MENT: ICCR’s contribution to male contraceptionMENT: ICCR’s contribution to male contraception...
Transcript of MENT: ICCR’s contribution to male contraceptionMENT: ICCR’s contribution to male contraception...
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MENT: ICCR’s contribution to male contraception
Vision for Contraceptive Research & Development The 100th Meeting of the ICCR
New York, April 20, 2012
E. Nieschlag, Center for Reproductive Medicine and Andrology
University of Münster N. Kumar, R. Sitruk-Ware Center for Biomedical Research Population Council, New York
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Hypothalamus
-
Pituitary
GnRH
Testes Leydig cells
Testosterone
Sertoli cells Spermatogenesis
LH FSH
Androgen effects Fertility
DHT
Testosterone
Estradiol
+
+ +
+ Spermien
+
F 1995 E
(Nieschlag, Behre, Nieschlag „Andrology“ 3rd ed, Springer 2010)
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Hypothalamus
Pituitary
GnRH
Testes Leydig cells
Testosterone
Sertoli cells Spermatogenese
LH FSH
Androgen effects Fertility
DHT
Testosterone
Estradiol +
Testosterone -
-
F 1996E
(Nieschlag, Behre, Nieschlag „Andrology“ 3rd ed, Springer 2010)
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Hypothalamus
Pituitary
GnRH
Testes Leydig cells
Testosterone
Sertoli cells Spermatogenese
LH FSH
Androgen effects Fertility
DHT
Testosterone
Estradiol +
Gestagen -
- Testosterone
-
-
F 1996 E
(Nieschlag, Behre, Nieschlag „Andrology“ 3rd ed, Springer 2010)
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Clinical trials for hormonal male contraception 1972 – 2011
- 60 surrogate trials counting sperm - 8 real contraceptive efficacy trials - 71 reviews
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Assessed for eligibility(n=589)
Randomized(n=354)
Excluded (n=235)Not meeting inclusion/exclusion: n=158Refused to participate: n=53Other reasons: n=24
High release ENG implant(n=152)
Low release ENG implant(n=149)
Placebo(n=53)
1 withdrew IC 2 withdrew IC, 1 switch1 1 switch1
Treated(n=52)
Discontinued treatment (n=36)Due to (S)AE: n=24Other reason: n=12
Discontinued treatment (n=15)Due to (S)AE: n=6Other reason: n=9
Discontinued treatment (n=3)Due to (S)AE: n=3Other reason: n=0
Completed treatment(n=112)
Completed treatment(n=134)
Completed treatment(n=49)
Did not start follow up (n=7)2
Discontinued follow up (n=5)Due to (S)AE: n=1Other reason: n=4
Did not start follow up (n=2)2
Discontinued follow up (n=3)Due to (S)AE: n=0Other reason: n=3
Did not start follow up (n=0)2
Discontinued follow up (n=3)Due to (S)AE: n=0Other reason: n=3
Treated (n=148)TU 1: n=47TU 2: n=50TU 3: n=51
Treated (n=149)TU 1: n=50TU 2: n=50TU 3: n=49
Completed follow up2
(n=136)Completed follow up2
(n=144)Completed follow up2
(n=49)
Phase II-b trial of TU i.m. and ENG implants for male contraception (Schering-Organon trial, 2008)
F 2061
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Sperm concentration (mill/ml) in 23 normal and 18 subnormal volunteers under testosterone undecanoate
(Nieschlag et al Int J Androl 34: 556-67, 2011)
0,0
0,1
1,0
10,0
100,0
1000,0
-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
normals
subnormals
0,01
0,1
1
10
100
-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
F 2093
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Male contraceptive efficacy trials based on hormones
PopCouncil 1977 TE + DMPA 100 WHO I 1990 TE 271 WHO II 1996 TE 225 Gu et al 2003 TUch 305 Gu et al 2009 TUch 898 Soufir et al 2011 Tgel + MPA 35 Turner et al 2003 TI + DMP 53 WHO/CONRAD 2011 TUeu + NETE (440) TUch = TU chinese = TU in tea seed oil
TUeu = TU european = TU in castor oil
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Multicenter clinical trial of DMPA and TE or TI for male contraception: Sperm concentrations (million/ml) in 9 / 100 men
around the time their wives became pregnant. (Barfield et al Contraception 20: 121-127, 1979)
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Preg
nanc
y ra
te (p
er 1
00 p
erso
n-ye
ars)
0
2
3
4
5
6
1
Azoospermia <=1.0 M/ml <=2.0 M/ml <=3.0 M/ml <=4.0 M/ml <=5.0 M/ml All sperm concentrations
Contraceptive efficacy of testosterone enanthate (200 mg biweekly) in 346 men: pregnancy rates per 100 person-years in
