dydrogesterone – from menarche to menopause

DYDROGESTERONE – FROM MENARCHE TO
MENOPAUSE
F GUIDOZZI
University of Witwatersrand Faculty of Health Sciences
DYDROGESTERONE
Classification
Threatened abortion
Recurrent abortion
Menstrual irregularities
Luteal phase support in IVF
Endometriosis
Postmenopausal hormone therapy
Classification of Progestogens
Progesterone
Retroprogesterone
Progesterone
Dydrogesterone
Progesterone Derivatives
17-OH-progesterone Derivates
Pregnane
•
Hydroxyprogesterone
caproate
•
Hydroxyprogesterone
heptanoate
•
Gestonorone caproate
•
Chlormadinone acetate
•
Medrogestone
•
Medroxyprogesterone
acetate
•
Cyproterone acetate
19-progesterone
Derivatives
Nor-Pregnane
•
Nomegestrole
acetate
•
Demegestone
•
Promegestone
•
Nestorone
•
Trimegestone
Testosterone Derivatives
19-nortestosterone Derivatives
Estranes
•
Lynestrenol
•
Levonorgestrel
•
Norethisterone
•
Norethisterone acetate
•
Ethinodiol aiacetate
•
Norgestrienone
•
Dienogest
Gonanes
•
Norgestrel
•
Desogestrel
•
Gestodene
•
Norgestimate
Spirolactone
Derivative
Drospirenone
Adapted from: Druckmann R. Journal Für Menopause. 2002;1–5.
3
Dydrogesterone
Dydrogesterone is a retroprogesterone – a steroisomer of
progesterone – with an additional double-bond between carbon 6
CH3
&7
CH3
CH3
CH3
C
O
CH3
CH3
H
O
H
O
Kuhl 2006
4
C
O
Progestogens have different hormonal activities
Dydrogesterone
Progesterone
Medroxy
Medrogestone
progesterone
acetate
Norethisterone
Levonorgestrel
Progestogenic
+
+
+
+
+
+
Oestrogenic
–
–
–
–
+
–
Androgenic
–
–
(+)
–
+
+
Glucocorticoid
?
+
+
?
–
–
Antiandrogenic
–
(+)
–
–
–
–
Antioestrogenic
+
+
+
+
+
+
(+)
+
–
–
–
–
Antimineralocorticoid
+ = effect
– = no effect
? = unknown
(+) = weak effect
Kuhl 2005
5
Dydrogesterone
 First marketed in 19611
 The only retroprogesterone commercially available1
 Molecular structure closely related to natural
progesterone
 Orally active at lower doses than micronised
progesterone2
 No oestrogenic, androgenic or glucocorticoid effects
DYDROGESTERONE
 Compared with oral micronised progesterone
– Has a more rigid structure (positively influences
selectivity)
– Better oral bioavailability
– Requires a 10 – 20 times lower oral dose
– Has good receptor binding selectivity
– Has metabolites with progestogenic activity
Schindler 2009
7
Dydrogesterone: Safety and Tolerability
Possible undesirable effects
Common
(≥1/100, <1/10)
Uncommon
(≥ 1/1,000, < 1/100)
Rare
(≥ 1/10,000, <1/1,000)
Migraines/headache
Depressed mood
Increase in size of progestogen
dependent neoplasms
Nausea
Dizziness
Hemolytic anemia
Menstrual disorders
(e.g. metrorrhagia,
menorrhagia, oligo/amenorrhea, dysmenorrhea
and irregular menstruation)
Vomiting
Hypersensitivity
Breast pain/tenderness
Weight increase
Somnolence
Abnormal hepatic function (with
jaundice, asthenia or malaise, and
abdominal pain)
Angioedema
Allergic dermatitis (e.g. rash, pruritus,
urticaria)
Edema
Dydrogesterone SmPC. 29 April 2011.
Breast swelling
Safety and Tolerability
Interaction with other medications
 In vitro data indicate that dydrogesterone and its main
metabolite 20 α –dihydrodydrogesterone (DHD) may be
metabolized by cytochromes P 450
 Metabolism may be increased by concomitant use of
substances known to induce these isoenzymes such as
anticonvulsants (e.g., phenobarbital, phenytoin,
carbamazepine), anti-infectives (e.g. rifampicin, rifabutin,
nevirapine, efavirenz) and herbal preparations containing e.g.
St John’s Wort (Hypericum perforatum), valerian root, sage,
or gingko biloba
.
Safety and Tolerability
 Ritonavir and nelfinavir, although known as strong
cytochrome enzyme inhibitors, by contrast exhibit
enzyme-inducing properties when used
concomitantly with steroid hormones
 Increased metabolism may lead to a decreased effect
 In vitro studies have shown that dydrogesterone
does not inhibit or induce CYP drug metabolizing
enzymes at clinically relevant concentrations
INDICATIONS FOR USE









Dysmenorrhoea
Threatened abortion
Recurrent abortion
Luteal phase support in IVF
Menstrual irregularities
Secondary Amenorrhoea
Dysfunctional uterine bleeding
Endometriosis
Menopausal hormonal therapy
Importance of progesterone for implantation and pregnancy
development











Preparation of endometrium for implantation (secretory changes)
Endometrial decidualisation
Production of endometrial proteins (e.g. uteroglobin)
Regulation of cellular immunity
Stimulation of prostaglandin E2 production
Stimulation of lymphocyte proliferation at foeto-maternal interface
Suppression of cellular cytotoxicity from increased interleukin-2
Suppression of T-cell and killer-cell activity
Shift from T-helper (Th)1 to Th2 cells
Synthesis of progesterone-induced blocking factor (PIBF)
Suppression of matrix metalloproteinases
Schindler 2004
12
Dydrogesterone Indications and Dosing
Relating to Pregnancy
Progesterone deficiencies
•
Treatment of threatened miscarriage
•
Treatment of habitual miscarriage
•
Luteal phase support in IVF
.
Dydrogesterone SmPC. 29 April 2011.
Dydrogesterone in threatened abortion:
pregnancy outcome
J Steroid Biochem Mol Biol 2005; 97: 421-425
Omar MH, Mashita MK, Lim PS, Jamil MA
14
Omar 2005 - Dydrogesterone in Threatened Abortion:
Pregnancy Outcome
Design
16
 Registration records of 154
(gestational age <13 weeks)
presenting with vaginal
bleeding were evaluated
12
Miscarriage rate (%)
10
 Dydrogesterone 40 mg at once
plus 10 mg b.i.d. until bleeding
stopped,bed rest and
received folic acid
 Control group: bed rest and
folic acid only
 Women followed up until 20
weeks gestation
 Malaysia
13.8
14
8
6
4.1
4
2
0
Dydrogesterone-treated
group (n = 74)
Control group (n= 80)
*p = 0.037
Odds ratio: 3.773, 95% CI: 1.009 – 14.108
Dydrogesterone had a significantly lower
miscarriage rate compared with the
control group (4.1% vs. 13.8%, P=0.037)
Adapted from: Omar MH, et al. J Steroid Biochem Mol Biol 2005; 97(5): 421-425.
