CC BY
31
The effect of low-dose drospirenone and 17|-estradiol for correction of the manifestations of climacteric syndrome...
DOI: http://dx.doi.org/10.20534/ESR-17-3.4-45-48
Gasparyan Susanna, Department of Obstetrics and gynecology Stavropol State Medical University, Russia Drosova Larisa, Department of Obstetrics and gynecology Stavropol State Medical University, Russia Khripunova Alesya, Stavropol State Medical University, Russia 2Department of Public Health, Health Care and Medical Informatics
Karpov Sergey,
Department of neurology, neurosurgery and medical genetics Stavropol State Medical University, Russia Vishlova Irina,
Department of neurology, neurosurgery and medical genetics Stavropol State Medical University, Russia E-mail: [email protected]
The effect of low-dose drospirenone and 17p-estradiol for correction of the manifestations of climacteric syndrome in postmenopausal women
Abstract: vasomotor symptoms are the most common symptoms of menopause, requiring treatment with estrogen or with progestogen. Recent international guidelines recognize the need to use the lowest effective dose of hormone replacement therapy. Drospirenone (DR) in combination with 17b-estradiol (E) is used as hormone therapy (HT) for relief the symptoms and prevention of postmenopausal osteoporosis. The review presents data of 2 large randomized controlled studies that evaluated the lowest effective dose combination of DR/E, the safety of this dose for endometrium, identified features of its pharmacodynamics and pharmacokinetics, depending on various factors. The minimum effective dose for the relief of HF without causing any significant impact on the endometrium is DR of 0,25 mg/E of 0,5 mg. According to the results of the pharmacokinetic study a correlation between effectiveness of low dose DR/E with DR and E exposure levels was showed, and smoking reduces the effectiveness of hormonal therapy. This drug not only copes with moderate to severe hot flashes, but also reduces the incidence of symptoms of vulvovaginal atrophy, improving quality of life.
Keywords: menopause, drospirenone, 17b-estradiol, hot flushes, endometrial hyperplasia.
Climacteric syndrome — a complex of vegetative-vascular, mental and metabolic and endocrine disorders, occurring in women on hormone background with fading of ovarian function and the overall age involution of the body — are observed, according to the literature, in 30-60% of women. In the pathogenesis of climacteric syndrome, the main role belongs to the mismatch of the activity of hypothalamic brain structures to ensure coordination of the cardiovascular, respiratory and temperature reactions with emotional and behavioral reactions. The earliest and specific manifestations of the climacteric syndrome, the so-called hot flashes, reflecting disruption in the central mechanisms controlling the synthesis and pulsatile release of neuropeptides hypothalamus (lyuliberina, thyrotropin-releasing hormone, corticotropin, and others.), which are involved in regulating the secretion of tropic pituitary hormones, cardiovascular activity and respiratory systems, as well as in the regulation of the formation of emotional-behavioral reactions. When menopause syndrome manifested that took place earlier, in violation of higher regulatory centers, as evidenced by the presence of a significant number of women burdened heredity, concomitant extragenital diseases and paroxysmal autonomic disorders.
These violations, together with changes in cognitive function and mood changes reduce the quality of life of both the patient and the next of kin, making the problem even more significant.
To this day, the only method of treatment of climacteric syndrome (CS) having evidence base remains MGT, whose efficiency reaches 95%. Medical intervention is required in approximately 1/3 of women with vasomotor symptoms of menopausal syndrome. Latest international clinical guidelines recognize the need to use the lowest effective dose of HT in accordance with the objectives of the treatment for each woman. The Endocrine Society in 2010 undertook a review of the existing data in order to assess the benefits and risks of HT in postmenopausal women.
Of all the natural estrogen estradiol it is the most active and has the highest affinity for the estrogen receptors. Target organs for estrogens include, inter alia, the uterus, the hypothalamus, the pituitary gland, vagina, mammary glands, bone (osteoclasts).