relation to sperm concentration. (WHO, Fertil. Steril. 65; 821, 1996)
Cumulative sperm concentration F 1846E
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enanthate implants
undecanoate
buciclate
OHCH3
CH3
O
Testosterone
19-Nortestosterone
The search for long-acting testosterone preparations
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Phase III trial of TU in tea seed oil in 10 Chinese centres
(Gu et al J Clin Endocr Metab 94: 1910-15,2009) Design: 1000 mg TU loading, 500 mg TU / month If sperm < 1 million/mL, efficacy phase for 2 years Volunteers: 1045 men recruited, 733 men completed efficacy and recovery phase Pregnancies:
F 2143/1
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Copyright ©2009 The Endocrine Society
The changes in sperm concentration with log scale during the study period
F 2143
Phase III trial of TU in tea seed oil in 10 Chinese centres
(Gu et al J Clin Endocr Metab 94: 1910-15, 2009)
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Phase III trial of TU in tea seed oil in 10 Chinese centres
(Gu et al J Clin Endocr Metab 94: 1910-15, 2009) Design: 1000 mg TU loading, 500 mg TU / month If sperm < 1 million/mL, efficacy phase for 2 years Volunteers: 1045 men recruited, 733 men completed efficacy and recovery phase Pregnancies: 1.1 in 100 men years (6 with sperm between 2-8 million/mL 3 with sperm < 1 million/mL)
F 2143/1
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FE 679
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Germany 2004
Nether- lands 1975 China 1993
O
OCO(CH2)9CH3
Testosterone undecanoate FH 118
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F1621E
T U ( 1 0 0 0 m g i . m . e v e r y 6 w e e k s ) / N E T E ( 2 0 0 m g i . m . e v e r y 6 w e e k s )
s t u d y w e e k A B 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6 4 4 5 2
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
T U ( 1 0 0 0 m g i . m . e v e r y 6 w e e k s ) / P l a c e b o p . o .
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
T U ( 1 0 0 0 m g e v e r y 6 w e e k s i . m . ) / L N G ( 0 , 2 5 m g p . o . / d )
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
I n j e c t a b l e t e s t o s t e r o n e u n d e c a n o a t e a l o n e o r w i t h o r a l l e v o n o r g e s t r e l o r i n j e c t a b l e n o r e t h i s t e r o n e e n a n t h a t e i n a c o n t r o l l e d c l i n i c a l t r i a l f o r m a l e c o n t r a c p n
s p e r m c o n c e n t r a t i o n > 1 - < 3 m i l l / m l s p e r m c o n c e n t r a t i o n > 3 m i l l / m l
a z o o s p e r m i a s p e r m c o n c e n t r a t i o n < 0 , 1 m i l l / m l
s p e r m c o n c e n t r a t i o n 0 , 1 - 1 m i l l / m l
Injectable testosterone undecanoate alone or with oral levonorgestrel or injectable norethisterone enanthate in a controlled clinical trial for male contraception
%
%
%
(Kamischke, Nieschlag et al. 2001 & 2002)
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Treatment schedule:
1000 mg testosterone undecanoate (TU) plus 200 mg norethisterone enanthate (NETE)
intramuscular every 8 weeks in 440 male partners of fertile couples
F 2304
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10 centers worldwide 487 couples screened since July, 2008 321 couples enrolled 260 entered efficacy phase 6 failed to suppress 55 discontinued before suppressing 114 couples completed efficacy
No further injections after April 6, 2011 F 2305
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enanthate implants
undecanoate buciclate
OHCH3
CH3
O
Testosterone
O
OH
CH3
CH3
MENT (7α-Methyl-19- nortestosterone)
F 1818
19-Nortestosterone
The search for long-acting testosterone preparations
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(Lyster & Duncan [Upjohn] Acta endocrinol 43: 399 - 411, 1963)
„Anabolic, androgenic and myotropic activi- ties of derivatives of 7α-methyl-19-nortesto- sterone“
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20 µg MENT / day ------ 100 µg TP / day (Lyster & Duncan (Upjohn) Acta endocrinol 43: 399 - 411, 1963)
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Development of MENT by the Population Council
