Progesterone 2 PDF

Estrogen and progesterone II Aikseng Ooi, Ph.D. Skaggs, Room 132 [email protected] slide-1 Menopause slide-2 Estrogen and progesterone in menstrual cycle slide-3 slide-4 Hormonal)changes)trigger)menopause) slide-5 Hormonal)changes)trigger)menopause) slide-6 Hormonal)changes)trigger)menopause)...

Estrogen and progesterone II Aikseng Ooi, Ph.D. Skaggs, Room 132 [email protected] slide-1 Menopause slide-2 Estrogen and progesterone in menstrual cycle slide-3 slide-4 Hormonal)changes)trigger)menopause) slide-5 Hormonal)changes)trigger)menopause) slide-6 Hormonal)changes)trigger)menopause) slide-7 Menopause 62 P. Tuomikoski, H. Savolainen-Peltonen / Maturitas 97 (2017) 61–65 Vasomotor symptoms Estrogen withdrawal Obesity Sympathetic overactivity Insulin resistance Dyslipidemia Hypertension Complex interplay between vasomotor symptoms, estrogen withdrawal and different features of the metabolic Fig. 1. Complex interplay between vasomotor symptoms, estrogen withdrawal and different features of the metabolic syndrome. Based on [4,5,8]. slide-8 sympathetic tone may result in altered vascular function , changes in blood pressure and lipids , and development of insulin resistance. The metabolic syndrome (MetS) is a cluster of closely related risk factors for cardiovascular disease and type Not all cross-sectional data are uniform on the detrimental effects of vasomotor symptoms and blood pressure. One study actually found that women with most frequent vasomotor symptoms during 24 h had lower systolic blood pressure. Also data Menopause Mean age of 51-53 year old (Freeman et al. 2014. Menopause. 21:924–32. ) Vasomotor symptoms - Mainly during the perimenopausal period ~ 11.6 years - Hot flushes flushing, chills, anxiety, sleep, and palpitations. During a hot flush, skin temperature rises as a result of peripheral vasodilation, particularly in the fingers and toes. Along with peripheral vasodilation and sweating, heart rate increases of 7–15 beats per minute occur. It may take 30 minutes or longer for the skin temperature to return to baseline. slide-9 Menopause Disruption of calcium homeostasis – Osteoporosis Vaginal dryness - painful sexual intercourse Insomnia Moodiness Skin dryness Obesity – redistribution of fat deposition slide-10 Estrogen as drug slide-11 Estrogen - vasomotor symptoms management Effectiveness is dose dependent. Oral and transdermal estrogen formulations have comparable efficacy. Estrogen à elevated risk of endometrial neoplasia Risk of endometrial neoplasia is reduced when combined with progesterone combination estrogen–progestin therapy preferred for women with an intact uterus. slide-12 is Estrogen)can)be)administered)through) Estrogen - administered through oral oral)or)transdermal)route) or transdermal route J E2)and)conjugated)equine)estrogens)are)the)most) E2 and conjugated equine estrogens are the most commonly used estrogen for systemic treatment. commonly)used)estrogen)for)systemic)treatment) J Standard)doses)of)oral)E2)and)conjugated)equine) Standard doses of oral E2 and conjugated equine estrogens are 1.0 mg and 0.625 mg, respectively estrogens)are)1.0)mg)and)0.625)mg,)respecFvely)) J Transdermal)E2)J)0.0375)mg)and)0.05)mg)E2)daily,) Transdermal E2 - 0.0375 mg and 0.05 mg E2 daily, higher lower doses are available (Patch). higher)lower)doses)are)available)(Patch).)) J Transdermal)gel,)emulsion,)spray) Transdermal gel, emulsion, spray J 3Jmonth)vaginal)E2J)releasing)ring)) 3-month vaginal E2- releasing ring slide-13 Some common estrogens Some)commonly)used)estrogens) Prepara&on) Average)Replacement)Dosage) Ethinyl)estradiol) Micronized)estradiol) Estradiol)cypionate) 0.005J0.02mg/d) 1J2mg/d) 2J5mg)every)3J4)weeks) Estradiol)valerate) Estropipate) 2J20mg)every)other)week) 1.25J2.5mg/d) NonJsteroidal)syntheFcs)) Quinestrol) 0.1J0.2)mg/week) Chlorotrianisene) Methallenestril) 12J25)mg/d) 3J9)mg/d) slide-14 Absorption, distribution, and metabolism Well absorbed by all routes Synthetic and semi-synthetic estrogens are slowly metabolized and highly bound to fat; slowly excreted. Estradiol binds to sex hormone-binding globulin(SHBG) Oral dose undergo enterohepatic circulation. Vaginal, transdermal, and