ORMELOXIFENE IN THE MANAGEMENT OF DUB
Bellad Girija C1, Lakshmi K. S2
HOW TO CITE THIS ARTICLE:
Bellad Girija C, Lakshmi K. S. “Ormeloxifene in the Management of Dub”. Journal of Evidence based Medicine and Healthcare; Volume 2, Issue 38, September 21, 2015; Page: 6125-6131,
DOI: 10.18410/jebmh/2015/845
ABSTRACT: Dysfunctional uterine bleeding (DUB) is abnormal genital tract bleeding based in the uterus and found in the absence of demonstrable. Structural or organic pathology. It occurs more frequently in anovulatory than ovulatory cycles. Dysfunctional uterine bleeding is most often the result of endocrinological dysfunction which responds well to conservative treatment. Ormeloxifene (also known as centchroman) is one of the selective estrogen receptor modulators, or SERMs, a class of medications which acts on the estrogen receptor. It is a steroidal, non-hormonal oral contraceptive which is taken once in a week. Ormeloxifene is suitable for the treatment of DOB, in all age groups with effective therapeutic efficacy and with least side effects. KEYWORDS: DUB, SERM, Ormiloxifene.
INTRODUCTION: Dysfunctional uterine bleeding (DUB) is abnormal genital tract bleeding based in the uterus and found in the absence of demonstrable structural or organic pathology.1 Altered hypothalamic - pituitary-ovarian function and/or local changes in PG production can give rise to DUB. It is typically characterized by heavy, prolonged flow with or without breakthrough bleeding. DUB is a diagnosis that does not apply to menorrhagia only, but also includes excessively prolonged and frequent bleeding (Menometrorrhagia). It occurs more frequently in anovulatory than ovulatory cycles,2 Dysfunctional uterine bleeding is a common debilitating problem among women in all age groups and accounts for 20% of gynaecology office visits.3 Inspite of current development of a minimal invasive surgical approaches, the traditional hysterectomy is still the only suitable definitive therapy for those who have no further wish to conceive. Cause of abnormal uterine bleeding should be ascertained quickly and appropriate therapy instituted. Dysfunctional uterine bleeding is most often the result of endocrinological dysfunction which responds well to conservative treatment.
Even though a number of treatment modalities are available, a reliable drug for management of dysfunctional uterine bleeding should meet the requirements like drug should be effective, convenient to take, cost of the drug must be low, with minimal side effects and the drug should have longest safety margin. Selective estrogen receptor modulator drugs (SERM) popularly known as Designer estrogens, Fantasy estrogens because they selectively bind with high affinity to estrogen receptors and mimic the effect of estrogen in some tissues but act as estrogen antagonists in others.
stimulating effect on vagina, bone, cardiovascular system and central nervous system5. Ormeloxifene not only preferred as oral contraceptive, but also useful for management of dysfunctional uterine bleeding and advanced breast cancer.6 In the pharmacological management of DUB the standard dosage is 60 mg orally twice weekly for a period of 12 weeks followed by weekly once in the next 12 weeks. The safety profile of Ormeloxifene is excellent with very few side effects like nausea, headache, weight gain, delayed or prolonged menstrual period.
CASE REPORT: Ormeloxifene, the drug of choice in patients of DUB who have completed their child bearing age as compared with norethisterone.
Efficacy of a selective estrogen receptor modulator:
Number of patients: 180 DUB cases
Age group of the patients: >35 years, who have completed child bearing age
Sample group: 60 subjects were randomly assigned into each groups
Ormeloxifene (O) group received 60 mg twice a week for 12 weeks followed by once a
week for next 12 weeks
Progesterone (P) group which received norethisterone, 10 mg daily for 12 days in every cycle from 14th day of the cycle for 6 cycles.
Iron (I) group received tablet ferric sulphate, 200 mg containing 60 mg of elemental iron 1 tablet daily only.
81.67% of patients in ormeloxifene group felt marked improvement of symptoms compared to 35% in Norethisterone group and 11.67% in the iron group.
PATHOLOGY:
Dysfunctional uterine bleeding (DUB): Dysfunctional uterine bleeding (DUB) defined as:
Abnormal uterine bleeding without any clinically detectable pelvic pathology – tumour, inflammation, medications.