Dydrogesterone support in threatened miscarriage
Maturitas 2009; 65S: S43-S46
El-Zibdeh MY & Yousef LT
16
El-Zibdeh 2009 - Dydrogesterone Support in Threatened
Miscarriage
Design
30
• 146 women with vaginal
bleeding during the first
trimester randomized
 Control
 All women received standard
supportive care: iron, folic
acid, multivitamin
supplements and
recommended bed rest
 Jordan
Adapted from: El-Zibdeh MY, Yousef LT. Maturitas 2009; 65(Suppl 1): S43-S46.
20
Miscarriage rate (%)
 Oral dydrogesterone 10 mg
b.i.d. until one week after
bleeding stopped
25
25
17.5
15
10
5
0
Dydrogesterone-treated group
(n = 86)
Control group (n= 60)
*p < 0.05 vs. control
Dydrogesterone had a significantly lower
miscarriage rate compared with the
control group (17.5% vs. 25%, P<0.05)
El-Zibdeh 2009 - Significantly Lower Miscarriage Rate with
Dydrogesterone
Results
 Dydrogesterone group experienced a significantly lower miscarriage rate
compared with the control group (17.5% vs. 25%, p<0.05)
 No significant differences between the dydrogesterone and control
groups in incidence of
 Pre-eclampsia (9.8% and 6.6%)
 Intra-uterine growth retardation (7.0% and 8.8%)
 Ante-partum hemorrhage (5.6% and 6.6%)
 Pre-term labor (8.4% and 11.1%)
 Congenital abnormalities (2.8% and 4.4%)
 No adverse events reported during treatment with dydrogesterone
El-Zibdeh MY, Yousef LT. Maturitas 2009; 65(Suppl 1): S43-S46.
Conclusion
 The miscarriage rate was lower in the dydrogesterone group
than in the control group
 Dydrogesterone was well tolerated and had no unwanted
effects on pregnancy outcome
 No placebo group
 Basic randomisation method and allocation performed by
physician
 Further large randomized trials are needed to establish the role
of dydrogesterone and to evaluate the impact of hormonal
levels in first trimester threatened miscarriage
El-Zibdeh & Yousef 2009
Dydrogesterone in threatened miscarriage:
a Malaysian experience
Maturitas 2009; 65S: S47-S50
Pandian RU
Pandian 2009
Objectives and methods
 To determine whether dydrogesterone more effective than
conservative management in women with threatened miscarriage
 Open, randomised study in Malaysia
 191 women with vaginal bleeding up to 16 weeks of pregnancy
randomised to:
– Oral dydrogesterone 40 mg at once followed by 10 mg twice
a day until week 16
– Control group: Conservative management with bed rest only
 Women in dydrogesterone group not recommended bed rest
 No placebo group, basic randomisation method
 Study not blinded to either physician or patient
Pandian 2009
Pandian 2009 - Dydrogesterone in Threatened Miscarriage: a
Malaysian experience
Design
 Prospective, randomized,
controlled, open (blinded data
analyses) study, n=191
 Study not blinded to either
physician or patient
• Malaysia
25
20
Miscarriage rate (%)
 Dydrogesterone 40 mg at once
followed by 10 mg twice a day
until week 16
 Control group: Conservative
management with bed rest
only
28.4
30
15
12.5
10
5
0
Dydrogesterone-treated
group (n = 96)
Control group (n= 95)
*p < 0.05 vs. control
Odds ratio: 0.36, 95% CI: 0.17 – 0.75
Pandian RU. Maturitas 2009; 65(Suppl 1): S47-S50.
Pandian 2009 – Outcome and Obstetric Complications
 Dydrogesterone group experienced a significantly lower miscarriage
rate compared with the control group (12.5 % vs. 28.4%; p<0.05)
Control
(n=96)
Dydrogesterone
p-value
(n=95)
Caesarean section
13
12
NS
Placenta previa (> 28 weeks)
3
4
NS
Preterm labor (28–36 weeks)
6
4
NS
Antepartum hemorrhage
4
6
NS
Pregnancy-induced hypertension
12
14
NS
Intrauterine death/congenital
abnormality
0
0
NS
Low birth weight (< 2,500 g)
3
2
NS
Pandian RU. Maturitas. 2009; 65(Suppl 1): S47-S50.
Conclusion
 The miscarriage rate was lower in the
dydrogesterone group than in the control group
 No babies born with congenital abnormalities and no
intrauterine deaths
 Large-scale, double-blind, randomized, controlled
trials are essential to confirm these initial findings
Pandian 2009
Dydrogesterone in the reduction of recurrent
abortion
J Steroid Biochem Mol Biol 2005; 97: 431-434
El-Zibdeh MY
El-Zibdeh 2005
25
El-Zibdeh 2005 - Dydrogesterone in the Reduction of
Recurrent Spontaneous Abortion
Design
 Randomized, controlled study
 Oral dydrogesterone 10 mg b.i.d.
 Intramuscular HCG 5000 IU
every 4 days
 No additional treatment
 Treatment started after
confirmation of pregnancy and
continued until 12th week
Adapted from: El-Zibdeh MY. J Steroid Biochem Mol Biol 2005; 97(5): 431-434.
29
30
25
Miscarriage rate (%)
 180 pregnant women (<35 years
old) with at least 3 previous
unexplained consecutive
miscarriages with the same
partner randomized
35
20
15
*
18
13
10
5
0
* p = 0.028 vs control
Dydrogesterone had a
significantly lower miscarriage
rate compared with the control
group (13.4% vs. 29%, p=0.028)
Dydrogesterone use during pregnancy:
overview of birth defects reported since 1977
Early Hum Dev 2009; 85: 375-377
Queisser-Luft A
Queisser-Luft 2009
27
Exposure
 Between 1977 and 2005:
 Based on sales figures, around 38 million women
treated with dydrogesterone
 Foetuses exposed to dydrogesterone in utero in more
than 10 million pregnancies
Queisser-Luft 2009
28
Results
 28 Reported birth defects
– 19 Malformations: musculoskeletal system, neural tube
defects, multiple defects, heart, facial clefts, eye,
gastrointestinal system, urogenital system
– 4 Abnormalities: myopia/amblyopia/refraction disorder,
hearing disorder, ovarian cyst, non-immune hydrops
– 3 Masculinisation: hermaphroditism, enlarged clitoris (2)
– 1 Embryonic tumour: adrenal neuroblastoma
– 1 Behavioural deviation: borderline personality disorder
29
Queisser-Luft 2009
Results
Threatened or recurrent miscarriage as the indication for
dydrogesterone treatment in 18 of 28 cases:
 79% of cases exposed during the first trimester
 54% of cases exposed to concomitant medications
 Types of concomitant medications varied, but none
recognized as potentially teratogenic
 Daily dosage mostly 10 – 30 mg
Queisser-Luft 2009
30
Conclusion
 Low number of birth defects reported
 No pattern of abnormalities with evaluation
of individual case reports
 However, limitations of pharmacovigilance
must be acknowledged. Robust
malformation rates cannot be determined
based on case reports

31
Queisser-Luft 2009
Dydrogesterone: safety and tolerability

Pregnancy
 It is estimated that more than 10 million pregnancies have
been exposed to dydrogesterone. So far there were no
indications of a harmful effect of dydrogesterone use
during pregnancy.
