2. Objectives
Describe female’s menstrual cycle and associated
hormonal changes
Evaluate literature for recent developments in
Flibanserin for premenopausal women
Describe the physiology of normal menopause
Describe available options for hormone
replacement therapies
Discuss the advantages and disadvantages of
bio-identical hormone replacement therapy
Discuss risks associated with hormone
replacement therapy
3. The Key Female Hormones
•Hypothalamus
–Gonadotropin-releasing hormone
•Anterior pituitary
–Follicle-stimulating hormone (FSH)
–follicular development
–Ovarian Function
–Luteinizing hormone (LH)
–Stimulates ovulation
–Production of Corpus Luteum
Alcohol Effects on Female Reproductive System. http://pubs.niaaa.nih.gov/publications/arh26-4/274-281
5. Menstrual Cycle
Gynecologic and Obstetric Disorders: Hormone Therapy in women. Pharmacotherapy: A Pathophysiologic Approach, 9th edition.
6. Menstrual Cycle
Follicular Phase:
Day 1: First day of menses
Day2-4: Small group of follicles grow and develop
Day 5-7: One follicle dominates
Ovulation:
LH surge and release of oocyte
Luteal Phase:
Formation of Corpus Luteum
If pregnant: Sustaining endometrial lining until formation
of placenta
Not pregnant: Progesterone levels decrease and cause
endometrial shedding.
7. Flibanserin (Addyi)
Indication Hypoactive sexual desire disorder in premenopausal
women
Dosage 100 mg PO QHS
Contraindicatio
n
Hepatic impairment, alcohol and CYP3A4 inhibitors
Warning Syncope, hypotension and CNS depression
Side Effects Dizziness, somnolence, nausea, fatigue, insomnia, dry
mouth
Interactions Oral contraceptives, digoxin, CYP3A4 inducers, CYP2C19
inhibitors
MOA Serotonin Receptor agonist (5-HT1A) and (5-HT2A)
antagonistHighlights of Prescribing Information: ADDYI (Flibanserin), 2015. Access on
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022526lbl.pdf
8. Studies on Flibanserin (ADDYI)
3 Trials over 24
weeks
SNOWDROP Trial:
(n=949)
VIOLET Study: (n=880)
DAISY Trial: (n=1581)
Outcome Measures:
Satisfying sexual events
Female sexual function
Female sexual desire
Female sexual distress
Results:
100 mg PO Daily
Effective in pre-
menopausal women
Increase in satisfying
sexual events
Increase Female sexual
function Index
Decrease Female Sexual
Distress
10. Menopause
Cessation of menses for at least 12 months
Loss of ovarian follicular activity leading to
hormonal insufficiency
In USA, average age is 51 years old
Goal of therapy: alleviate symptoms, improve
quality of life and minimize side effects
11. Menopause Symptoms
Hot flush and night sweats
Depression and anxiety
Sleep disturbances and mood changes
Problems with concentration and memory
Sexual dysfunction and vaginal dryness
Joint pain
Headache
Weight gain
12. Menopausal Treatment
Non-Pharmacological
Layered clothing
Lowering room temperature
Decrease intake of hot spicy foods
Decrease intake of caffeine and hot drinks
http://www.markwoodcartoonist.myzen.co.uk/menopause1.html
13. Menopausal Treatment
Pharmacological
PO
equine estrogen
Premarin
Synthetic estrogen
Cenestin, Enjuvia
Esterified estrogen
Menest
Estradiol acetate
Femtrace
Micronized estradiol
Estrace
Vaginal
Ring
Cream
Tablet
Implanted
Not Available in USA
Transdermal
Emulsion
Gel
Spray
Estrogen
15. Side Effects
Breast tenderness
Nausea
Hypertension
Cerebrovascular
accidents (rare)
Thromboembolic
complications (rare)
Increase in cholesterol
Heavy bleeding
Irritability
Increased appetite
Weight gain
Decreased libido
Pruritus (itchiness)
Acne and oily skin
Tiredness and
depression
Bloating
Headache
Estrogen Progesterone
16. Bio-identical Hormone
Replacement Therapy
Identical to natural
hormones
Individualized
Dosage
Allergies
Preferred route
Lack of scientific
evidence for superiority
Safety and efficacy
Lack of FDA regulation
Labeling issues
Advantages Disadvantages
Compounded bioidentical menopausal hormone therapy. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and
American Society for Reproductive Medicine Practice Committee. ertility and Sterility® Vol. 98, No. 2, August 2012 0015-0282
18. REFERNCES
Alcohol Effects on Female Reproductive System.
