Non-Contraceptive Estrogen and Progestins Flashcards
Physiologic Effects from loss of estrogen
during menopause: Vasomotor symptoms
-Vasomotor symptoms (hot flashes, night sweats) develop on postmenopausal women- which can cause sleep loss and irritability.
Non contraceptive -Therapeutic uses of progesterone
Dysfunctional uterine bleeding
-Dysfunctional uterine bleeding: In the absence of sufficient progesterone, estrogen puts the endometrium in a state of continuous proliferation.
Excessive bleeding can be stopped by administering a progesterone for 10 to 14 days.When dosing is stopped, withdraw bleeding takes place educate patient it can be profuse and associated with cramping.
Treatment objectives include cessation of hemorrhage and long-term goal is to establish regular monthly cycle. Cyclic therapy is used to establish regular monthly cycle.
Transdermal Gel administration for Estrogen
-Apply once daily after showering to one arm , from the shoulder to the rest
Effects progesterone during pregnancy
- Levels increase during pregnancy and these high level suppress contraction of uterine smooth muscle and help sustain pregnancy
- High levels of progesterone can also lead to prolonged transit time and constipation Hi suppressing contraction of the Gastro intestinal smooth muscle
- In the breast, progesterone promotes growth and proliferation of alveolar to tubules (acini), the structures that produce breastmilk
- Progesterone may help suppress maternal immune system, they are by preventing immune attack on the fetus
Estrogen’s role in Glucose homeostasis
Estrogens play an active role in maintaining glucose levels by increasing insulin sensitivity and promotes glucose uptake.
Estrogens also have a role in insulin secretion by protecting pancreatic beta cells
Physiologic Effects from loss of estrogen
during menopause: Bone Loss
bone reabsorption accelerates leading to a 12% loss of bone density (osteoporosis) and also can lead to more compression fractures of the spine and can decrease the height and produce a hump
Metabolic Actions of Estrogen on Blood Coagulation
Suppresses and Promotes
Estrogens promotes blood coagulation by increasing levels of coagulation factors (factors II, VII, IX, and XII) and decreasing factors that suppress coagulation (antithrombin)
Estrogen also suppresses coagulation by increasing the activity of of factors that breakdown fibrin (a protein that reinforces blood clots)
Estrogen During Pregnancy
The placenta produces estrogen in large amounts and the estrogen then stimulates uterine blood flow and growth of uterine muscle.
Transdermal Spray administration for Estrogen
-Apply 1 to 3 sprays once daily to the inner forearm and let it dry at least two minutes before dressing and at least 30 minutes before washing
Physiologic Effects from loss of estrogen
during menopause: Genitourinary Syndrome
- the highest concentrations of ERs are in urethra and vagina and activation of these ERs maintains functional integrity of urethra and vaginal epithelium.
- declining estrogen levels results in atrophic changes in urethra and this can result in urinary incontinence and more UTI’s
- declining estrogen levels results in atrophic changes in the vaginal epithelium result in dryness and dyspareunia (painful intercourse)
- alterations in vaginal secretions result in decreased acidity which can result in more vaginal infections
IV estrogen
Administration is rare and limited to acute emergency control of heavy uterine bleeding
ER beta’s
This is a type of ER receptor that is highly expressed in the :
- Ovary, prostate, bones, blood vessels, and brain
Transdermal Patch administration for Estrogen
Transdermal patches
-alora, climara, vivelle dot
- apply to a clean dry area of skin on the abdomen Or some of the region of the trunk. (Not the breasts or waist line)
- Remove the old patch and apply a new patch once or twice weekly
- Rotate the application site so the same site is not use more than once a week
PR betas
Stimulatory actions are mediated by this receptor
Metabolic Actions of Estrogen on the Bone
Estrogens effect the remolding process by blocking the bone reabsorption part of the process.
This is a positive outcome on bone mass because rapid reabsorption leads to rapid loss in bone density and osteoporosis
Tamoxifen MOA when used
for Osteoporosis
By activating ERs this drug protects against osteoporosis and has a favorable affect on serum lipids.