It is the most common cause of abnormal uterine bleeding.
Pathophysiology:
Anovulatory DUB (Common).
Uvulatory DUB.
Anovulatory DUB:
Accounts for more than 70 percent of cases of DUB.
In anovulation, estrogen levels are high whereas progesterone levels are less, which normally counteracts uterine lining proliferation
The endometrium undergoes continuous growth, becomes vascular and fragile and sloughs
irregularly.
Causes of anovulatory DUB (Peremenarchal or perimenopausal female):
Perimenopausal women: A decline in estradiol and progesterone production results in decreased hypothalamic feedback, leading to anovulation.
Ovulatory DUB:
The mechanisms of ovulatory DUB are not well understood.
It may result from luteal phase deficiency.
A deficient luteal phase leading to a disruption of the hypothalamic-pituitary – ovarian functioning and results in DUB.
With ovulatory cycles, menorrhagia, polymenorrhea or oligomenorrhea may occur.
DIAGNOSIS: If abnormal uterine bleeding is not severe and does not require emergent intervention, patients should be evaluated as under:
Medical history.
Physical examination to rule out.
PID.
Fibroid.
Cancer.
IUCD.
Treatment of DUB: The ideal therapy should be a designer drug which can block the action of estrogen on the endometrium but not its beneficial actions on other issues. Selective ostrogen receptor modulators.
Estrogen Receptors:
Estrogen acts on target tissues by binding to parts of cells called estrogen receptors (ER).
An estrogen receptor is a protein molecule found inside those cells (cytosol) that are targets for estrogen action.
ER are the part of nuclear receptor family.
Estrogen receptors contain a specific site to which only estrogens (or closely related molecules) can bind.
There are two types of estrogen receptors.
Alpha () and beta () receptors.
Estrogen Receptors:
Both ERs (alpha () and beta () receptors) are physiologically important, have distinct, non-overlapping functions.
Target organs:
ER: Uterus, breast, pituitary, bone, CNS and cardiovascular system.
ER: Ventral prostate, ovarian granulose cells etc.
Mode of action of Serm:
Structure of some SERM – estrogen-receptor complexes favors core pressor recruitment and that of others favors some affinity for known co-activators.
SERM activity will be influenced by the relative levels of expression of the cofactors (corepressors and co-activators) in target cells.
Ormeloxifene: An optimally designed SERM with varied tissue response. Its action lasts long after the drug is withdrawn.
It blocks the cytosol receptors by its competitive binding affinity over estradiol
It not only causes a slow buildup of the receptors, but also causes their prolonged retention.
Benefits of ormeloxifene:
Estrogen antagonist in uterus and breast.
Mild estrogenic action on vagina, bone, CNS and serum lipids.
No action on hypothalamic pituitary ovarian function, thyroid or adrenal.
No progestational, androgenic or anti androgenic properties.
Ormeloxifene: Ideal selective estrogen receptor modulator: Due to unique MoA it prevents bone loss, has no risk of uterine or breast cancer, a positive effect on lipids and cardiovascular system, relieves PMS and maintains cognitive function of the brain.
Ormeloxifene Contraindication:
Has an excellent safety profile, very well tolerated and practically without any undesirable side effects
Few contraindications
Liver dysfunction or clinical jaundice.
PCOD.
Cervical dysplasia (abnormality of development), chronic cervicitis.
Hypersensitivity to the drug.
Nursing mothers (6 months).
Ormeloxifene-DUB Summary of Results:
Significant improvement in number of bleeding episodes as early as 12 weeks after treatment.
Significant reduction in heavy flow (85.7%) and dysmenorrheal (78.26%).
The difference in mean hemoglobin concentration of 1.31 gm/dl between pretreatment and
post-treatment levels is statistically significant.
74 out of 85 subjects (87.05%) showed a reduction in endometrial thickness.
85.71% of patients reported improvement by absence of clots at the end of the therapy.
Summary:
Dysfunctional uterine bleeding is a very common disorder at all ages from menarche to menarche to menopause.
Though its pathophysiology is still unclear, estrogen progesterone imbalance is usually the basis of bleeding.
