This document discusses medical management options for dysfunctional uterine bleeding (DUB). It begins by defining DUB and outlining treatment goals of controlling bleeding, correcting related conditions, preventing recurrence, and improving quality of life. First line treatment is recommended to be a levonorgestrel-releasing intrauterine system. Other options discussed include tranexamic acid, NSAIDs, combined oral contraceptives, and various progestogen therapies. Ormeloxifene is presented as an ideal selective estrogen receptor modulator for DUB due to its tissue-specific effects and safety profile. Studies demonstrate its effectiveness in reducing bleeding and improving outcomes for women with DUB.
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Medical management of dub – new modalities
1. MEDICAL MANAGEMENT
OF DUB – NEW
MODALITIES
Dr.Jyoti Bhaskar
MD MRCOG
Director Lifecare IVF
Consultant
Lifecare Centre, Pushpanjali Crosslay Hospital
Lecture 2 (2013)
Save Uterus Campaign
2. Definition Of HMB
“Excessive menstrual blood loss which
interferes with the woman’s physical,
emotional, social and material quality of
life, and which can occur alone or in
combination with other symptoms.”
Nice guidelines 2007
3. Treatment of DUB
Woman Centred Care
Goals
Control bleeding
Correct anemia/associated conditions
Prevent recurrence
Improve quality of life
Any interventions should aim to improve quality of life measures.
[D] -- NICE guidelines
5. Ideal Treatment Choice–Points toIdeal Treatment Choice–Points to
PonderPonder
Whether cycles are
ovulatory or not
Age
Whether the patient requires
contraception
Desires Fertility
Choice of the patient
6. First Line Levonorgestrel-releasing intrauterine
system (LNG-IUS)
Second Line Tranexamic acid (non-hormonal)
Can be used in parallel with investigations. If
no improvement, stop treatment after 3 cycles
Non-steroidal anti-inflammatory drugs (NSAIDs)
If no improvement, stop treatment after 3 cycles.
Can be used in parallel with investigations
Preferred over tranexamic acid in dysmenorrhoea
Combined oral contraceptives
Pharmaceutical Treatment – Nice Guidelines
7. Third Line Oral progestogen
Norethisterone (15 mg) daily from days 5 to
26 of the menstrual cycle
Injected progestogen
Others Gonadotrophin-releasing hormone
analogue (Gn-RH analogue)
If used for more than 6 months add back
HRT therapy is recommended
8. Following Treatment Not Recommended
Oral progestogens in the luteal phase
only
Danazol
Ethamsylate
Dilatation and curettage (D and C)
9. GUIDELINES FOR THE MANAGEMENT OF
ABNORMAL UTERINE BLEEDING
Age, desire to preserve fertility, coexisting medical
conditions, and patient preference are essential
considerations.
For each of the suggested methods, the patient should
be aware of the risks and contraindications to allow
informed choice.
Progestogens given in the luteal phase of the
ovulatory menstrual cycles are not effective in
reducing regular heavy menstrual bleeding.
S O G C C L I N I C A L P R A C T I C E G U I D E L I N E S 2001
13. “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 tissues”
Need of the Hour --- Medical DrugsNeed of the Hour --- Medical Drugs
15. IDEAL SERM FOR DUBIDEAL SERM FOR DUB
“An optimally designed SERM with Varied Tissue Response”
16. Ormeloxifene – An Ideal SERMOrmeloxifene – An Ideal SERM
Dysfunctional uterine bleeding at any age
Relief of PMS in perimenopausal women
For women desiring contraceptive property
Has an excellent safety profile, very well-tolerated &
practically without any undesirable side-effects
17. Ormeloxifene– Dosing StrategyOrmeloxifene– Dosing Strategy
Convenient dosage – twice or once weekly
60 mg tablets twice a week ( for example, Sunday &
Wednesday) for 12 weeks followed by one tablet of 60 mg
once a week for another 12 weeks
18. Ormeloxifene
CDR Institute Lucknow 1991
Once a week Non Hormonal
Contraceptive
Marketed in India in 1992 as
Saheli and Choice-7 and
Centron