However, receptor Activation also increases the risk for endometrial cancer and thromboembolism
What should be scheduled for any vaginal bleeding that continues for six months?
An endometrial biopsy
Menopausal hormone therapy
Two regimen types
Can be taken in two different regimens
- ET (Estrogen alone therapy)
- EPT (estrogen plus progestin therapy)
- The purpose of estrogen is to control menopausal symptoms by replacing estrogen that is lost from menopause
- The purpose of protesting is to counterbalance estrogen mediated stimulation of the endometrium which can lead to endometrial hyperplasia and cancer
- *Progestins should not be prescribed for women who have no uterus
- Where women who have had a hysterectomy, ET should be used
Physiologic affects of progesterone during the menstrual cycle
Progesterone is a creative during the second half of the menstrual cycle.
If implantation does not occur, progesterone production by the corpus luteum declines
**The resultant fall and progesterone levels is the principal stimulus for the onset of menstruation and bleeding
- Progesterone affects the endocervical glans as they become scant and viscous (estrogen makes them watery and profuse)
- Progesterone causes the partial pressure of carbon dioxide and blood to fall
at mid cycle, once ovulation occurs, progesterone raise his body temperature by 1°F
Drug Interactions with Estrogens
Inducers of estrogen isoenzymes may LOWER estrogen levels because there’s more bound estrogen.
Inhibitors of estrogen isoenzymes may RAISE estrogen levels because there is more free drug.
Intravaginal Estrogens
- Available as inserts, creams, and vaginal rings.
- Primarily use for treatment of vulval and vaginal atrophy associated with menopause (local effects)
- to apply, for creams apply cream as deeply and as high as possible, Usually at bedtime
- to apply a ring, Insert the ring out deeply as possible, and to leave it in place for three months then replace it with a new ring
- To apply an insert, inform the patient that does it consist of one insert daily for two weeks followed by once or twice a week thereafter
Follicular phase
Days 1-14 of the menstrual cycle
Estrogen is produced in ovaries and secreted from the ovarian follicles.
Estrogens act on the uterus and cause proliferation of the endometrium. One of the ripe follicles ruptures causing ovulation.
Mid cycle- on of these ovarian follicles ruptures and turns in the corpus luteum. (ovulation)
NonContraceptive Therapeutic Effects of Estrogen
HRT THERAPY - usually in combination with progesterone. Menopausal a hormonal treatment alone with estrogen increases the risk for endometrial carcinoma. Adding a progestin in lowers the risk
Female Hypogonadism- absence of ovarian estrogens causes puberty delay. This can be caused by bilateral oophorectomy, Turner syndrome. Treatment promotes reproductive maturation.
Acne-oral estrogen
Cancer palliation- estrogens are used for some palliative therapy in management of prostrate cancer and select metastatic breast cancer.
Gender affirmation therapy for transgender women
Physiologic Effects from loss of estrogen
during menopause: Female Interest- Arousal Disorder
FSIAD presents a decrease in libido or decrease arousal during sexual activity.
Oral Routes of Administration for Estrogen
Most common
Most active compound is estradiol
Transdermal administration for Estrogen Benefits
- The total dose of estrogen is greatly reduced because the liver is bypassed
- There is less nausea and vomiting space
- Less fluctuation of estrogen levels
Selective estrogen receptor modulators
SERMS
- These are drug that activate ER’s in some tissues and block them and others.
- SERMS Or developed in an effort to provide the benefits of estrogen while avoiding its drawbacks
Four SERMS are available in the United States
- tamoxifen, toremifene, raloxifene and bazedoxidine
- None of these offers all the benefits of estrogen and none avoids all of the drawbacks*** teach
PR alphas
Inhibitory actions are mediated by this receptor
Non contraceptive -Therapeutic uses of progesterone
Endometrial hyperplasia and carcinoma
Progestins can provide palliation and women with metastatic endometrial carcinoma, but it does not prolong life
Endometrial hyperplasia, a pre-cancerous condition, can be suppressed with progestins -
benefits derive from counteracting the proliferative effects of estrogen
Treatment options:
Oral:
- megestrol acetate (Megace)
- medroxyprogesterone acetate (Provera)
What are the inappropriate uses for HT treatment?