Other effects of estrogens include: reducing insulin and glucose concentrations in the blood, mediated by receptors vasoactive effects and independent effect on the receptors of the smooth muscle cells of the vessel walls. Estrogen receptors have been identified in the heart and coronary arteries.
Oral administration of natural estrogens has advantages in cases of hypercholesterolemia due to more favorable effects on lipid metabolism in the liver. Monotherapy estrogen has a dose dependent stimulatory effect on mitosis and proliferation of the endometrium, and thus, increases the incidence of endometrial hyperplasia and
therefore the risk of endometrial cancer. To avoid endometrial hyperplasia, need combination with progestogen. According to the analysis, Endocrine Society concluded: the minimum effective dose of estrogen used in postmenopausal symptomatic treatment provides and maintains bone mineral density. In addition, standard or low dose of hormones used in healthy postmenopausal women did not significantly increase the risk of cardiovascular diseases.
Also, to facilitate postmenopausal symptoms and prevention of osteoporosis as HT in combination with 17b-estradiol effectively used drospirenone. Drospirenone pharmacological profile similar to endogenous progesterone, in addition, it has antimineralocorticoid and antiandrogenic effects, which makes it leader programs antiag-ing therapies. Drospirenone is a potent progestogen with a central system inhibitory action on the hypothalamic-pituitary-gonad. In women of reproductive age drospirenone has a contraceptive effect; when administered as a single agent in drospirenone, ovulation is suppressed. The threshold dose of drospirenone for the suppression of ovulation is 2 mg/day. Complete transformation subjected previously exposed endometrial estrogen dosing occurs after 4 or 6 mg/day for 10 days. Drospirenone is capable of competitive antagonism with aldosterone. Women who are in the clinical study were obtained in addition to estradiol, drospirenone, rarely mentioned peripheral edema than those taking only estradiol [10].
It should also be emphasized that drospirenone has neither the glucocorticoid or antiglucocorticoid activity and has no effect on glucose tolerance and insulin resistance. In 2007-2008. in the US was a randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone/estradiol for the treatment of moderate to severe vasomotor symptoms of menopausal syndrome in women in post-menopause. Its purpose was to identify the lowest effective dose of drospirenone/estradiol for their leveling [11].
The study enrolled women aged 40 years and older who developed spontaneous amenorrhea for 12 months or more, or spontaneous amenorrhea with the level of follicle-stimulating hormone in the blood is higher than 40 mIU/mL within 6 months or more, or patients after bilateral oophorectomy with/without a hysterectomy within
6 weeks previously conducted after surgery. Patients experiencing hot flashes per day 7-8 moderate-to-severe hot flushes or 50-60 week of moderate to severe manifestations of climacteric syndrome for at least
7 consecutive days during the study. The results of mammography data transvaginal ultrasound (TSS) in women with preserved uterus and endometrial biopsies corresponded to the reference values.
Exclusion criteria were: use of any hormones (progestogens, estrogens or combinations thereof in any form of steroid hormones), anticoagulants, antibiotics, anti-epileptic drugs and CYP3A4-inhib-itors and inducers of selective serotonin reuptake inhibitors, norepinephrine or monoamine, raloxifene or tamoxifen for last 8-24 weeks. 735 partitioned into groups of women depending on the preparation obtained in a ratio of1: 1: 1: 1-0.25 mg drospirenone/estradiol 0.5 mg, 0.5 mg drospirenone/estradiol 0.5 mg or 0.3 mg oestradiol placebo. The women were asked to record the daily frequency and severity of hot flashes during the entire period of observation in the diaries of self-control. Evaluates the primary indicators: frequency weekly dynamics of the tides from baseline to the current rate to 4 and 12 weeks, and the average weekly rate of frequency of hot flushes and 4 and 12 weeks of observation. Scale of severity varied from 0 (no symptoms), 1 (mild symptoms, sensation of heat without perspiration), 2 (moderate symptoms, sensation of heat through sweat may continue the current activities), 3 (severe symptoms, sensation of heat with sweating, causing termination of current activity), in accordance with the recommendations of the GT acceptance [12].