Included in the National Family
Welfare Programme in 1995
19. Efficacy in Dysfunctional Menorrhagia (AIIMS)Efficacy in Dysfunctional Menorrhagia (AIIMS)
PILOT STUDYPILOT STUDY
Study Population: Forty-two women with menorrhagia were recruited for the
study
Dosage: Ormeloxifene was given to each patient 60 mg twice a week for 3
months and then once a week for 1 month. Patients were followed up at 2
and 4 months of therapy, then at 3 and 6 months after treatment was stopped
Assessments:
Menstrual blood loss (MBL) was measured objectively by a pictorial
blood loss assessment chart (PBAC) score and subjectively by a
visual analog scale (VAS)
J. Obstet. Gynaecol. Res. vol. 35, No. 4: 746–752, August 2009
20. Efficacy in Dysfunctional MenorrhagiaEfficacy in Dysfunctional Menorrhagia
The pretreatment median PBAC
score was 388 (range 169–835)
Median PBAC reduced to 80
(range 0–730) and 5 (range 0–
310) at 2 and 4 months,
respectively (p-value <0.001)
The percentage reduction in
PBAC score - 97.7% at 4
months
J. Obstet. Gynaecol. Res. vol. 35, No. 4: 746–752, August 2009
Reduction in PBAC Score
21. Efficacy in Dysfunctional MenorrhagiaEfficacy in Dysfunctional Menorrhagia
Amenorrhea with the
therapy – 18 patients
(42.9%)
Adverse effects included
ovarian cyst (7.1%),
cervical erosion and
discharge (7.1%), gastric
dyspepsia (4.8%), vague
abdominal pain (4.8%) and
headache (4.8%)
J. Obstet. Gynaecol. Res. Vol. 35, No. 4: 746–752, August 2009
Percentage Reduction in PBAC ScorePercentage Reduction in PBAC Score
97.7%97.7%
2.3%2.3%
22. Ormeloxifene Versus MPA in the treatment of
Dysfunctional uterine Bleeding : A Double- Blind
Randomised Controlled Trial
Journal of South Asian Federation of obstetrics and Gynaecology Jan –April 2011
.Study Population: 84 women attending gynae OPD in Belgaum India were
enrolled , 42 in each arm.
Dosage: Group A – 60 mg ormeloxifene twice a week for 3 consecutive cycles
and Group B – 10 mg MPA from day 5-25 for 3 cycles. All were made to use
same type of sanitary napkins and TVS done for ET before and after treatment
Data Analysis : Mean PBAC score and endometrial thickness were compared
Result: Mean PBAC score reduction of 85.7 % and 54% in group A and B resp
ET reduction was more in Ormeloxifene group but not statistically sign.
Conclusion: oremloxifene is more effective in reducing bleeding than MPA
23. Role of Sevista in the Management of
Dysfunctional Uterine Bleeding
Study Population: 35 cases diagnosed to have DUB after having ruled out
other causes
Dosage: Ormeloxifene was given in the dosage of a 60 mg tablet twice a week
for 3 months, followed by once a week for another 3 months.
Assesment : Hb g/dl and the endometrial thickness before and after 3
months of treatment with sevista.
Observation & results: Statistically significant increase in the Hb g/dl (p <
0.001) and a statistically significant decrease in the endometrial thickness
(p< 0.001) after the treatment with ormeloxifene.
Dhananjay BS, Sunil Kumar Nanda , Journal of Clinical and Diagnostic Research, 2012.
Conclusion: Ormeloxifene can be used as an effective drug in
the treatment of Dysfunctional uterine bleeding
24. Our Experience ( Over 500 cases)
Indications
1. Puberty Mennorhagia
2. Postnatal Bleeding
3. DUB- after TVS r/o Ovarian Cyst
Dose- 60mg twice weekly for 3months.
Effective upto 1 year after stopping it.
25. Held Back
1. Postmenopausal Bleeding
2. Endometrial Hyperplasia
3. Infertile patients
4. PCOS
Special mention:
1. In PMB , after balloon therapy – once a week
for 3 months
2. In hyperplasia – along with progesterone's
28. Breaking Myths with Scientific EvidenceBreaking Myths with Scientific Evidence
No effect on hypothalmo-pituitary-ovarian axis
Its effect as a contraceptive is local with no effect on hypothalmo-
pituitary-ovarian axis
No effect on ovulation
It does not affect ovulation as evidenced by good luteal activity, but
causes an increase in cycle length by lengthening the follicular phase.