Okay HT should not be prescribed for purpose of preventing heart disease.
HT should not be used to prevent dementia including Alzheimer’s disease, there is evidence that the EPT may cause dementia and ET can increase the risk for dementia
Physiologic Effects from loss of estrogen
during menopause: Mental Changes
cognitive changes such as difficulty in problem solving, memory
can increase depression and anxiety.
ER alpha’s
This is a type of ER receptor that is highly expressed in the :
-Vagina, Uterus, Ovaries, mammary glands, vascular epithelium and hypothalamus.
Estrogen:
Physiologic Effects on the body: Sex Characteristics
Estrogen is responsible for secondary sex characteristics :
Estrogen is responsible for growth and development of the uterus, vagina, fallopian tubes, and breasts. It also directs pigmentation of the nipples and genitalia.
Adverse Effects of Estrogen medications
-principle concern is potential for endometrial hyperplasia, endometrial cancer, breast cancer and cardiovascular thromboembolic events.
- nausea is most common effect but diminished quickly.
- Educate the patient can take food or take the pill at night to help
- estrogens can cause headaches (migraine), jaundice and liver failure.
- estrogen can cause fluid retention with edema
- cholasma (patchy brown discoloration on face)
Menopausal hormone treatment benefits
Most women seek HT because of vasomotor symptoms.
-Medical benefits include suppression of vasomotor symptoms, prevention of urogenital atrophy, and prevention of osteoporosis and related fractures fractures
Pituitary Hormones Role in Menses
FSH & LH
During the first half, FSH acts on the developing ovarian follicles causing them to mature and secrete estrogens.
The resultant rise in estrogen causes a negative feedback system to pituitary thereby suppressing FSH secretion.
At mid cycle (ovulation), LH levels rise abruptly. This LH surge causes the dominant follicle to swell, burst and release its ovum.
After ovulation, the ruptured follicle becomes a corpus luteum and still under the influence of LH, it begins to secrete progesterone.
Contraindications of Estrogens
SHOHLD NOT be taken by anyone with history of DVT, pulmonary embolism, stroke, MI SECONDARY to thromboembolic events.
Do NOT give to pregnant women
Do NOT GIVE TO women with unknown cause vaginal bleeding
Do not give to patients with histories of liver disease, estrogens dependent tumors or breast cancer
Adverse effects of progesterone
Breast tenderness, headache, abdominal discomfort, depression, arthralgias
Effects on the endometrium can lead to spotting, breakthrough bleeding, and irregular menses
Transdermal Emulsion administration for Estrogen
Example: Estrasorb
-Apply each morning to the top of both sides and the back of both calves
Luteal phase
Days 15- end of cycle
Estrogens and progesterone are not produced by the corpus luteum. These hormones maintain the endometrium in a hypertrophied state.
If fertilization does not occur:
At the end of the cycle, the corpus luteum atrophies and progesterone and estrogens levels decline.
Thickened Endometrium will start to break down causing menstruation.
Non contraceptive -Therapeutic uses of progesterone
Pre-term pregnancy
Progestins are used to support early pregnancy and women with corpus luteum deficiency syndrome and in women who undergo in vitro fertilization
Makena injections are approved for preventing preterm birth in women with the Singleton pregnancy and history of preterm delivery
Raloxifen
Similar to tamoxifen but it does not activate ERs in the endometrium and hence does not pose a risk for uterine cancer.
This drug protects against breast cancer and osteoporosis, and increases the risk for thromboembolism and hot flashes
*This is the only approved drug for prevention and treatment of osteoporosis and for prevention of breast cancer and high-risk women
Metabolic Actions of Estrogen on CNS
Estrogens have a neuroprotective effects by defending the neurons from the effects of oxidative stress.