Also monitor the secondary indicators: changes in vaginal pH and vaginal maturation index of discharge; the ratio of participants to vulvovaginal atrophy and urogenital symptoms.
The average daily level of tidal gravity calculated by the formula: [(2 x number of moderate hot flushes) + (3 x number of severe hot flushes]/the total number of hot flushes Average weekly rate of frequency of hot flushes was calculated by calculating the average value of the daily severity of hot flashes In addition to clinical assessment indices performed.. laboratory tests (general clinical and biochemical blood tests, urinalysis), evaluation of endometrial thickness (ultrasound), immunohistochemistry (endometrial biopsy), physical examination, Pap test, identification of adverse effects of treatment, were a record degree of blood loss (in women with preserved uterus).
The mean age of subjects was 53.5 years. Time elapsed from the date of last menstrual period, amounted to an average of 9.36 years. Patients with hysterectomy accounted for 54.4%, ovariectomy -34.4% (including 77.1% with bilateral ovariectomy). The most common co-morbidities were hypertension (20% of participants) and dyslipidemia (13.5%). The frequency of these states was comparable in all groups. Fully completed the study (12 weeks), only 635 (86.4%) participants. The remaining 100 (13.6%) patients had never taken or prematurely discontinued use of the drug that has been associated with non-participation, adverse effects (NOE) or the loss of contact with the test. Average weekly frequency of hot flashes in patients of all 4 groups was similar and ranged between 73.25 (group estradiol 0.3 mg) to 74.64 (0.25 mg drospirenone/estradiol 0.5 mg). The average daily level of severity of hot flushes was similar between groups: 2.52 (placebo group) - 2.58 (0.25 mg drospirenone/estradiol 0.5 mg).
In the group of patients receiving drugs registered more significant decrease in average weekly frequency ofhot flushes and the mean daily severity of hot flushes compared with placebo at 4 and 12 weeks of the study. The frequency and severity of hot flushes were significantly different in the drospirenone group compared with the placebo group. Averages of frequency and severity of hot flushes by 12-week study were significantly different in the group of 0.5 mg of drospirenone/estradiol 0.5 mg group as compared to 0.25 mg of drospirenone/estradiol 0.5 mg, with estradiol group 0.3 mg were much smaller. Reducing vaginal pH at the end of the study it was more pronounced in all treatment groups compared to placebo: 0.63 (0.94) 0.63 (0.87) 0.66 (0.97) and 0.06 (0,7) group drospirenone 0.25 mg/estradiol 0.5 mg, 0.5 mg drospirenone/estradiol 0.5 mg Estradiol 0.3 mg and placebo, respectively (p < 0,0001). Reducing the percentage of parabasal cells and an increase in surface epithelial cells counted using the maturation index of the vaginal fluid were much more significant in all treatment groups compared with placebo (p < 0,0028). Only a few women complained of symptoms ofvulvovaginal atrophy or urogenital complaints in addition to the tides (the statistical analysis of this group has not been done).
Therefore, the combination of drospirenone 0.25 mg/estradiol 0.5 mg is the lowest effective dose. Reducing vaginal pH and increase the maturation index of the vaginal fluid in all the studied groups treated compared to placebo demonstrate the beneficial effect in the treatment of symptoms ofvulvovaginal atrophy, increasing compliance in patients older age group.
The second important aspect of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of drospirenone and estradiol, as well as the influence of factors such as body weight, body mass index (BMI) and smoking. Also demonstrated the relationship between exposure to estradiol and drospirenone
The effect of low-dose drospirenone and 17|-estradiol for correction of the manifestations of climacteric syndrome.
and efficiency, based on the measured decrease in the number of hot flushes.