http://pubs.niaaa.nih.gov/publications/arh26-4/274-281.htm
The hormones: Coticoids. Tulane University
http://e.hormone.tulane.edu/learning/corticoids.html
Gynecologic and Obstetric Disorders: Hormone Therapy in women. Pharmacotherapy: A
Pathophysiologic Approach, 9th edition.
http://accesspharmacy.mhmedical.com/book.aspx?bookID=689
Highlights of Prescribing Information: ADDYI (Flibanserin), 2015. Access on
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022526lbl.pdf
DeRogatis, L.R. Komer, L. et. Al. Treatment of Hypoactive Sexual Desire Disorder in
Premenopausal Women: Efficacy of Flibanserin in the VIOLET Study. 2012 International
Society for Sexual Medicine. DOI: 10.1111/j.1743-6109.2011.02626.x
Thorp, J. Simon, J. et. al. Treatment of Hypoactive Sexual Desire Disorder in
Premenopausal Women: Efficacy of Flibanserin in the DAISY Study. 2012 International
Society for Sexual Medicine. DOI: 10.1111/j.1743-6109.2011.02595.x
Simon, J. Kingsberg, S.A. et. Al. Efficacy and safety of flibanserin in postmenopausal
women with hypoactive sexual desire disorder: results of the SNOWDROP trial. 2013 The
North American Menopause Society. DOI: 10.1097/gme.0000000000000134
Menopause Comical Image. http://wefollowpics.com/menopause-cartoons-humor/
Compounded bioidentical menopausal hormone therapy. American College of
Obstetricians and Gynecologists Committee on Gynecologic Practice and American
Society for Reproductive Medicine Practice Committee. ertility and Sterility® Vol. 98, No.
2, August 2012 0015-0282
Ovarian steroids
Estrogen
Estradiol – most potent - produced by the developing follicle
Estrone
Progesterone - produced by the corpus luteum
Androgens (androstenedione)
Produced by the ovarian stroma and adrenal gland
Extra-ovarian sites for steroid production
Adrenal gland - androstenedione
Adipose tissue – estrone
Skin fibroblasts – testosterone/estrone
Corticoids are a group of chemically related steroid hormones. Steroids are a special kind of fat molecule with a four-ringed, carbon atom backbone or core, like their cholesterol predecessor. A series of chemical reactions, spurred by proteins called enzymes, remove and add groups to cholesterol's polycyclic (many-ringed) core. These actions transform it first into the steroid pregnenolone, then into 11-deoxycorticosterone or 17-α-hydroxyprogesterone, and finally into the corticoid hormones corticosterone, cortisol, and aldosterone.
The adrenal glands, nestled atop the kidneys, produce glucocorticoids and mineralocorticoids in humans and other mammals. Fish, amphibians, reptiles, and birds make them in a similar organ called the interrenal gland.
Follicular:
The first day of menses is referred to as day 1 of the menstrual cycle and marks the beginning of the follicular phase.
The follicular phase continues until ovulation, which typically occurs on day 14.
The time after ovulation is referred to as the luteal phase, which lasts until the beginning of the next menstrual cycle.
The median menstrual cycle length is 28 days, but it can range from 21 to 40 days.
In the first 4 days of the menstrual cycle, FSH levels increase and recruitment a small group of follicles for growth and development.
Between days 5 and 7, one follicle becomes dominant and later ruptures, releasing the oocyte. The dominant follicle develops increasing amounts of estradiol and inhibin, which cause a negative feedback on the hypothalamic secretion of GnRH and pituitary secretion of FSH, causing atresia of the remaining follicles recruited during the cycle.