Its contraceptive action is primarily due to the prevention of
endometrial decidualization and failure of implantation
J. Obstet Gynaecol Res. Vol. 35, No. 4: 746–752, August 2009.
29. Breaking Myths with Scientific EvidenceBreaking Myths with Scientific Evidence
It does not cause cystic enlargement of ovaries
It is reported that only 15% patients may develop these, which
disappear in subsequent cycles. In the study by Kriplani et al, ovarian
enlargement was found only in three patients (7.1%)
It does not cause endometrial thickness
In the study by Kriplani et al, increased endometrial thickness was
found in 9.5% of patients, but there was no atypia on histology.
J. Obstet Gynaecol Res. vol. 35, No. 4: 746–752, August 2009.
30. Conclusions
First Line of management of DUB should be
pharmaceutical
Available medical modalities are far from satisfactory
Important to individualize the treatment
Mirena is the first line of treatment – Nice Guidelines
Ormeloxifene is safe, efficacious, cheap and easy to
administer.
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33. Ideal SERM for DUBIdeal SERM for DUB
Ideal SERM for DUB is one that has
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
Estrogen in CNS
Antiestrogen in
the breast
No DNA adducts
Lowers cholesterol
No uterine
stimulation
Maintains
bone density
34. SERM’s – The Designer EstrogensSERM’s – The Designer Estrogens
Depending on their functional activities, SERMs could then
be developed for a variety of clinical uses, including
Prevention and treatment of osteoporosis
Treatment and prevention of estrogen-regulated
malignancies
Fibrofatty disease of breast and mastalgia
J Clin Oncol 2000 18:3172-3186.
35. Levonorgestrel Intrauterine System
Cost limits its widespread use
Irregular bleeding in the first 3 months and
leads to amenorrhea 15-20% of patients by 1
year
Needs to be changed every 5 years
It acts as a contraception and cannot be used
in women desiring pregnancy.
First line of treatment in DUB – Nice
guidelines
36. Ormeloxifene
Central Drug Research Institute, Lucknow, is a nonsteroidal once-a-
week oral contraceptive.
It was introduced in Delhi in July, 1991, marketed in India in 1992 as
Saheli and Choice-7 and Centron
Included in the National Family Welfare Programme in 1995.
100,000 women were using this pill and apprx 1100,000 menstrual
cycles were covered until 1996
Long terminal serum half life of 168 hr in women and exhibits
duration of anti-implantation/estrogen antagonistic action of 120 hr.
In lactating women, it is excreted in milk in quantities considered
unlikely to cause any deleterious effect on suckling babies
Med Res Rev. 2001 Jul;21(4):302-47.
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Notes de l'éditeur
Once DUB has been diagnosed and pathologic causes ruled out, there are several goals of therapy. No single method is always effective. Many factors play a role in the decision to begin one therapy over another: age, severity of bleeding, no. of children, desire for fertility presence of associated pelvic pathology
Inevitably, a profuse but painless menstrual bleed frightens the patient into seeking medical help. It is paramount that the treating clinician probes the following aspects before initiating the treatment. Several treatment aspects will be discussed in the subsequent slides. Although many of them look promising there are some serious concerns, which should be clearly understood by the clinician.
Some of the agents for the chronic treatment of DUB include progestational agents, clomiphene citrate, antiprostaglandins, danozol and GnRH analogs. Surgical management may include hysterectomy or less invasive, uterus-sparing procedures. Reference: Ferri: Ferri's Clinical Advisor 2010, 1st ed.
Medical therapy discussed in the previous slides although quite effective, have several limitations. This can be attributed to their direct estrogenic and progesterone action. Research has focused on compounds that are selective for specific tissues thereby minimizing the unwanted effects in some areas and augmenting action in necessary tissues. The ideal therapy to treat DUB should be a designer drug, which can block the action of estrogen on the endometrium, but not its beneficial actions on other tissues.
Estrogens have agonistic or stimulating effects on all of the estrogen receptor sites Antiestrogens at the other end of the spectrum have antagonistic effects on the same sites. SERM’s like tomoxifine, ormeloxifene are designed to act in specific ways at each of the receptor sites. Reference: J Clin Oncol 2000 18:3172-3186.
Ormeloxifene is a nonsteroidal, SERM and has been in use as a weekly oral contraceptive for approximately last 20 years, particularly in India, where it was originally developed. Ormeloxifene interacts with ER, eliciting tissue-specific responses. It is also undergoing clinical evaluation for the treatment of advanced breast cancer and the prevention of osteoporosis due to its potent antiestrogenic, weak estrogenic and antiprogestational activities. Reference: Ormeloxifene (Sevista) Product Monograph. Data on file.