injection slide-15 Other uses of estrogen - Prostate cancer treatment – phasing out due to cardiovascular complications - Contraception - Hypogonadism. For example Turner syndrome - Delayed puberty – for example betathalassemia slide-16 Side effects Headache Nausea Enlarged breasts Breast pain Water retention Cardiovascular complications Uterine cancer Altered lipid profile slide-17 Selective Estrogen Receptor Modulators (SERMs) slide-18 Selective Estrogen Receptor Modulators (SERMs) - Compounds that can act as antagonist and agonist dependent on tissue type. - Tamoxifen and Raloxifene - ER positive breast cancer - Gynecomastia (off label) - Menopause - Clomiphene – induce ovulation by inhibiting ER in hypothalamus. Side effects: Ovarian enlargement, eye sight problem, headaches, hot flashes. - Some phytoestrogens have similar effects. slide-19 Selective Estrogen Receptor Degrader (SERD) slide-20 Selective Estrogen Receptor Degrader (SERD) - Compounds that bind to ER causing it to degrade – causing ER to become more hydrophobic causing it to misfold - Fulvestrant – metastatic breast cancer. - Side effects : headaches, weakness, liver damage. slide-21 Aromatase Inhibitors (AIs) slide-22 Aromatase inhibitors (AIs) - Compounds that inhibit aromatase, preventing the conversion of testosterone into estrogen. - Anastrozole and Letrozole – indicated for ER+ breast cancer - Side effects of anastrozole : similar to menopause :: Hot flashes, bone fracture, headaches, osteoporosis. slide-23 Learning objectives 1. 2. 3. 4. 5. Menopause Estrogen as drugs Selective estrogen receptor modulators (SERMs) Selective estrogen receptor degrader (SERD) Aromatase inhibitors (AIs) slide-24 Progestin and hormonal contraceptives Aikseng Ooi, Ph.D. Skaggs, Room 132 [email protected] slide-25 Learning objectives 1. 2. 3. 4. 5. 6. Progestins are pregestational hormones. Progesterone is a natural progestin. Some progestins are androgenic. Progestins are used as hormonal contraceptives. All hormonal contraceptives must contain progestin. Progestins prevent pregnancy by inhibiting ovulation through suppression of mid cycle LH surge. slide-26 Proges-ns) Progesterone) Progestins – Most)important)proges-n) Progesterone Precursor)to)estrogens,)androgens,)and)adrenocor-cal) –– Most important progestin steroids.) – Precursor to estrogens, androgens, and adrenocortical steroids. Progesterone)is)synthesized)from)cholesterol)in)ovary) )(corpus)luteum),)tes-s,)adrenal,)and)in)placenta.) Progesterone is synthesized from cholesterol in ovary (corpus luteum), testis, adrenal gland, High)dose)micronized)prepara-on)is)required)due)to) and in placenta. )almost)complete)metabolism)in)first)passage) ) )through)the)liver.) High dose micronized preparation is required due to almost complete metabolism in first passage through the liver. slide-27 Progesterone)and)progesta-onal) Progestins agents) slide-28 Major functions of progesterone Females: Preparation of the uterus for pregnancy; maintenance of pregnancy; suppression of menstruation and uterine contractility during pregnancy. Males: May be inhibitory to spermatogenesis; sometimes used as a contraceptive. slide-29 Progesterone effects: many oppose the effects of estrogen Stimulates lipoprotein lipase activity and favors fat deposition Increases body temperature Increases ventilatory response to CO2 Has depressant effects Causes maturation of endometrium to a secretory stage and decreases estrogen-driven proliferation Increases nitrogen excretion Cervical secretions are thick and lowered in pH Supports pregnancy by suppressing menstruation and uterine contractions In breast, triggers single round of mitotic activity each cycle and ductal development slide-30 Clinical uses of progestins Progesterone is the major progestin in human. Some progestin are androgenic – Older synthetic progestins (i.e: L-norgestrel and norethindrone) are more androgenic than newer progestins (eg, norgestimate, desogestrel). Progestins effects: – Induces secretory changes in the endometrium – affect carbohydrate metabolism – stimulate the deposition of fat. – High doses suppress gonadotropin secretion and often cause