Estradiol stops the menstrual flow from the previous cycle, thickening the endometrial lining of the uterus to prepare it for embryonic implantation. Estrogen is responsible for increased production of thin, watery cervical mucus, which will enhance sperm transport during fertilization.
Ovulation:
When estradiol levels continue to be elevated, the pituitary gland releases a midcycle LH surge which causes ovulation.
This LH surge stimulates the final stages of follicular maturation and ovulation (follicular rupture and release of the oocyte). On average, ovulation occurs 24 to 36 hours after the Conception is most successful when intercourse takes place from 2 days before ovulation to the day of ovulation.
Luteal phase:
Remaining luteinized follicles become the corpus luteum, which synthesizes androgen, estrogen, and progesterone
Progesterone helps to maintain the endometrial lining, which sustains the implanted embryo and maintains the pregnancy.
It also inhibits development of new follicles.
If pregnancy occurs, human gonadotropin hormones prevent corpus luteum from breaking down and continue to produce estrogen and progesterone for a successful pregnancy until the placenta is formed. If fertilization or implantation does not occur, the corpus luteum degenerates, and progesterone production declines. As progesterone levels decline, endometrial shedding (menstruation) occurs, and a new menstrual cycle begins. At the end of the luteal phase, when estrogen and progesterone levels are low, FSH levels start to rise, and follicular recruitment for the next cycle begins.
Flibanserin or ADDYI was recently approved by FDA in August 2015 and it has been labeled as “women’s Viagra” and it is no surprise that the color of the pills are pink just like Viagra is blue. It is only available though the REMS program (Risk evaluation and mitigation strategy)
Interestingly: it is indicated for hypoactive sexual desire disorder in premenopausal women and not post menopausal women, probably because decrease in libido is expected with menopause.
Before prescribing ADDYOI, the physician must rule out other physiologic and mental conditions, and medications that may cause hypoactive sexual desire as well as relationship problems.
Current approved dosage is 100 mg PO at bedtime because taking this medication during daytime increases the risk of syncope, hypotension and possible accidental injuries. Patients must discontinue medication if no improvement is seen within 8 weeks. This medication is not recommended for nursing or pregnant women.
This medication is contraindicated in patients with liver disease, alcohol use and P450 inhibitors.
Warnings and precautions include: Hypotension and Syncope with ADDYI Alone and CNS Depression (e.g., Somnolence, Sedation). Exacerbated by other CNS depressants, Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how ADDYI affects them.
Commonly observed side effects are Dizziness, somnolence, nausea, fatigue, insomnia, dry mouth but at this point, FDA is looking for more adverse drug reactions since the drug has been manufactured and released to public.
Addyi mainly interacts with Oral contraceptives, digoxin, CYP3A4 inducers (St. John Wort, phenobarbitals, rifampin, glucocorticoids), CYP2C19 inhibitors (omeprazole, esomeprazole, cimetidine, modafinil)
The mechanism of action of this drug is still unknown however, flibanserin has high affinity for some serotonin receptors and acts as an agonist while for some other receptors, it acts as an antagonist.
Research has shown that 25% of women experience severe vasomotor symptoms (e.g., hot flushes and night sweats), 30% experience severe psychological symptoms (e.g., depression, anxiety), and 50% report moderate to severe symptoms of sleep disturbance, joint pain, or headache, and at least one in four women have sexual dysfunction.6,7
Women who experience severe symptoms, either from early in the menopause transition or from their final menstrual period, are likely to continue to experience severe symptoms for several years.6
Women with a history of depression are nearly five times as likely to be diagnosed with depression during the perimenopause, whereas women with no history of depression are two to four times more likely to have a diagnosis compared with premenopausal women.8
In addition to the symptoms of menopause, loss of estrogen production results in significant metabolic changes including effects on body composition, lipids, vascular function, and bone metabolism. The menopause transition is associated with a significant increase in central abdominal fat, which may occur without commensurate change in body weight.9
Nonpharmacological options may alleviate mild symptoms but are unlikely to be effective for severely symptomatic women.