In line with the features discussed earlier, ormeloxifene has all the characteristics of an ideal SERM. Key points are highlighted in this slide. Reference: Ormeloxifene (Sevista) Product Monograph. Data on file.
Ormeloxifene can be given as 2 tablets of 60 mg twice a week; every Sunday and Wednesday for the first 12 weeks and then one tablet of 60 mg on the following Sunday/Wednesday for 12 weeks. Reference: Ormeloxifene (Sevista) Product Monograph. Data on file.
In another clinical study 42 women with menorrhagia were studied. Ormeloxifene was given to each patient, 60 mg, twice a week for 3 months and then once a week for 1 month. Patients were followed up at 2 and 4 months of therapy, then at 3 and 6 months after the treatment was stopped. Investigators measured menstrual blood loss objectively by a PBAC score and subjectively by a Visual Analog scale. Reference: J. Obstet. Gynaecol. Res . vol. 35, No. 4: 746–752, August 2009.
The pretreatment median PBAC score was 388 (range 169–835). Eighteen patients (42.9%) had amenorrhea with the therapy. Median PBAC reduced to 80 (range 0–730) and 5 (range 0–310) at 2 and 4 months, respectively (p-value <0.001). Reference: J. Obstet. Gynaecol. Res. vol. 35, No. 4: 746–752, August 2009
The percentage reduction in the PBAC score was 97.7% at 4 months. Adverse effects included ovarian cyst (7.1%), cervical erosion and discharge (7.1%), gastric dyspepsia (4.8%), vague abdominal pain (4.8%) and headache (4.8%). Ormeloxifene is an effective and safe therapeutic option for the medical management of menorrhagia. Reference: J. Obstet. Gynaecol. Res . Vol. 35, No. 4: 746–752, August 2009.
There were several myths around the treatment with ormeloxifene. Research has proven that these myths are indeed not true. For contraception, centchroman (ormeloxifene) is given at a weekly dose of 30 mg/week after a twice-weekly loading dose for 12 weeks to build up adequate blood levels to prevent failures in the beginning of the therapy due to inadequate steady state concentrations. Its effect is local with no effect on hypothalmo–pituitary–ovarian axis. In healthy females, it does not affect ovulation as evidenced by good luteal activity, but causes an increase in cycle length by lengthening the follicular phase. Its contraceptive action is primarily due to the prevention of endometrial decidualization and failure of implantation. Reference: J. Obstet Gynaecol Res . Vol. 35, No. 4: 746–752, August 2009.
Although there is the concern of cystic enlargement of ovaries, it is reported that only 15% patients may develop these, which disappear in subsequent cycles. In the study by Kriplani et al. , ovarian enlargement was found only in three patients (7.1%). Increased endometrial thickness observed has been documented in 40% of cases with levormeloxifene. In the study by Kriplani et al ., increased endometrial thickness was found in 9.5% of patients, but there was no atypia on histology, which corroborates well with previous studies in which the authors did not document any endometrial hyperplasia with atypia. Evaluation of endometrium in one study revealed hyperplasia in only 2.6% of cases and most of the cases had a secretory, proliferative or a decidual pattern. Reference: J. Obstet Gynaecol Res . vol. 35, No. 4: 746–752, August 2009.
An ideal SERM for DUB should not cause uterine stimulation. There should be no bone loss and the risk of breast cancer. It should have a positive effect on patients with cardiovascular diseases. Some compounds can affect the HDL and LDL levels there by jeopardizing the health of patients with cardiovascular diseases. Maintaining cognitive functions is also paramount.
SERMs bind ER, alter receptor conformation and facilitate binding of coregulatory proteins that activate or repress transcriptional activation of estrogen target genes. Depending on their functional activities, SERMs could then be developed for a variety of clinical uses like DUB, osteoporosis, cancer, etc. Reference: J Clin Oncol 2000 18:3172-3186
High-dose progestin therapy, for example, 5-mg tablets of norethindrone acetate reduces ovarian estradiol production, but long-term use can be associated with loss of bone density. This therapy can reduce high-density lipoprotein (HDL) and increase low-density lipoprotein (LDL) levels and should be used carefully in patients with cardiovascular disorders. The levonorgestrel intrauterine system is very effective, but the cost limits its widespread use, especially in developing countries, such as India where the initial cost is 8,100 rupees. Reference: Medscape Ob/Gyn & Women's Health . 2004;9(1).