 Some progestogens have been reported in the literature to
be associated with an increased risk of
hypospadias. However due to confounding factors during
pregnancy, no definitive conclusion can be drawn
regarding the contribution of progestogens to
hypospadias.
32
SAFETY AND TOLERABILITY IN PREGNANCY
 Clinical studies, with limited number of women treated
with dydrogesterone early in pregnancy, have not shown
increase in risk. No other epidemiological data available

 Effects in non-clinical embryo-fetal and post-natal
development studies were in line with the
pharmacological profile. Untoward effects occurred only
at exposures which exceeded the maximum human
exposure considerably
 Dydrogesterone can be used during pregnancy if clearly
indicated.
Safety and tolerability
 Breastfeeding
– No data exist on excretion of dydrogesterone in milk.
Experience with other progestogens indicates that
progestogens and the metabolites pass to mother’s milk in
small quantities. Whether there is a risk to the child is not
known. Therefore, dydrogesterone should not be used
duringthe lactation period.
 Fertility
– There is no evidence that dydrogesterone decreases fertility
at therapeutic dose.
34
Comparing Three Systematic Reviews of
Progestogens in Threatened Miscarriage
Progestogen for Treating
Threatened Miscarriage
Wahabi 20071
Progesterone and
Dydrogesterone
Wahabi 20112
Data set:
Intravaginal progesterone: 2
studies (n=84)
Dydrogesterone: no studies
Data set
Data set:
Intravaginal progesterone: 2
Dydrogesterone: 5 studies
studies (n=84)
(n=660)
Dydrogesterone: 2 studies (ElZibdeh, Pandian)3,4 (n=337)
Main results:
Main results
Main results:
No effectiveness for
vaginal progesterone
compared to placebo in
reducing risk of
miscarriage
Evidence of a significant
reduction of spontaneous
miscarriage by
progestogens vs. placebo
no treatment of 0.53
(CI = 0.35 to 0.79)
Statistically significant
reduction with
dydrogesterone in the odds
ratio for miscarriage
compared to standard care
of 0.47
(CI = 0.31–0.7)
1. Wahabi HA, et al. Cochrane Database Syst Rev 2007 Jul 18; (3): CD005943. 2. Wahabi HA, et al.
Cochrane Database Syst Rev 2011 Dec 7; (12): CD005943. 3. El-Zibdeh MY, Yousef LT. Maturitas
2009; 65(Suppl 1): S43-S46. 4. Pandian RU. Maturitas. 2009; 65(Suppl 1): S47-S50. 5. Carp H.
Gynecol Endocrinol 2012; 28(12): 983-990.
Dydrogesterone
Alone
Carp 20125
Clinical Outcomes in Threatened Miscarriage
Dydrogesterone Is More
Effective Than Standard Care
 Omar 2005
Dydrogesterone showed a
significantly
higher continuing pregnancy success
rate (95.9% vs. 86.3%; p = 0.037 )1
 El-Zibdeh 2009
Dydrogesterone showed a
significantly lower miscarriage rate
(17.5% vs. 25%; p < 0.05)2
 Pandian 2009
Dydrogesterone showed a
significantly
higher successful delivery rate
(87.5% vs. 71.6%; p < 0.05)3
Dydrogesterone Is as effective
as Micronized Progesterone
 Czajkowski 2007
Dydrogesterone (30 mg/day for 6
weeks) had a miscarriage rate of 8.3%
compared to 13.8% with vaginal
micronized progesterone (300 mg/day
for 6 weeks) in a study to evaluate
spiral artery pulsatility & resistance
index (difference not significant)4
 Pelinescu-Onciul 2007
Dydrogesterone (40 mg/day until 16th
week) had a miscarriage rate of 7%
compared to a rate of 18.7% obtained in
a previous study in women with
treated with micronized progesterone
(significance in difference not
determined)5
1. Omar MH, et al. J Steroid Biochem Mol Biol 2005; 97(5): 421-425. 2. El-Zibdeh MY, Yousef LT. Maturitas
2009; 65(Suppl 1): S43-S46. 3. Pandian RU. Maturitas 2009; 65(Suppl 1): S47-S50. 4. Czajkowski K, et al.
Fertil Steril 2007; 87(3): 613-618. 5. Pelinescu-Onciul D. Gynecol Endocrinol 2007; 23(Suppl.1): 77-81.
SYSTEMATIC REVIEW OF DYDROGESTERONE FOR
TREATMENT OF THREATENED ABORTION
21 REPORTS
1380 PATIENTS
5 RANDOMIZED STUDIES
47% significant reduction in odds for miscarriage
.
H Carp . GYNECOLOGICAL ENDOCRINOLOGY 2012
2012 United Kingdom NICE Guidelines
Progesterone/progestogen for threatened miscarriage
Approximately 20% of pregnancies miscarry in the first trimester
and many women will experience some bleeding and/or pain in
early pregnancy that does not cause miscarriage.
In many countries, women with bleeding and/or pain will be
treated with progesterone or progestogens to try and decrease
the risk of miscarriage.
The evidence for the effectiveness of this treatment has been
inconclusive, but data from a meta-analysis of several
small studies suggest that progestogens are better
than placebo. However, there are theoretical risks to
prescribing any treatment in pregnancy and for many practitioners
this will be a major change in practice. The lack of strong evidence
makes this a priority area for research.
National Institute for Health and Care Excellence (NICE) clinical guideline 154. December 2012.
http://guidance.nice.org.uk/cg154 (last accessed March 2014).
2013 Australian and New Zealand Guidelines
Recommendation
For women presenting with a clinical diagnosis of
threatened miscarriage, there is now preliminary
evidence of a reduction in the rate of spontaneous
miscarriage with the use of progestins.
Grade and Reference
Consensus-based
recommendation
Reference: Wahabi 2011
This conclusion is based on data from four RCTs including 411 women. Miscarriage was
significantly less likely to occur on progestins than placebo or no
treatment (risk ratio 0.53; 95% CI 0.35 to 0.79), with no evidence of increase in the
rate of antepartum hemorrhage, pregnancy-induced hypertension, or congenital
abnormalities. Again, there was clinical heterogeneity in these trials, with two reporting on
the use of oral dydrogesterone and two reporting on vaginal progesterone.
The evidence suggesting benefit of progestins for women with recurrent
miscarriage and now, particularly, for women with threatened miscarriage,
remains preliminary and additional well designed studies are required to confirm
these findings.
Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) 2013.
http://www.ranzcog.edu.au/doc/progesterone-support-of-the-luteal-phase-and-early-pregnancy.html
(Last accessed March 2014).
Cochrane Systematic Review of Progestogens in
Miscarriage
Progesterone and Dydrogesterone
Haas & Ramsey 2013
Data set
14 trials (n=2158) regardless of gravidity or previous miscarriages
Main results
No evidence of reduction of miscarriage by progestogen
No evidence of reduction by route of administration (oral, vaginal,
intramuscular)
Subgroup analysis of 4 trials (225) in recurrent miscarriages (3+)
compared to placebo or no treatment progestogen treatment showed
a statistically significant decrease in miscarriage rate (Peto OR 0.39;
95% CI 0.21 to 0.72) but poor methodological quality (2 dydrogesterone
studies)
Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD003511.
Luteal Phase support in IVF

CHAKRAVARTY et al. J Steroid Bio Mol Bio 2005
 430 IVF women
 Randomized to oral dydrogesterone vs vaginal micronized
progesterone
 Luteal phase support from embryo transfer
 12 weeks
 No difference in outcome
 More women were satisfied with dydrogesterone with
view to tolerability
DYDROGESTERONE IN LUTEAL INSUFFICIENCY
 Luteal phase is defined as the period from occurrence of ovulation until
the establishment of a pregnancy or the resumption of menses 2 weeks
later1
luteal phase
1. Ghanem ME, Al-Boghdady LA. Luteal Phase Support in ART: An Update. Available from:
http://cdn.intechopen.com/pdfs/41085/InTech-Luteal_phase_support_in_art_an_update.pdf (last accessed
February 2014). 2. Schindler AE. Gynecol Endocrinol 2004; 18(1): 51-57.
Figure adapted from: Schindler AE. Gynecol Endocrinol 2004; 18(1): 51-57.
Luteal Phase Defect
Luteal Phase Defect is a
Corpus luteum with inadequate progesterone secretion
Characterized by:
Short luteal phase interval (<12 days between ovulation and menses)
A normal-length luteal phase with inadequate progesterone production
Or inadequate endometrial response to otherwise normal progesterone
concentrations
Luteal phase defect may occur sporadically in fertile women e.g. in
teenagers post menarche, during stress or strenuous exercise
Miller, P, Soules, M, Glob libr Women's Med (ISSN: 1756-2228) 2009; DOI10.3843/GLOWM.10327.
Dydrogesterone for Luteal Phase
Insufficiency
Dosages, treatment schedule and duration of
treatment may be adapted to severity of
dysfunction and clinical response.
 Infertility due to luteal insufficiency: 10 or 20 mg
dydrogesterone daily starting with the second
half of the menstrual cycle until the first day of
the next cycle. Treatment should be maintained
for at least three consecutive cycles
.
Luteal Phase Defect
Regulation of Menstrual Cycle with Dydrogesterone
Dydrogesterone to treat teenagers with defective luteal phase
suffering from menorrhagia, oligomenorrhea or polymenorrhea
40%
Menstrual cycle normalization
Subjects: N=50, age 16-19yrs
Menorrhagia n=39
30%
Oligomenorrhea n=8
20%
Polymenorrhea n=3
Treatment: 10 mg/day,
day 11-25 of cycle
10%
Treatment duration: 6 cycles
0%
In cycles 1-3
In cycle 4
In cycle 5
In cycle 6
Curettage
Menstruation was regulated in 96% after 6 cycles
Adapted from: Dutta DK. Asian J Ob Gyn 2001; 5(2): 3-5.
Comparison of dydrogesterone and progesterone
in irregular dysfunctional uterine bleeding
 Randomised controlled study in Turkey
 69 Women with DUB
 Treated with oral dydrogesterone (20 mg/day for 10
days starting on day 15) or vaginal progesterone
(90 mg alternate days from day 17 – 27) for 3 months.
 Improvements in menstrual cycle characteristics and
endometrial histology similar in both groups.
 No adverse events with dydrogesterone reported.
Growing pain and weight gain reported with
progesterone.
Karakus et al 2009 Aust N Z J Obstet Gynaecol
Comparison of dydrogesterone and progesterone
in irregular dysfunctional uterine bleeding
Karakus et al 2009
47
Double-blind, placebo-controlled study of dydrogesterone in
secondary amenorrhoea
 Double-blind, randomised, placebo-controlled study
 104 Premenopausal women with secondary amenorrhoea or
oligomenorrhoea and normal oestrogen
 Treated with dydrogesterone (10 mg/day) for 14 days and placebo on
the other 14 days each cycle, or placebo alone, for 6 cycles
 Occurrence of withdrawal bleeding during the first cycle: significantly
higher with dydrogesterone than placebo (65% vs. 31%, p = 0.0004)
 Regularity of withdrawal bleeding significantly better with
dydrogesterone
 Dydrogesterone well tolerated. Adverse events in 12 women on
dydrogesterone and 13 on placebo
10 or 20 mg daily for 14 days during the second half of the cycle to produce optimum
secretory transformation of an endometrium adequately primed with oestrogen
Panay et al 2007
Treatment Algorithm for Endometriosis
Chronic pelvic pain and endometriosis in young women
Functional disorder
Dietary changes, GI referral
Physical therapy, trigger points
Psychological evaluation
• IBS
• Pelvic floor myalgia
• Depression
ENDOMETRIOSIS
Chronic pelvic pain
• Detailed history
• Examination
• Imaging
Alternative diagnoses
• Adnexal cyst
• Chronic appendicitis
• IBD
Medical management
presumptive diagnosis
NSAIDs
OCs
GnRH agonists + add-back
Progestins
Danazol
Solnik J. Curr Opin Obstet Gynecol 2006; 18: 511–518 .
Conservative surgery
Surgical diagnosis
Surgical therapy
Other diagnosis
Treatment of Endometriosis with Progestogens
ESHRE recommends
 Use of progestogens or anti-progestogens as one option to
reduce endometriosis-associated pain
 Side-effect profiles should be taken into account especially
irreversible side effects (e.g. thrombosis, androgenic
effects)
 Consider prescribing a levonorgestrel-releasing
intrauterine system as one option to reduce endometriosisassociated pain
ESHRE: European Society of Human Reproduction and Embryology
Dunselman GAJ et al. Hum Reprod. 2014 Mar;29(3):400–12.