Equilibrium concentrations of estradiol were described using a one-compartment model with first-order elimination, and absorption of the zero order, which showed that the elimination of estradiol concentration dependent, whereas the absorption is not dependent. The initial concentration of estradiol increased with BMI (p < 0,001), which was confirmed by other researchers [13]. The clearance (CL/F) of estradiol at steady state was 39%, which is significantly higher in smokers than non-smokers (1,559 l/h against 1,120 l/h; p < 0,001). The effect of smoking on CL/F can be explained estradiol complicated complex metabolic effects, including the induction of CYP1A1, which is involved in the metabolism of estradiol [14; 15]. Other indicators, such as age, height, body mass, muscle mass, body surface area, body fat mass, race, dose, and treatment of alcohol use, no significant influence, in addition to BMI and smoking, the concentration of estradiol.
FC drospirenone is described by a linear two-compartment open model with first-order elimination from the central chamber and sustained absorption of the first order orally administered dose. Individual variability described for CL/F drospirenone. CL/F increases linearly with an increase in body weight (p < 0,001), but this ratio is not preserved when 5% were excluded women weighing 110 kg or more. This was not found other factors that have a significant impact on the FC drospirenone.
A generalized linear model with a negative binomial distribution was used to model the changes in the frequency of hot flushes from baseline to week 12 according to the area under the curve of concentration vs. time to estradiol, and other factors. In addition to the expected strong relation (p = 0,02) between the exposure of estradiol and a relative reduction in the incidence of moderate to severe hot flashes degree, it was awarded an additional pharmacodynamic effect of smoking on the effectiveness of treatment (p < 0.01).
According to the data, smoking reduces the effectiveness of HT estradiolnezavisimy through a mechanism that leads to the lower level of estradiol in the blood, which complements the previous findings about the effects of smoking on the metabolism of estradiol [10].
Consequently, this study demonstrated that the efficacy of low doses of drospirenone/estradiol to reduce vasomotor symptoms correlates with an exposure of drospirenone and estradiol in the serum, while smoking adversely affects the effectiveness of treatment.
Another large study focused on assessing the risks of endometrial hyperplasia and characteristics of bleeding in patients receiving 0.25 mg drospirenone/estradiol 0.5 mg for 12 months. The objective was to characterize the changes of the endometrium and bleeding pattern during continuous, long-term therapy of 0.25 mg drospire-none/estradiol 0.5 mg compared to treatment norethisterone acetate (NETA) 0.5 mg/1.0 mg estradiol (a preparation containing a double dose of estradiol, unlike drospirenone 0.25 mg/estradiol 0.5 mg), [16].
Inclusion criteria: women with an intact uterus between the ages of 40 and 65 years, who developed spontaneous amenorrhea for 12 months or more, or spontaneous amenorrhea with the level of follicle-stimulating hormone in the blood is higher than 40 mIU/mL within 6 months or more, or the patient after bilateral oophorectomy without a hysterectomy (6 weeks after surgery). Women had to have indications for induction of menopausal hormone therapy confirmed by researchers, with no evidence of endometrial hyperplasia or cancer, according to the screening endometrial biopsy.
Exclusion criteria were: use of vaginal hormone preparations or estradiol in the form of nasal sprays for 1 week, transdermal estrogen or estrogen-progestin drugs for 4 weeks, oral estrogen and/or
progestogen, or intrauterine forms of progestogen for 8 weeks to provide informed consent. Progestogen implants and injectable forms of estrogen for 3 months, estrogens tablets or injectable forms of progestogen for 6 months and have been banned. The presence of clinically significant disease (including contraindications to HT) or laboratory abnormalities were additional exclusion criteria. supplementation was expelled the following drugs: steroids, anticoagulants, antiepileptic drugs, antibiotics, inhibitors of CYP3A4-inducers, and selective estrogen receptor modulators (raloxifene or tamoxifen).
