase and 0.1 mm/day in the luteal phase Thickness ranging from 9-14 mm has higher implantation and pregnancy rates as compared with an endometrial thickness of 7-8mm * *Fertil Steril, 2008
Defined as a temporary unique sequence of factors that make the endometrium receptive to the embryonic implantation Is the window of time when the uterine environment is conducive to blastocyst acceptance Maximal endometrial receptivity is seen between 20 th -24th day of a 28 day cycle Endometrial expression of Estrogen receptor & progesterone receptor may be ascribed for the receptive properties of endometrium
To use ovarian stimulation protocols that cause a minimum reduction in endometrial receptivity or may even increase it . Routine assessment of the endometrium before IVF Improve the Endometrium thickness (with supplementation of estrogen and progesterone)
An endometrial thickness of 9-14 mm is associated with higher implantation & pregnancy rates as compared to endometrial thickening of < 7mm ET (<7mm ) ET (9-14 m m)35% 30%30% 27% 25%25% 19% 18%20% 16% 14%15% 12%10% 5% 0% Im plantation rate Clinical pregnancy Ongoing Live birth rates rate pregnancy rate Fertil Steril, 2008
Menopause is a physiological event that bringsclinicians and patients together, providing the opportunity to enroll patients on health maintenance
Menopause – Indian Perspective• According to IMS research there are about 65 million Indian women over the age of 45.• Average age of menopause is around 48 yrs but it strikes Indian women as young as 30-35 years. So menopausal health is of higher priority in Indian scenario.• The onset of menopause appears to occur earlier in rural areas than in urban areas.
Staging of Menopause, Dr. Behram. S. Anklesaria, 1997STAGES Stage I Stage Stage II B Stage III IIAYEARS Roughly 3-5 years before ONE Up to five From five years the menopause YEAR years after the after menopause menopause up to her life time.EVENTS I A: Menstrual M C * Local III A: Late irregularity E 0 atrophic atrophic changes I B: Vasomotor N N changes 111 B: Ischemic instability 0 F * Late heart disease I C: Early P I psychosomatic III C: psychosomatic A R symptoms Osteoporosis symptoms U M III D: Very late S A complications: E T e.g.. Cerebro – I Vascular 0 accidents, N Alzheimers disease, etc.ACTION Palliative treatment Active treatment Preventive measures
Alterations in mean circulating hormonelevels during the perimenopausal transition
Inhibin, estradiol Hypothalamus(pituitary gland) Ovary FSH, LH FSH, LH Norepinephrine Dopamine Prostaglandins Insomnia Bone Mood swings Hot flushes Cardiovascular Vagina, breast, Depression system Uterus Osteoporosis Atherosclerosis Atrophy
Menopausal Symptoms Hot flashes and vasomotor instabilitySwan study (2009) has identified hot flashes as the mostbothersome symptoms that a woman experience. There is sudden sensation of warmth on skin of face andchest with a small increase in core body temperature, heartrate accompanied by increased sweatingPatient experiences chill as a consequence of lowerestrogen levels. symptoms are more bothersome at night *Jour womens health & gender based medicine, 2000
Sleep disturbances Sleep problems affect midlife women as they approach and pass through menopause* Upto 38 % of women may report some form of sleep disturbance including sleep latency, night time wakening and sleep apnea** Disruption of sleep has well-known daytime effects- tiredness, impaired alertness and mental acuity, decreased productivity at work, carelessness, forgetfulness and irritability*** This is a more prevalent symptom in perimenopausal woman and those experiencing surgical menopause*Gend Based Med 2000**Canadian Consensus Conference on Menopause, 2006 Update***Health qual life outcomes 2005
Mood changes and depressionDepresive symptoms are more common duringpremenopauseThe Pennsylvania ovarian study supports the destabilizingeffects of the cyclic variations of oestradiol are animportant factor both for depressive symptoms and thediagnosis of depressive disorders.This is in concurrence with studies that found ERT to bemore effective than placebo in treating depressivesymptoms in perimenopausal women (80% vs. 22% withplacebo*) * Amer Jour Obs 2000
Urogenital atrophy Low estrogen is the primary cause of deterioration in vaginal and urethral tissues Multiple changes occur in the vaginal tissue Decreased collagen content Decreased mucosal thickness Decreased blood flow Vaginal surface becomes less elastic, thin & friable Vaginal pH becomes neutral providing less protection against enteric organisms causing UTI Urinary incontinence (Stress & Urge) occurs as a consequence of urogenital atrophy* Frequency, urgency, nocturia, dysuria, infections are common * Int urogynaecol, 1994, vol-5, 208
Osteoporosis There is considerable increase in bone loss during the 5 years immediately following menopause (2-3% on an average during the 1st year and is more marked in trabecular bone*) During menopause, there is PTH function Ca2+ absorption Secondary decrease in the renal conversion of 25-OH D3 to 1,25-dihydroxy D3 due to decrease in PTH Int J Fertil 1986
Cardiovascular lipid changes Total cholesterol HDL LDL Risk of heart attack and stroke in women after menopause Premature menopause <35 yrs, 7 fold higher incidence of MI
Therapeutic options in menopauseThe goal of therapy is symptom relief and improved QoL(Quality of Life). Available therapeutic options are : Dietary and life style modifications Exercise Medical therapy
Dietary modificationsBalance calorie intake and physical activity to achieve ormaintain a healthy body weightConsume a diet rich in vegetables and fruitsChoose whole-grain, high-fiber foodsLimit intake of saturated fat to < 7% of energyFoods with little salt and high fiber dietAvoid smoking and alcohol.