Mechanism of Action of Progestogens
Progestogens have a therapeutic action in women with
endometriosis by acting at different levels:1
 They have an anti-gonadotropic effect and therefore
inhibit the ovarian function thus creating a stable hypoestrogenic environment1
(not dydrogesterone at approved doses*)2
 They reduce peritoneal inflammation1
1. Streuli I, et al, Expert Opin Pharmacother..2013; 14(3): 291–305
2. Schindler AE. Maturitas 2009; 65S: S3–S11.
3. Dydrogesterone Summary of Product Characteristics. 29 April 2011.
Management of Endometriosis
Baseline controlled studies in patients with surgically confirmed endo
Entered /
Completed
Author
(year)
Johnston
WI, 19761
49
Dydrogesterone
Treatment
Results
Adverse events (n)
5 mg BID (10 mg/d)
9 months
Symptoms (n=45): 89% symptom-free
Culdopscopy (n=32): 66% on signs
Transient mastalgia (1),
dizziness (1)
Walker SM,
19832
14/10
10 mg TID (30 mg/d) on
day 5 to 25
6 months
Symptoms: 60% showed improvement
in pelvic pain pain scores
Laparoscopy (n=9): 56% showed
improvement
Breast tenderness (3),
increased breast size (4),
edema (1), hirsutism (1)
Cornillie FJ,
et al. 19873
18/18
20 mg/d (n=14)
2-5 months
60 mg/d (n=4) 2 months
Laparoscopy: 30% showed significant
improvement, 61% showed some
improvement
None stated
Kaiser E,
Wagner
ThA. 19894
20
10 mg/d day 5 to 15 and 20
mg/d day 16 to 25 of each
cycle
6 months or longer
Symptoms: 30% elimination, 60%
improvement
Laparoscopy: 75% elimination, 20%
improvement
Mainly nervousness or
weight gain (11)
Trivedi P et
al. 20075
98/90
10 or 20 mg/d day 5 to 25
3-6 months
Symptoms: 21% symptom-free, 67%
showed improvement. Pelvic pain,
dysmenorrhea, dysparunia improved
after 1 month (p<0.05)
None reported
Dosing 10 or 30 mg/day from day 5 to 25 of the cycle or continuously6
1. Johnston WI. Br J Gynaecol 1976; 77–80; 2. Walker SM. Br J Clin Practice 1983; 24(Suppl.):40–
46; 3. Cornillie FJ, et al. Eur J Obstet Gynecol Reprod Biol 1987; 26: 39–55; 4. Kaiser E, Wagner
ThA. TW Gynäkologie 1989; 2: 386–388; 5. Trivedi P et al. Gynecol Endocrinol 2007; 23 Suppl
1:73–76; 6. Dydrogesterone Summary of Product Characteristics. 29 April 2011.
Symptoms
After Treatment with Continuous Dydrogesterone
Alleviation of symptoms with dydrogesterone1
Patients: Endometriosis confirmed by culdoscopy/laparoscopy, treated with 5 mg dydrogesterone BID for 9 months
(n=49)
Symptoms at baseline
Dysmenorrhoea
Symptoms after treatment*1
Complete relief
89%
Improved
7%
No improvement
4%
Dyspareunia
Infertility , primary
Menorrhagia
Pelvic pain, chronic
Infertility, secondary
Dyspareunia improved
significantly only after 12-16
weeks of treatment1
No symptoms
Pelvic pain, acute
Pain on defaecation
0%
20%
40%
60%
80%
Approved dosing 10 or 30 mg/day from day 5 to 25 of the cycle or contiunously2
* Patients with symptoms at beginning of study only, n=45
1. Johnston WI. Br J Gynaecol 1976; 83: 77–80. Graph adapted.
2. Dydrogesterone Summary of Product Characteristics. 29 April 2011.
Laparoscopy
After Treatment with Continuous Dydrogesterone
Regression of endometriotic lesions with dydrogesterone
Patients: Endometriosis confirmed by laparoscopy, treated with 5 mg dydrogesterone BID for 9
months (n=49), repeat culdoscopy at end of treatment (n=32)
Sites of endometriosis at baseline
Repeat laparoscopy results
Ovarian, unilateral
n=17
Normal, no lesions
n=21
Ovarian, bilateral
n=16
Regression of lesions
n=9
Uterosacral
ligaments
n=28
No regression
n=2
Pelvic peritoneum
n=9
Previously uncharted
lesions
n=3
21 out of 32 patients with repeat laparoscopy showed no lesions after 9
months of daily treatment with dydrogesterone
Approved dosing 10 or 30 mg/day from day 5 to 25 of the cycle or continupously2
1. Johnston WI. Br J Gynaecol 1976; 83: 77–80.
2. Dydrogesterone Summary of Product Characteristics. 29 April 2011.
Symptoms and Laparoscpy
After Treatment with Dydrogesterone Day 5 to 25
Improvement in clinical findings after treatment with dydrogesterone
Treatment: 10 mg/day dydrogesterone from day 5 to 15 and 20 mg/day from day 16 to 25 of
each cycle, treatment period 6 months or longer (n=20)
Improvement in subjective
symptoms, palpatory
findings and laparoscopic
finding
Proportion of patients (%)
100%
75%
50%
25%
0%
Subjective
symptoms
Unchanged
Palpatory
findings
Laparoscopic
findings
Improved
No symptom
Kaiser E, Wagner ThA. TW Gynäkologie 1989; 2: 386–388 .
Symptoms
After Treatment with Dydrogesterone Day 5 to 25
Pain during treatment with dydrogesterone of women suffering
from endometriosis (n=90)
Pain score
Treatment: 10 mg/day dydrogesterone or 20 mg/day (in severe cases) on days 5 to 25 of
each cycle for 3 to 6 months
• Overall 21% symptom free, 67%
2
showed an improvement
• Pelvic pain, dysmenorrhea,
dyspareunia improved (by 29, 32,
1.5
1.5
38% respectively, p<0.05) after 1
month and after 6 months (by
95, 87, 85%, respectively, p<0.05)
1
Pelvic pain score
0.5
Dysmenorrhoea
score
Dyspareunia score
0
0
1
2
3
4
5
6
Treatment month
Trivedi P, et al. Gynecol Endocrinol 2007; 23 Suppl 1: 73–76.
Pregnancy Rates after treatment with
Dydrogesterone
Pregnancy rates were approximately 50% after
dydrogesterone therapy for endometriosis
First author (year)
Treatment regimen
Pregnancy
rate (%)
Johnston WI (1976)2
2 x 5 mg/day for nine months
53
Makhmudova (2003)3
10 mg/day on days 5-25 of cycle
50
Tumasyan (2001)4
10 mg/day on days 5 to 25 of cycle
57
1.
2.
3.
4.