Estrogen also stimulates growth of nerve factors.
Estrogen preserves cognitive function, enhances short term memory and regulates mood.
Discontinuing hormone therapy
What are the two methods?
They are no firm guidelines for stopping HT, but it can be immediate cessation or tapering slowly.
Regardless of which method is used only the dosage of estrogen should be lowered.
**For women on EPT, the progesterone dosage should remain unchanged because lowering the progesterone my permit estrogen to stimulate endometrial growth
Non contraceptive -Therapeutic uses of progesterone
Amenorrhea
Progestins can induce menstrual flow
Treatment with a progestin for 5 to 10 days will be followed by with job leading one stopped
Estrogen:
Physiologic Effects on the body: Reproductive Tract
Estrogen’s effect the menstrual cycle by:
- promoting ductal growth in breast
- promotes thickening the vaginal epithelium
- promotes proliferation of the uterine endothelium
- promotes copious secretion of thickened mucus from the endocervical glands
At the end of the cycle estrogen levels decline.
- Estrogen also increases vaginal acidity
HT treatment for prevention of osteoporosis
HT reduce his post menopausal bone loss and decrease the risk for osteoporosis and fractures.
-Requires long-term HT treatment, when HT has stopped bone mass rapidly decreases
HT therapy
Treatment of vasomotor symptoms
Lowest effective door should be used
Vasomotor symptoms subside overtime so they need for continued HT should be reassessed at regular intervals
Other options are available for high risk women:
- lexapro (SSRI) and pristiq (SNRI)
- pregabalin (gabapentin)
Phytoestrogens do not help
Mechanism of Action:
Estrogen
estrogen acts primarily through its receptors in the cell nucleus; NOT ON CELL SURFACE
In order to produce effects, Estrogen must diffuse INTO the cells, migrate to nucleus and then binds with estrogen receptor (ER)
The ER complex then binds with an estrogen response element on a target gene, then altering the rate of gene transcription.
Phytoestrogens
These are plant-based compounds that have a weak estrogenic activity. The most commonly used are the Isoflavones which Come from plant such as soy beans and red clover
This is considered the natural way to manage symptoms for menopause
Women should not use these if they have a history of thromboembolic events or personal history of breast uterine or ovarian cancer
Metabolic Actions of Estrogen on the Cardiovascular System
Estrogens lower the risk for cardiovascular disease.
ER alpha receptor’s in the vascular smooth muscle respond to activation which then results in the release of nitric oxide, vasodilation and increased perfusion.
Estrogens also decrease atherosclerosis by reducing LDL levels and elevating HDL levels.
Cardiovascular disease is less common in premenopausal then postmenopausal.
MOA of Progestins
As with estrogen, receptors for progesterone are found in the cell nucleus.
Progesterone must diffuse across the cell membrane, migrate to the nucleus, and then bind with a progesterone receptor (PR)
Progesterone-PR complex Then vines with a progesterone regulatory element on a target Jean, there by rapidly increasing Gene transcription
Menopausal hormone treatment risks
-When making decisions regarding whether or not to prescribe we HT, risk factors for the individual must be inventoried.
Younger populations are better to prescribe for
For women with history of breast cancer, cardiovascular disease the risks go up
For most women, the benefits of long-term HT for disease prevention do not outweigh the risks so long-term HT should be avoided
-The only approve indication for long-term projects done therapy is protection against endometrial cancer
Short term HT therapy often do justify the risks.
**HT should be used in the lowest dosage for the shortest time needed
Physiologic Effects from loss of estrogen
during menopause: Lipid Metabolism
significant increases in LDL cholesterol with decreases in HDL
Tamoxifen MOA when used
for Breast cancer
First SERM to be widely used
MOA: By blocking ERs in the breast this drug can inhibit cell growth in the breast and as a result can be used to treat breast cancer.
-Unfortunately blockade of the ERs also produces hot flashes