anovulation in women. Clinical uses: – Hormonal contraception – HRT to reduce the risk of uterine cancer – In assisted reproductive technology methods to promote and maintain pregnancy. slide-31 Progestin toxicity Increase blood pressure Decrease HDL HPG axis interruption Delayed resumption of ovulation after therapy cessation. slide-32 Hormonal contraceptives slide-33 3 types of hormonal contraceptives Combined Estrogen-progestin tablets in constant dosage Combined Estrogen-progestin tablets in varying dosages Progestin only preparations Postcoital contraceptives (a.k.a. emergency contraception / plan B) – high dose progestin to be taken within 72 hours after unprotected sex. slide-34 Some IUDs contain progestin slide-35 General mechanisms of action Preventing mid-cycle LH surge Affects cervical mucus glands, uterine secretion, and endometrium Mechanism-of-action of emergency contraception is not well understood. slide-36 Estrogen and progesterone in menstrual cycle slide-37 Other uses of hormonal contraceptives Female hypogonadism Acne Hirsutism Dysmenorrhea Endometriosis Lower the risks of : – – – – – – – ovarian cysts ovarian and endometrial cancer benign breast disease pelvic inflammatory disease ectopic pregnancy iron deficiency anemia rheumatoid arthritis. slide-38 The new england journal Hirsutism of medicine of free testosterone is often elevated when the total testosterone level is normal in hirsute women. This reflects the relatively low levels of sex hormone–binding globulin in such women, which determines the fraction of plasma testosterone that is free or bound to albumin.14 The levels of sex hormone–binding globulin are suppressed by the hyperinsulinemia of insulin resistance and by androgen excess itself,12,15 so that the total testosterone level may be normal despite excess androgen levels. The level of sex hormone–binding globulin is also low in persons with hypothyroidism; rarely, it is congenitally absent.16 A strategies and evidence B n engl j med 353;24 differential diagnosis Hirsutism must be distinguished from hypertrichosis — generalized excessive hair growth that occurs as the result of either heredity or the use of medications such as glucocorticoids, phenytoins, minoxidil, or cyclosporine. Hypertrichosis, in which hair is distributed in a generalized, nonsexual pattern, is not caused by excess androgen (although hyperandrogenism may aggravate this condition). Approximately half of women with mild hirsutism (i.e., hirsutism with a score of 8 to 15, out of a maximum of 36, on the Ferriman–Gallwey scale) have the idiopathic condition,6 whereas in the remainder of these women and in most of those with more marked hirsutism, androgen levels are elevated. Hyperandrogenism is most often caused Figure 2. Varying Degrees of Hirsutism. by the polycystic ovary syndrome.9,17 As discussed Panel A demonstrates hirsutism with a Ferriman–Gallin a recent review article,18 this diagnosis is made wey score of 1 for the lip and 4 for the chin. In Panel B, when there is otherwise unexplained chronic hythe score is 3 to 4 for the lip and 3 for the chin. Photographs courtesy of Dr. David Ehrmann. perandrogenism and oligo-ovulation or anovulation.19 Documentation of polycystic ovaries is not necessary for the diagnosis of polycystic ovary synen, hirsutism develops without the presence of ex- drome but is a criterion for it if evidence of anovucess androgen (termed idiopathic hirsutism). lation is lacking.20,21 About half of the cases are 6-9 Toxicity Generally very well tolerated because the amount of estrogen is rather low Thromboemobolitic events – side effects of estrogen Breast cancer – weak correlation Breakthrough bleeding during initial phase of the treatment Hirsutism – androgenic effects of some synthetic progestins Weight gain – side effects of progestins slide-39 Learning objectives 1. 2. 3. 4. 5. 6. Progestins are pregestational hormones. Progesterone is a natural progestin. Some progestins are androgenic. Progestins are used as hormonal contraceptives. All hormonal contraceptives must contain progestin. Progestins prevent pregnancy by inhibiting ovulation through suppression of mid cycle LH surge. slide-40