Overton CE, et al. Fertil Steril 1994; 62: 701–707;
2. Johnston WI. Br J Gynaecol 1976; 83: 77–80;
3. Makhmudova GM et al. Akush Ginekol (Sofiia) 2003; 42:42–46;
4. Tumasian KP et al. Lik Sprava 2001; 3:103–105.
Conclusions
DYDROGESTERONE AND ENDOMETRIOSIS
• Decreases inflammatory cytokines1
• Is anti-inflammatory2 and decreases angiogenic factors2
• Effectively treats pelvic pain, dyspareunia and dysmenorrhea3
• Tolerability and safety profile of dydrogesterone makes it suitable
to treat clinically suspected endometriosis3
• Highly selective for the progesterone receptor and its metabolites
are progestogenic4
• Does not suppress ovarian function when given at therapeutic
doses5
• Pregnancy rates of approximately 50% after therapy6-9
1. Schweppe KW. Maturitas 2009; 65 Suppl 1: S23-21; 2. Tariverdian N et al. J Mol Med 2010; 88: 267–278; 3.
Trivedi P, et al. Gynecol Endocrinol 2007; 23 Suppl 1: 73–76; 4. Schindler AE, et al. Maturitas 2009; 65(Suppl 1):
S3–S11; 5. Bishop PM, et al. Acta Endocrinol 1962; 40: 203–216; 6. Overton CE, et al. Fertil Steril 1994; 62: 701–
707; 7. Johnston WI. Br J Gynaecol 1976; 83: 77–80; 8. Makhmudova GM, et al. Akush Ginekol (Sofiia) 2003; 42:
42–46; 9. Tumasian KP, et al. Lik Sprava 2001; 3: 103–105.
DYDROGESTERONE IN HORMONAL THERAPY
Equivalent dose for bone endpoints*
Estrogen
Ultra Low
Low
Standard
High
Conjugated equine estrogens (mg)
0.151
0.3
0.625
1.25
Micronized 17β-estradiol (mg)
0.52
1
2
4
1
2
25
50
Estradiol valerate (mg)
Transdermal 17β-estradiol (μg)
143
The Estrogen Dose Counts
*Estrogenic effects may vary for other endpoints
Table reproduced from Maturitas, 40, Gambacciani M, Genazzani AR. Hormone replacement therapy: the
benefits in tailoring the regimen and dose. 195–201, Copyright (2001), with permission from Elsevier.
1. Lindsay R et al. Obstet Gynecol 1984;63:759–63; 2. Panay N et al. Climacteric 2007;10:120–31;
3. Ettinger B et al. Obstet Gynecol 2004;4:443–51.
100
Role of progestogens in hormone therapy
 Estrogen provides the benefits of HRT on menopausal symptoms
 For women who have not had a hysterectomy, the addition of a progestogen to
HRT is necessary to protect the endometrium from the stimulatory effects of
unopposed estrogen
PEPI Trial: Results of Endometrial Biopsy
Placebo
CEE alone
CEE+MPA
sequential
CEE+MPA
continuous
N
119
119
118
120
Normal
98%
38%
95%
99%
Simple hyperplasia
1%
28%
3%
1%
Complex hyperplasia
1%
23%
2%
0%
Atypia
0%
12%
0%
0%
Adenocarcinoma
1%
0%
0%
0%
Conclusion: Adding a progestogen is needed to safeguard the endometrium
Writing Group for the PEPI Trial. JAMA 1996;275:370–5.
Femoston® Formulations and Indications
• Sequential 1/10 HRT for estrogen deficiency symptoms in postmenopausal women ≥6 months
since last menses
17β-estradiol 1 mg/d
Dydrogesterone 10 mg/d
Day 14
•
Bleeding at end of cycle
Continuous 1/5
– HRT for estrogen deficiency symptoms in postmenopausal women ≥12 months since last menses
17β-estradiol 1 mg/d
Dydrogesterone 5 mg/d
Day 14
.
.
No bleeding
Sequential
Vasomotor Symptoms
In a study of 193 peri- and postmenopausal women:
• Mean number of hot flushes per day decreased by 86%
• Improvement supported by changes in Greene climacteric symptom score
12.0
E/D (1/10)
CEE/norgestrel (0.625/0.15)
Mean number of
hot flushes per day
10.0
8.0
6.0
4.0
2.0
0.0
-4
-2
0
2
4
6
8
10 12 14 16 18 20 22 24 26
Weeks
Figure reproduced with kind permission from Springer Science+Business Media: Arch Gynecol Obstet, Clinical study
comparing the effects of sequential hormone therapy with oestradiol/ dydrogesterone and conjugated equine oestrogen/
norgestrel on lipids and symptoms. 274, 2006, 74–80. Cieraad D, Conradt C, Jesinger D, Bakowski M, Figure 1.
Sequential :
Menopausal Symptoms
In a study of 186 postmenopausal women using estradiol/dydrogesterone
• Proportion of women bothered by symptoms decreased during treatment
Proportion of women
bothered by symptom (%)
80
70
Baseline
6 weeks
52 weeks
60
50
40
30
20
10
0
Hot
flushes
Night
sweats
Amy JJ, Eur Menop J 1995;2(Suppl):16–22. ©1995, Informa Healthcare.
Figure reproduced with permission of Informa Healthcare.
Sweating
attacks
Vaginal
dryness
Painful
intercourse
Continuous 0.5/2.5 & 1/5:
Vasomotor Symptoms
 Significant reduction in moderate-to-severe hot flushes vs. placebo (n=305)
Mean (95% CI) change from
baseline in number of moderateto-severe hot flushes per day
-0
Placebo
E 0.5 mg/D 2.5 mg
E 1 mg/D 5 mg
-1
-2
-3
-4
*
-5
*
-6
**
***
**
-7
***
-8
1
2
3
4
5
6
7
8
Week
9
10
11
12
*p<0.05, **p<0.01, ***p<0.001 vs. placebo
Figure reproduced from Maturitas, 67, Stevenson JC, Durand G, Kahler E, Pertyński T. Oral ultra-low dose continuous combined hormone replacement therapy with 0.5mg 17β-oestradiol and 2.5mg dydrogesterone for the treatment of vasomotor symptoms: Results from a double-blind, controlled study. 227–
32, Copyright (2010), with permission from Elsevier.
13
Sequential
Endometrial Safety and Bleeding in 579 women, 26 cycles

(n=579)1
 Endometrial safety was recorded across groups
 No cases of hyperplasia or malignancy with 1/10 and 2/10
 1 polyp occurred with 1/10
 Cyclic bleeding patterns were seen
 Percentage of women with cyclic bleeding was 79% with 1/10 and
91% with 2/10
 E 1 mg associated with less cyclic and intermittent bleeding vs. E 2 mg
 Higher doses of D assoc with higher incidence of bleeds later day of onset
 Endometrial safety was recorded across groups
 No cases of hyperplasia or malignancy with 1/10 and 2/10
1. Ferenczy A et al. Climacteric 2002;5:26–35;
2. Burch DJ et al. Brit J Obst Gynaecol 1995;102:243–8.
Continuous :
Endometrial Safety and Bleeding Patterns (1 year n= 290)
 1 case of simple hyperplasia without atypia (treatment
failure rate of 0.4%)
 Women without bleeding increased from 71% (cycle 1) to
~80% by end of the study
 ~50% of bleeding episodes were spotting
 41% women were amenorrheic throughout the study
 7 women withdrew prematurely due to uterine
bleeding
1. Quereux C et al. Maturitas 2006;53:299–305;
2. Bergeron C et al. Maturitas 2010;66:201–5.
Sequential : BMD
 Sequential E/D effective vs. placebo in preventing loss of bone mass in the
lumbar spine and femoral neck over 2 years (n=595)
*
Mean change from
baseline in BMD (%)
8
6
*
6.7%
1 mg E2 + D
5.2%
*
4
2.7%
*
2mg E2 + D
2.5%
2
Placebo
0
-2
-4
- 1.6%
Lumbar spine
*p<0.001 vs. placebo
Lees B et al. Osteoporos Int 2001;12:251–8.