The primary measure of efficacy was the proportion of women with histological conclusion endometrial biopsy "hyperplasia or transition typical form in atypical" ("hyperplasia, or atypia") at any time during the trial or after the 13 cycles of treatment, which was evaluated by three independent pathologists [17; 18].
The secondary measure of effectiveness was the rate of amenorrhea (defined as no bleeding or spotting) for 1-3, and 10-12 months of treatment, according to the self-monitoring diaries, fills patients. Also assessed the frequency ofurogenital symptoms, the symptoms ofvulvovaginal atrophy, emotional and physical symptoms with the help of women's health profiles [19].
According to the study of any one patient in the group drospirenone/estradiol have been reported histological conclusion "hyperplasia, or atypia." The ratio of women with urogenital symptoms was similar in both treatment groups at baseline. General urogenital symptoms at the beginning of the study included urinary frequency (36.6% in the drospirenone/estradiol, 35.7% of NETA/estradiol group) and urinary incontinence (30.3 and 33.3%, respectively). Among the women who complained of frequent urination in the beginning of the study, about 56% reported relief of this symptom in both groups by the end of the study. Similarly, women complaining of urinary incontinence in beginning of the study, more than 50% longer observe this phenomenon in both groups at endpoint.
The proportion of participants who have had vaginal dryness, decreased from 64% at baseline to 37% at the end of the study in both groups, and the proportion of women with vulvovaginal atrophy -from 27 to 13%. dyspareunia rate decreased from 40.3 to 18.2% in the drospirenone/estradiol and from 36.8 to 16.0% in the NETA/estradiol. NE were reported in 386 (58.4%) women in the study, including 279 (57.1%) - a group of drospirenone/estradiol and 107 (62.2%) -a group of NETA/estradiol. NEs that are considered as side effects of the treatment have been reported in 90 (18.4%) and 44 (25.6%) women groups drospirenone/estradiol and NETA/estradiol, respectively. Serious adverse events were reported in one patient treated with drospirenone/estradiol (acute pancreatitis), and 1 - in the group of NETA/estradiol (thrombosis of retinal vessels).
Accordingly, this 12-month double-blind, randomized, active drug use as a control study, the first opportunity to assess and confirm the safety of the endometrium and bleeding profile characterized allowed in patients receiving low-dose combination of drospirenone (0.25 mg) and estradiol (0.5 mg) in women with an intact uterus in postmenopausal women.
A meta-analysis of randomized controlled trials found that the lowest effective doses ofthe combination ofHT in postmenopausal women are drospirenone 0.25 mg/0.5 mg of estradiol. This therapy can successfully arrest vasomotor symptoms, not providing, at the same time, a significant effect on the endometrium. According to a randomized controlled trial on the therapy with drospirenone 0.25 mg/0.5 mg estradiol fixed very low risk of developing endometrial hyperplasia, or atypia, while as the number of episodes of bleeding or spotting decreases with continued dosing. In the appointment
of HT should be considered comorbid conditions such as obesity and smoking. The study of PK and PD was discovered that the effectiveness of low doses of drospirenone/estradiol correlated with exposure estradiol and drospirenone in serum, and a significant factor as smoking, reduces the efficiency of HT through estradiol-nezavisimy mechanism which leads to a lower level of estradiol in the blood.
Receiving drospirenone 0.25 mg/estradiol 0.5 mg contributes to the prevention of cardiovascular disease and osteoporosis, which is most important in terms of anti-aging prevention. Combination of 0.25 mg drospirenone/estradiol 0.5 mg is effective in reducing moderate to severe vasomotor symptoms of menopausal syndrome, can reduce the frequency of symptoms of vulvovaginal atrophy, significantly improving compliance and quality of life of patients.
Currently, the Russian market registered the first ultranizkodoz-irovanny drug for menopausal hormone therapy (MHT) Anzhelik® Micro (17p-estradiol 0.5 mg/0.25 mg drospirenone).