Although it is frequently suggested that menopausal symptoms can be managed effectively with lifestyle modifications, including wearing layered clothing that can be removed or added as necessary, lowering room temperature, decreasing intake of hot spicy foods,caffeine, and hot beverages, exercise, and other good general health practices.
Role of estrogen in body:
Stimulate development of vagina, uterus, and uterine tubes and secondary sex characteristics
Contribute to growth of auxiliary and pubic hair
Alter distribution of body fat
Role in development of endometrial lining
Sensitize the myometrium to oxytocin to stimulate labor
Stimulate protein synthesis in the brain and may affect mood and emotions
Prevent osteoporosis
Increase in HDL, slight reduction in LDL
Enhance coagulability of blood
Facilitate loss of intravascular fluid into extracellular space
Cholelithiasis
Role of Progesterone in body:
Reproductive tract
Influences endocervical glands and changes secretions to scant, viscid material
Very important for maintenance of pregnancy
CNS effects
Increases body temperature
Respiratory
Alters function of respiratory centers
Metabolic
Favors fat distribution
Increases basal insulin and insulin response to glucose
Progesterone:
Changing from a cyclic to a continuous-combined regimen or changing from one progestogen to another may decrease the incidence or severity of untoward effects.Newer methods and routes of progestogen delivery (intrauterine device or vaginal gel) may be associated with fewer adverse effects.
Bioidentical hormones are plant-derived hormones that are chemically similar or structurally identical to those produced by the body
Compounded bioidentical hormones are made by a com- pounding pharmacist from a health care provider's prescrip- tion and are available in various routes of administration, including oral, sublingual, and percutaneous or as implants, injectables, and suppositories. Unlike drugs that are approved by the FDA to be manufactured and sold in standardized dos- ages, compounded preparations often are custom-made for a patient according to a health care provider's specifications. For example, in the case of menopausal hormone therapy, there is an FDA-approved progesterone product that contains peanut oil. A health care provider's prescription to compound progesterone to eliminate the peanut oil can allow a patient with a peanut allergy to safely use the drug.
Other potential advantages of compounded hormone therapy compared with FDA-approved conventional hormone therapy include greater dosage flexibility, availability of low-dose preparations, and potential lower cost.
Disadvantages:
Because of a lack of FDA oversight, most compounded prep- arations have not undergone any rigorous clinical testing for either safety or efficacy, the purity, potency, and quality of compounded preparations are a concern. Because of variable bioavailability and bioactivity, underdosage and overdosage are both possible
Compounded preparations are not regulated by the FDA. Al- though technically all compounded prescription drug prepa- rations could be considered unapproved new drugs, the FDA has adopted a policy of enforcement discretion, allowing legitimate preparation of compounded formulations to be regulated by state boards of pharmacy, with a provision of stepping in when dangerous practices must be addressed and when drug manufacturing occurs under the guise of com- pounding. There are currently no specific regulations by the FDA on what constitutes a legitimate claim for compounded drug preparations. In general, states regard compounding to be part of the practice of pharmacy. In addition, individual states' pharmacy acts usually permit other licensed practi- tioners (e.g., physicians, nurse practitioners, and others with prescriptive authority) to engage in the practice of pharmacy compounding for their own patients.
The FDA requires manufacturers of FDA-approved products that contain estrogen and progesterone to use class labeling (the black box warning indicating a drug with special prob- lems, particularly ones that may lead to death or serious in- jury) reflective of the findings of the WHI. However, because compounded preparations are not approved by the FDA and have no official labeling (i.e., a package insert), they are exempt from including contraindications and warnings.
The potential risk of hormone therapy include ovarian cancer, endometrial cancer, breast cancer, venous thromboembolism, gallbladder disease, and possibly cardiovascular disease and lung cancer in older women. The level of risk may depend on the hormonal regimen used), the route of administration, dose, duration of therapy, age at treatment initiation, and the patient’s other risk factors.
Current recommendations are to evaluate the patent annually for the need to continue hormone replacement therapy and for certain regimens such as Estrogen therapy alone, there is a maximum of 5 years of use