- 1.8%
Femoral neck
Continuous : BMD
• Continuous 1/5, 1/10, and 1/20 significantly increased lumbar vertebrae
and hip BMD vs. baseline (n=214) after 1 year
3.63% *
L2–L4
2.40%*
12 months
6 months
1.16%
Femoral neck
*
0.20%
0
+1
+2
+3
+4
Mean percentage change from baseline in BMD
*p<0.01 vs. baseline
Stevenson J et al. Maturitas 2001;38:197–203.
HRT Effect on Cardiovascular Risk Parameters
 Meta-analysis of 107 randomized, controlled trials (>8 weeks duration), HRT was
found to have an effect on following metabolic parameters vs. placebo/no therapy
% Change from baseline
in patients on HRT
HOMA-IR
LDL/HDL
Triglycerides
*†
Mean
BP
*
Waist
Abdominal
circumference
fat
*
*
*
*
*
All HRT
Transdermal
Oral
*
*†
• Oral agents generally produced larger effects than transdermal agents, except
with triglycerides, which appeared to increase with oral agents
*p<0.05 vs. no HRT; †p<0.05 vs. transdermal
Salpeter SR et al. Diabetes Obes Metab 2006;8:538–54.
HDL Cholesterol Profile
Increase in HDL cholesterol (%)
25
Placebo
1/5 mg
1/10 mg
2/10 mg
2/20 mg
(n=54)
(n=62)
(n=74)
(n=60)
(n=67)
*
*
20
*
15
10
*
* *
*
5
0
Cycle 13
*p≤0.05 vs. placebo
Stevenson JC, Rioux JE, Komer L, Gelfand M. Climacteric 2005;8:352–9. ©2005 Informa Healthcare.
Figure reproduced with permission of Informa Healthcare.
Cycle 26
Lipid profile vs. CEE/Norgestrel
In a 24 week study of 193 peri- and postmenopausal women:
 HDL significantly increased with E/D
 HDL reduced with CEE/norgestrel (0.625/0.15 mg)
Mean change (mmol/L)
from baseline at week 24
Total
cholesterol
HDL
cholesterol
LDL
cholesterol
***
**
*
****
****
*p<0.05, **p=0.01, ***p=0.003, ****p=0.001 vs. baseline
Cieraad D et al. Arch Gynecol Obstet 2006;274:74–80.
****
Triglycerides
E/D
CEE/norgestrel
Low-Dose Sequential E / D: Blood Glucose and Insulin
•
Mean concentration of
glucose or insulin
Low-dose sequential E/D (1/5, 1/10) (n=15)
6
5
4
5.13
4.96*
4.87**
Fasting glucose (mmol/L)
4.14
3
3.12*
2
2.88**
Fasting insulin (mU/L)
1
0
Baseline
Year 1
Year 2
• E/D can affect menopausal changes in insulin secretion
*p<0.05, **p<0.01 vs. baseline
Godsland IF et al. Clin Endocrinol (Oxf) 2004;60:541–9.
Risk of thromboembolism associated with different
progestogens
Adjusted ORs (95% CI) for
VTE with oral and transdermal
estrogen vs. non-users
ESTHER case-control study
271 consecutive VTE cases (mean age: 61.6 years) and 610 controls (mean age: 61.5 years)
3.9 (1.5–10.0)
4.2 (1.5–11.6)
0.7 (0.3–1.9)
0.9 (0.4–2.3)
(e.g. Nomegestrol acetate)
(e.g. Dydrogesterone)
 Micronized progesterone and pregnane
derivatives appear to have an acceptable
thrombotic risk profile
Canonico M. Circulation 2007;115:840–5.
Risk of Stroke Associated with Route of Administration
Adjusted RR vs. never-use
of HRT (95% CI)
 Case-control study from the UK General Practice Research Database
(1.15–
3.11)
(0.62–
1.05)
(1.12–
1.40)
(1.16–
1.90)
• Low-dose transdermal HRT did not appear to increase stroke risk
Renoux C et al. BMJ 2010;340:c2519.
HRT and the Risk of
Coronary Artery Disease and Ischemic Stroke
Risk of Coronary Artery Disease
• The risk of coronary artery disease is slightly increased in users of combined
estrogen-progestogen HRT over the age of 60 years
Risk of Ischemic Stroke
• The use of estrogen-only and estrogen-progestogen therapy is associated with an
up to 1.5-fold increased relative risk of ischemic stroke. The risk of hemorrhagic
stroke is not increased during use of HRT. This relative risk is not dependent on
age or on duration of use, but as the baseline risk is strongly age-dependent, the
overall risk of stroke in women who use HRT will increase with age
US WHI studies combined - additional risk of ischemic stroke1 over 5 years’ use
Age range
(years)
Incidence per 1,000 women
in placebo arm over 5 years
Risk ratio
(95% CI)
Additional cases per 1,000
HRT users over 5 years (95% CI)
50–59
8
1.3 (1.1–1.6)
3 (1–5)
1No
differentiation was made between ischemic and hemorrhagic stroke
Netherlands Summary of Product Characteristics (SmPC) , estradiol/dydrogesterone 2/10, 1/10, 1/5, 0.5/2.5 issued 13 April 2012.
Is menopausal hormone therapy Associated with Increased Breast
Cancer Risk? Evidence from WHI
WHI RR for breast cancer:
1.26 (95% CI 1.00–1.59)
for current use of HRT
(CEE + MPA)1
• Later studies with adjusted
CIs showed this was a nonsignificant result2
Excess risk of breast cancer
from HRT increases with
increase in underlying risk5
Determination of risk should
underlie decision to use HRT
WHI
evidence
• No increased risk was
identified for women who
had had hysterectomy
receiving CEE alone3
Relative risk of 1.26 with combined HRT
translates to an excess (attributable) risk of
4 per 1000 women taking HRT for 5 years4
1. Rossouw JE et al. JAMA 2002;288:321–33; 2. Langer R et al. Climacteric 2012;15:206–12; 3.
Stefanik M et al. JAMA 2006;295:1647–57; 4. Santen R et al. J Clin Endocrinol Metab
2010;95(Suppl 1):s1–66; 5. Gompel A et al. Climacteric 2012;15:241–9.