ExerciseRegular exercise (aerobics like swimming, running) reducestotal and cardiovascular mortalityExercise improves the body’s ability to moderate andmonitor temperature regulationBetter metabolic profile, balance, muscle strength, cognitionand QoL are observed in physically active persons. Heartevents, stroke, fractures and breast cancer are significantlyless frequent.
Medical – Hormonal therapyEstrogen (hormone) therapy is a logical choice for thetreatment of menopausal symptoms and should be partof an overall strategy, including lifestylerecommendations regarding diet and exercise formaintaining the health and quality of life ofpostmenopausal women
ESTRADIOL VALERATEThe most trusted form of estrogen
Estradiol valerate is a naturally occurring form of the main female sex hormone, estrogen
MECHANISM OF ACTION Estradiol Valerate Diffuses across the cell membrane ↓ Binds to estrogen-receptor protein forming hormone-receptor complex ↓ Complex interacts with DNA ↓ estrogen-receptor-DNA complex interacts with co- activator proteins in target genes ↓ Transcription of mRNA and hormone-regulated genes ↓ protein synthesis in the cytoplasm and results in cellular activity
Estradiol valerate, like most natural estrogens, is readily and fully absorbed from the GI tract 50% bound to plasma proteins and is rapidly metabolised in the liver to estriol and estrone. When given orally in doses of 1-2 mg, peak levels of estradiol are observed 3-6 hours after ingestion; however, by 24 hours (range 6-48 hours) concentrations returned to baseline (i.e. pre-treatment concentrations).
Treatment of moderate to severe vasomotor symptoms associated with the menopause (natural or surgical) Treatment of urogenital atrophy Prevention of osteoporosis Preparation of endometrium 1,2 Treatment of secondary amenorrhea/Cyclical disorders Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure1.Jung H, J Assist Reprod Genet 2000; 17: 28-332. Farhi J, Fertility and Sterility 2000; 73(4): 761-6
Day Dose (mg)/day Estradiol valerate is given 1-5 1 in the following 6-9 2 concentrations throughout 10-13 6 the cycle* 14-17 2 18-26 4 27-28 1 Day Dose (mg)/day According to Norfolk’s protocol, the following 1-5 2 10-13 4 concentrations of 14-28 1 micronized estradiol is given.** ** - Resenwaks Z. Fertil Steril 1987*Human reprod update 1990,91
Progesterone may be delivered in the form of oral tablets, intravaginal suppositories or rings and i.m. injections. Some of the most commonly used progesterone regimens are: Day Dose Day Dose (mg)/day (mg)/day 14 50 14 100 or 200 15-26 100 15-26 300 or 600 Natural progesterone (i.m) Micronized progesterone (Vaginal) * Human reprod update 1998 ** Human reprod update 1989, 1992
Most widely used protocol : Estradiol valerate with 2 mg/ day between 1-8 days, increase to 4 mg/day between 9 to 11 day of cycle and then upto 6mg/day from day 12 of the cycle. On the day of egg donation add micronized P4 600 mg/day maintaining the 6mg/day EV. Embryo transfer is performed on the 3rd day after starting the administration of P4 If pregnancy occurs, same dose is maintained till day 40 of gestation or as per the response of the therapy
Endometrial receptivity (ER) is tolerant to a wide duration of E2 treatment, but best results are achieved with a treatment range of about 40 days1 Uterine preparation consisting of 6 mg EV can be extended as long as 5 weeks with no significant decrease in ER 21 Journal of Assisted Reproduction & genetics ,vol 18 ,No 4,april 20012 . Fertil steril 1995 jun ;63(6):1284-6
Commonly followed regimens Regimen Estrogen Progestogen Cyclic Days 1 to 25 Last 10 to 14 days of ET cycle Continuous cyclic or Daily 10 to 14 days/month sequential Continuous cyclic or long Daily 14 days every 2 to 6 cycle months Continuous combined Daily DailyFor women with an intact uterus, use estrogen with continuous or sequential progestogen.Estrogen therapy for alleviation of menopausal symptoms can be continued as long aspatient desires under medical supervision and regular follow-up** *NAMS position statement, 2008; adapted from Currie and Guttinger, 2007 **Speroff’s Textbook of gynecologic endocrinology