Anzhelik® Micro is fully consistent with modern strategies MGT application in the lowest effective dose and extends the capa-
bilities of hormone replacement therapy in postmenopausal women. Most warranted Anzhelik® appointment in early postmenopausal women, and then transition to Anzhelik® Micro, while maintaining the indication for treatment. This is because in the early postmenopausal required dose of 1 mg estradiol for rapid and more effective relief of menopausal syndrome, the patient can then go to the ultra-low dose estradiol.
Keep in mind that more than one third of women vasomotor symptoms persist for more than 10 years of menopause and when you try to stop the MHT renewed. MGT combined continuous mode capable ofultra-low dose empower patients individualization of treatment in postmenopausal women with vasomotor symptoms, as MGT efficacy against these symptoms fully retained, while side effects are minimized.
Now two drugs presented in the Russian market with the same composition of the hormonal components, but in different doses: a well-established low-dose Anzhelik® (17^-estradiol 1 mg/2 mg drospirenone) and Anzhelik® Micro (17p-estradiol 0.5 mg/drospi-renone 0,25 mg).
References:
1. Stearns V., Ullmer L, Lopez J. F. et al. Hot flushes. Lancet - 2002; 360: 1851-61.
2. Maclennan A. H., Broadbent J. L., Lester S., Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev - 2004; - CD002978.
3. Sturdee D. W., Pines A. International Menopause Society Writing Group. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric - 2011; 14: 302-20.
4. The North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause - 2012; 19: 257-71.
5. Santen R. J., Allred D. C., Ardoin S. P. et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab - 2010; 95: 1-66.
6. Archer D. F., Thorneycroft I. H., Foegh M. et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, doubleblind, multicenter trial. Menopause - 2005; 12: 716-27.
7. Schurmann R., Holler T., Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric - 2004; 7: 189-96.
8. Warming L., Ravn P., Nielsen T., Christiansen C. Safety and efficacy of drospirenone used in a continuous combination with 17A-estradiol for prevention of postmenopausal osteoporosis. Climacteric - 2004; 7: 103-11.
9. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric - 2005; 8: 4-12.
10. Mueck A. O., Seeger H. Smoking, estradiol metabolism and hormone replacement therapy. Curr Med Chem Cardiovasc Hematol Agents - 2005; 3: 45-54.
11. Archer D. F., Schmelter T., Schaefers M. et al. A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17b-estradiol for moderate to severe vasomotor symptoms in postmenopausal women. Menopause - 2014; 21.
12. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms -recommendations for clinical evaluation. Available at: URL: http://www.fda. gov/downloads/Drugs/DrugSafety/Informationby-DrugClass/UCM135338.pdf
13. Rose D. P., Vona-Davis L. Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas - 2010; 66: 33-8.
14. Anttila S., Hakkola J., Tuominen P. et al. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res - 2003; 63: 8623-8.
15. Kisselev P., Schunck W. H., Roots I., Schwarz D. Association of CYP1A1 polymorphisms with differential metabolic activation of 17A-estradiol and estrone. Cancer Res - 2005; 65: 2972-8.
16. Genazzani A. R., Schmelter T., Schaefers M. et al. One-year randomized study of the endometrial safety and bleeding pattern of 0,25 mg drospirenone/0,5 mg 17b-estradiol in postmenopausal women. Climacteric - 2013; 16: 490-8.
17. Gerlinger C., Gude K., Alincic-Kunz S., Schafers M. Recommendation for the collection and analysis of endometrial biopsies for hormone therapies. Climacteric - 2012; 15: 52-8.
18. Kurman R. J., Ellenson H. L., Ronnett B. M. Blaustein's Pathology of the Female Genital Tract, 6th edn. - New York: Springer, - 2011.
19. Hunter M. S. The Women's Health Questionnaire: a measure of mid-aged women's perceptions of their emotional and physical health. Psychol Health - 1992; 7: 45-54.