HRT and Breast Cancer Risk - WHI
US WHI studies – additional risk of breast cancer after 5 years’ use
Age range
(years)
Incidence per 1,000 women
in placebo arm over 5 years
Risk ratio
(95% CI)
Additional cases per 1,000
HRT users over 5 years (95% CI)
CEE estrogen-only
50–79
21
0.8 (0.7–1.0)
-4 (-6–0)1
CEE + MPA estrogen & progestogen ‡
50–79
1
14
1.2 (1.0–1.5)
+4 (0–9)
‡ When the analysis was restricted to women who had not used HRT
prior to the study there was no increased risk apparent during the first 5
years of treatment: after 5 years the risk was higher than non-users
WHI study in women with no uterus, which did not show an increase in risk of breast cancer
Netherlands Summary of Product Characteristics (SmPC) , estradiol/dydrogesterone 2/10, 1/10, 1/5, 0.5/2.5 issued 13 April 2012.
Choice of progestogen and breast cancer risk:
E3N French Cohort Study
Relative risk (95% CI)
Risk of all breast cancer
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
1.69
(1.50–
1.91)
1.00
(0.83–
1.22)
1.16
(0.94–
1.43)
Estrogen/
Estrogen/
Estrogen/other
Baseline risk
without HRT progesterone dydrogesterone progestogens
Risk of breast cancer subtypes with
E/D
2.1
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
(1.2–
3.8)
1.5
1.1
1.1
(0.8–
1.5)
(0.8–
1.17)
<5 years
≥5 years
Ductal carcinoma
(0.8–
2.7)
<5 years
Lobular carcinoma
Not statistically significantly different from risk without HRT
Significantly different from the risk without HRT
N = 80,377 women, for an average treatment duration of 8.1 years
Overall 77.7% were ductal breast cancers vs. 22.3% lobular breast cancers
Risk elevation may not be uniform for all progestogens
Fournier A et al. Breast Cancer Res Treat 2008;107:103–11;
Fournier A et al. J Clin Oncol. 2008 ;26:1260–1268.
≥5 years
Standard incidence ratio (95% CI)
Choice of Progestogen and Breast Cancer Risk: Finnish Cohort
Study
2.2
2.0
1.8
1.64
1.6
1.4
1.2
2.03
2.07
(1.88–
2.18)
(1.76–
2.04)
(1.49–
1.79)
1.13
1.0
0.8
0.6
(0.49–
2.22)
0.4
0.2
0
Estradiol/
Estradiol/
Baseline risk
MPA
without HRT dydrogesterone
Estradiol/ Estradiol/other
NETA
progestogens
N = 50,210 women >50 years of age, treatment duration 5 years
Risk elevation may not be uniform for all progestogens
Lyytinen H et al. Obst Gyn 2009;113:65–73.
Breast Cancer with HRT: Risk Perception vs. Reality
REALITY
Actual causes of death
among US women
PERCEPTION
Leading causes of death
perceived by women
Old age (1%)
Smoking (1%)
Stress (2%)
Other/don’t
know (16%)
Heart
disease
(18%)
Ovarian
cancer (9%)
Breast cancer
(39%)
Other (25%)
Other
cancer
(13%)
Pneumonia (4%)
COPD (4%)
Lung
cancer
(2%)
Ovarian cancer (<2%)
Breast cancer (4%)
Lung
cancer
(5%)
Figure reproduced with permission from http://www.keepstudy.org/why_keeps/keeps_causeDeath.pdf.
Accessed 1 November 2012
Other
cancer
(11%)
Heart
disease
(45%)
Statements from International Societies
International Menopause Society Statement on Breast Cancer1
 Women should be reassured that the possible increased risks of breast cancer
associated with HRT are small
 <0.1% per annum, or an incidence of <1.0 per 1000 women per year of use
 Less than the increased risks associated with common lifestyle factors such as reduced
physical activity, obesity and alcohol consumption
 WHI study demonstrated no increased risk in first-time users of HRT during the first
5–7 years of treatment

 Micronized progesterone or dydrogesterone used with estradiol may be associated with a
better risk profile for breast cancer than synthetic progestogens
USA Endocrine Society Scientific Statement on Breast Cancer2
• Emerging data from 2 independent studies suggest that progesterone (and perhaps
dydrogesterone) in combination with estrogen does not increase breast cancer risk
if given for 5 years or less
1. De Villiers TJ et al. Climacteric 2013;16:316–337.
2. Santen R et al. J Clin Endocrinol Metab 2010;95(Suppl1):S1–S66.
Conclusion
Used by the right woman, at the right dose, Femoston® can:
 Relieve vasomotor and other menopausal symptoms
 Provide protection against bone loss (second line)
 Provide acceptable bleeding patterns
 Favourable CVS profile
 Seemingly less impact on breast cancer risk
2013 IMS Recommendations on Menopausal
Hormone Therapy – General Principles for Use
 HRT remains the most effective therapy for vasomotor symptoms
 Use lowest effective dose of estrogen
 Tailor to the individual
 Use as long as there is symptomatic benefit and aware of risks
 Risk/benefit balance
 More favorable if treatment is started earlier in menopause
 Re-evaluate risk/benefit
 Dydrogesterone and micronized progesterone may be associated with a
better risk profile for breast cancer than synthetic progestogens
 Under 45 years, HRT advised at least until average age of menopause
De Villiers TJ et al. Climacteric 2013;16:316–337.
.
DYDROGESTERONE- FROM MENARCHE TO MENOPAUSE
THANK YOU FOR YOUR ATTENTION
Pandian 2009 – Outcome and Obstetric
Complications
 Dydrogesterone group experienced a significantly lower
miscarriage rate compared with the control group (12.5 % vs.
28.4%; p<0.05)
Control
(n=96)
Dydrogesterone
p-value
(n=95)
Caesarean section
13
12
NS
Placenta previa (> 28 weeks)
3
4
NS
Preterm labor (28–36 weeks)
6
4
NS
Antepartum hemorrhage
4
6
NS
Pregnancy-induced hypertension
12
14
NS
Intrauterine death/congenital
abnormality
0
0
NS
Low birth weight (< 2,500 g)
3
2
NS
Pandian RU. Maturitas. 2009; 65(Suppl 1): S47-S50.
Method
 Randomised, controlled study in Jordan
 180 Pregnant women (<35 years old) with at least 3 previous
unexplained consecutive miscarriages with the same
partner randomised to:
– Oral dydrogesterone 10 mg b.i.d.
– Intramuscular human chorionic gonadotrophin (hCG)
5000 IU every 4 days
– No additional treatment
 Treatment started as soon as possible after confirmation of
pregnancy and continued until 12th gestational week
 All women received standard supportive care: multivitamin
supplements and recommended bed rest
El-Zibdeh 2005
87
Objective and methods
 To determine whether dydrogesterone therapy for
threatened miscarriage in the first trimester improves
pregnancy outcome
 Prospective open study in Malaysia
 Registration records of 154 pregnant women (gestational
age <13 weeks) presenting with vaginal bleeding were
evaluated
 Treatment group: dydrogesterone 40 mg at once plus
10 mg b.i.d. until bleeding stopped. Women were also
recommended bed rest and received folic acid
 Control group: bed rest, folic acid only (standard care)
 Women followed up until 20 weeks gestation
Omar et al 2005
88