Estrogen supplementationTypes of E2 Dose /dayEstradiol Valerate (most widely used) 1-2 mgConjugated Equine Estrogen 0.3-1.25 mgPercutaneous Estradiol Valerate 0.2-0.4 mg Progesterone supplementationTypes of P4 supplementation Dose /day(in women with intact uterus)Progesterone (P4) micronized 200 mg(orally /vaginally)
Breast Cancer Perception All types of HRT cause an increased risk of breast cancer within a short duration of use. EvidenceWith 5 years combined E + P use there was a small increasein breast cancer risk (8/10,000 women per year). [A]Chlebowski RT. JAMA 2003. Stefanic ML. JAMA 2006;
Cardiovascular disease PerceptionHRT increases the risk of coronary heart disease(CHD) EvidenceHRT in women aged 50–59 years does not increase CHDrisk in healthy women and may even decrease the risk in thisage group. [A]A 24% reduction in risk for CHD events in womenstarting HT <10 yrs after menopause*Rossouw J. JAMA 2007;297:1465 *J. Am Med Association
Bone Perception HRT should not be used for bone protection because of its unfavourable safety profile. Official recommendations (MHRA,EMEA, FDA) limit HRT to a second-line alternative. EvidenceFor the age group 50–59, HRT is safe and cost-effective.Overall, HRT is effective in the prevention of allosteoporosis-related fractures, even in patients at low riskof fracture. [A]Rossouw J. JAMA 2007: Cauley JA. JAMA 2003; Jackson RD. J Bone Min Res 2006;
Benfits of ERT outweigh the potential risks Benefits RisksAcute ↓ VM symptoms ↑ Risk of breast, endometrial ↓ Mood disturbances cancer (unopposed) ↓ urogenital atrophy (Type, dose and duration ↓ Bone loss dependent) ↑ Risk of venousLong Term Thromboembolism & stroke ↓ Risk of onset of Alzheimers disease. ↓ Osteoarthritis ↓ Tooth loss and ARMD ↓ Colon Cancer Source: www.thebms.org.uk
Management strategies with HT in 2010I. HT must be individualized and tailored according to symptoms and the need for prevention, as well as personal and family history, results of relevant investigations, the woman’s preferences and expectationsII. Assess for medical conditions on which HRT may have adverse effects i.e. established heart disease.III. If HRT is chosen, select an appropriate regime, select an optimal duration of use & re-evaluate it periodically. *Adapted from NAMS position statements 2004, 2008
Management strategies with HT in 2010….contIV. Assess the woman’s concerns & discuss potential risks and make a collaborative decision.V. Dosage should be titrated to the lowest effective doseVI. Progestogen should be added to systemic estrogen for all women with a uterus to prevent endometrial hyperplasia and cancerVII. HT may not be prescribed as a preventive treatment for CVD. *Adapted from NAMS position statements 2004, 2008
Absolute contraindications for ERT Undiagnosed vaginal bleeding Existing breast carcinoma Existing endometrial carcinoma Thromboembolic disorders Acute liver and gall bladder disease Endometriosis
Algorithm for the administration of HRT Decision made to use HRT Yes Absolute contraindication No HRT No Baseline investigations completed Commence HRTPrevious hysterectomy Intact uterus + Intact uterus + amenorrhoea <2 years amenorrhoea > 2 yearsUnopposed oestrogen Continuous combined therapy Cyclical (Sequential) HRT HRT Monitor every 2 years *HKMJ, 1999
Pre-HRT screening test History Physical examination : General and Systemic Gynecological and Breast Pelvic Ultrasonography Cervical Pap Smear Mammography In special cases : Screening for diabetes Screening for dyslipidemia Thrombophilia screening Tests for thyroid function BMD measurement
Follow-up and management Follow up after a month, 3 months, yearly is suggested Follow-up includes checking for adequate symptom control, physical examination laboratory investigations (FSH, LH, serum estradiol) mammography Ultrasound abdomen