Available medical treatment modalities are far from satisfactory.
Ormeloxifene, the latest selective estrogen receptor modulator, is closest to the perfect SERM, having the desired antirestrogenic and estrogenic action in different issues.
Ormeloxifene Ideal SERM for DUB:
No uterine stimulation
Prevents bone loss
Has no risk for breast cancer
Has a positive effect on lipids & cardiovascular system
Maintains cognitive function of the brain
Ormeloxifene - Mechanism of Action
Normalizes the bleeding from uterine cavity by regulating the expression of estrogen receptors on the endometrium
Prevents proliferation of endometrium and not affecting the cornification of vaginal and cervical epithelium
Blocks cytosol receptors and also causes their prolonged depletion and therefore its action lasts long after the drug has been withdrawn.
Safety
Excellent therapeutic index and is considered safe for chronic administration7
Safety data of 100,000 women and 1100,000 menstrual cycles 8
Non Teratogenic - Ormeloxifen ingested by the infants via breast milk is unlikely to be of any physiological consequence to the infants
No drug interaction when co administered with other drugs 7
Efficacy
Significantly controls bleeding.9
97.7% reduction in Pictorial Blood Loss Assessment Chart (PBAC) score.
Decreases endometrial thickness.10
Pre-treatment 11.4 mm Vs. Post-treatment 7.8 mm
Reduces chances of hysterectomy.10
8.2% patients in Sevista Group vs. 20 to 30% in DUB patients Excellent safety profile.
Superior to Medroxiprogestrone (MPA):
Overall reduction in Blood loss by 85.7% in Ormeloxifene Group compared to MPA Group21
Ormeloxifene is more effective as compared to MPA in reducing the blood loss in the treatment of DUB.
Excellent safety profile.
DISCUSSION: Dysfunctional uterine bleeding occurs more commonly in the first five years after a women starts menstruating and as she approaches menopause, but it can occur at any time period. For women with DUB who wish to retain fertility, pharmacological approaches are the only currently available options. Among the other pharmacological agents, some are effective only for anovulatory DUB, some are useful only for ovulatory DUB, and still others may be effective for both. Pharmacological agents such as NSAIDS, oral contraceptive pills, progestins, danazol, GnRH agonists and antifibrinolytic drugs all reduce menstrual blood loss, however, the assets are limited to the duration of treatment.
CONCLUSION: Ormeloxifene was found effective in reducing menstrual blood loss in patients with DUB. It was found to be an excellent drug in controlling the systems of dysfunctional uterine bleeding without effecting normal endocrinal and physiological parameters. Pharmacological agents such as NSAIDs, oral contraceptive pills, progestins, danazol, GnRH agonists and antifibrinolytic drugs, they reduce menstrual flow, however, the benefits are limited due to the duration of therapy and as single agent is not suitable to all age groups. Ormeloxifene is suitable for the treatment of DOB, in all age groups with effective therapeutic efficacy and with least side effects.
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10.Biswas Subhash Chandra, Saha Sudip Kumar, Bag Tara Shankar, Ghosh Roy Samir
Chandra.Roy Asit Chandra, Kabiraj Shankar Prasad. Ormeloxifene A Selective Estrogen Receptor Modulator, For Treatment of Dysfunctional Menorrhagia. J Obstet Gynecollnd Vol. 54, No.1: January/February 2004 Pg 56-59.
NAME ADDRESS EMAIL ID OF THE CORRESPONDING AUTHOR:
Dr. Bellad Girija C, Flat No. GF-1,
Simply OM Apartment, 2nd Main, 6th Cross,
Sadashiv Nagar, Belagavi.
E-mail: rajashekarphy@gmail.com
Date of Submission: 21/08/2015. Date of Peer Review: 22/08/2015. Date of Acceptance: 11/09/2015. Date of Publishing: 21/09/2015.
AUTHORS:
1. Bellad Girija C. 2. Lakshmi K. S.
PARTICULARS OF CONTRIBUTORS:
1. Assistant Professor, Department of Obstetrics & Gynecology, Belagavi Institute of Medical Sciences, Belagavi. 2. Assistant Professor, Department of