Superiority ofEstradiol Valerate over other Estrogen preparations
Distinctly Superior to Ethinyl Estradiol Parameters Estradiol Ethinyl Comments Valerate EstradiolLipid Profile ↑ HDL ↑ HDL Increase levels of TGs causes ↓ LDL ↓ LDL increase risk of atherogenesis and other cardiovascular No effect on ↑ TGs diseases. Triglycerides EE is contraindicated in (TGs) coronary artery disease.Blood No effect on renin- Increases the Increased plasma renin activityPressure aldosterone plasma renin is a a risk factor for system. activity and hypertension. alsosterone excretionCoagulation No effect on factor ↑ factor VII Increase levels of factor VIIFactor VII (Prothrombin may cause abnormal increase conversion in clotting of blood. accelerator)
Distinctly Superior to Conjugated Estrogens Parameters Estradiol Conjugated Comments Valerate Estrogens (CE)Source Natural Pregnant mare’s urine productEstrogenic activity Estradiol valerate CE contains 52 –61% Ten hormones present in CE are contains the most of estrone that is 1/3 chemically different from female active estrogen i.e 17β- of Estradiol activity. hormones. estradiol. CE also contains Unknown ingredients may cause any unknown ingredients. possible adverse effect.Mammographic No significant effect1 Significant increase in Increase in mammographic densitydensity mammographic may be a concern as it is a predictor of density 2 cancerous growth in the breasts.Blood Pressure No effect on renin- Stimulates the liver CE by stimulating renin-angiotensin(BP) aldosterone system. production system is associated with the risk of angiotensinogen, hypertension. therofore increases BPCoagulation Factor No effect on factor VII ↑ factor VII CE ( by ↑ factor VII) may cause abnormal increase in clotting of blood.
Parameters Estradiol valerate Conjugated estrogen comments (CE)Vasomotor symptoms Hot flushes, severe throbs, Presence of vasomotor EV could be an option that and breast tenderness is symptoms are higher with CE is better accepted by lower 3 postmenopausal women. It is the drug approved by US FDA for such condition.Lipid profile and Offers favorable lipid Lesser favorable lipid profile. EV has bettercardioprotective effect profile4 bioavailability and therefore, is a better option in dealing with concerns of postmenopausal cardiovascular protectionEndothelial function EV improves endothelial Vasoprotective effect not EV has fast effects on function and reduces reported endothelial function thus plasma levels of acutely vasoprotective endothelin-15Plasma homocysteine level EV has no effect on plasma Effect on homocysteine level Homocysteine is a risk homocysteine level6 not reported factor for CHD. EV reduces the risk of CHD
1. Effect of long-term continuous combined hormone replacement therapy with estradiol valerate and either dienogest or norethisterone acetate on mammographic density in postmenopausal women. Medscape Womens Health. 2002 Jul-Aug;7(4):1.2. Conjugated equine estrogen influence on mammographic density in postmenopausal women in a substudy of the womens health initiative randomized trial. J Clin Oncol. 2009 Dec 20;27(36):6135-43. Epub 2009 Nov 9.3. Comparative study between estradiol valerate combined with cyproterone acetate, and conjugated equine estrogens combined with medroxyprogesterone acetate as hormone replacement therapy in climacteric. Ginecol Obstet Mex. 2000 Nov;68:442-7.4. Metabolic effect of two hormonal preparations in postmenopausal women. Maturitas. 1997 Jul;27(3):275-84.5. Effect of estradiol valerate alone or in association with cyproterone acetate upon vascular function of postmenopausal women at increased risk for cardiovascular disease. Maturitas. 2001 Dec 14;40(3):239-45.6. Effect of oral hormone replacement therapy on plasma homocysteine levels. Acta Obstet Gynecol Scand. 2006;85(11):1304-6.