1963 MENT first described by Lyster & Duncan (Upjohn)
1988 C.W. Bardin and B. Monder identified MENT as suited for replacement therapy and male contraception
1990 RIA for MENT by Kumar et al.
1990- Pharmacology, modes of application and toxicology 1995 by Kumar & Sundaram since 1995 Clinical trials for treatment of hypogonadism since 2000 2001- 2004 2006
F 2325
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at start
TE 24 wks
MENT 24 wks
Serum androgen levels, prostate volumes and lumbar bone density in 2 x 8 hypogonadal men receiving
one (group 1) or two (group 2) MENT implants (Anderson et al. JCEM 88: 2784, 2003)
Prostate volume
Bone density
FE 646
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FE 930
MENT (12 ug/day) vs. testosterone implants (72 ug/day) over 4 months for hypogonadal osteoporosis:
a preclinical study in the aged orchidectomized rat model
(Sinnesael et al Int J Androl 34: e601-e611, 2011)
Trabecular bone volume
Trabecular bone number
Trabecular thickness
Trabecular microstructure
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Development of MENT by the Population Council
1963 MENT first described by Lyster & Duncan (Upjohn)
1988 C.W. Bardin identifies MENT as suited for replacement therapy and male contraception
1990 RIA for MENT by Kumar et al.
1990- Pharmacology, modes of application and toxicology 1995 by Kumar & Sundaram since 1995 Clinical trials for treatment of hypogonadism since 2000 Clinical trials for male contraception 2001- 2004 2006
F 2325
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F 2317
Effect of 100 μg MENT/day Silastic implants on sperm counts in Bonnet monkeys: no pregnancy
(Ramachandra et al. Reproduction 124: 301-309, 2002)
5 controls 10 treated monkeys
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Clinical trials using MENT Silastic implants for suppression of spermatogenesis
MENT applied to bonnet monkeys
MENT applied to 35 volunteers in 3 centres (Münster, Santiago de Chile, Santo Domingo)
F 2326
(Ramachandra et al. 2002)
(von Eckardstein et al. 2003)
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FE565
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Suppression of spermatogenesis and LH, FSH in 34 men treated with 1, 2 or 4 MENT implants
0.001
0.010
0.100
1.000
10.000
100.000
1000.000
Spe
rmco
ncen
trat
ion
(Mill
/mL)
0.001
0.010
0.100
1.000
10.000
100.000
1000.000
Spe
rmco
ncen
trat
ion
(Mill
/ m
l)
0 30 60 90 120 150 1800.001
0.010
0.100
1.000
10.000
100.000
1000.000
10000.000
days
Spe
rmco
ncen
trat
ion
(Mill
/ m
l)
Sperm concentration
0
1
2
3
4
5
6
LH (I
U/ L
)
0 60 120 1800
1
2
3
4
1 implant 2 implants 4 implants
Values below detection limitstudy day
FSH
(IU
/ L)
Gonadotropins
1 implant Azoo: 0 / 12
2 implants Azoo: 2 / 11
4 implants Azoo: 8 / 11
(von Eckardstein et al. JCEM 88:5232-39, 2003)
F1750
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Clinical trials using MENT Silastic implants for suppression of spermatogenesis
MENT applied to bonnet monkeys
MENT applied to 35 volunteers in 3 centres (Münster, Santiago de Chile, Santo Domingo)
Etonogestrel combined with MENT or testosterone implants in 29 volunteers (Edinburgh)
F 2326
(Ramachandra et al. 2002)
von Eckardstein et al. 2003
(Walton et al. 2007)
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F 2314
Serum hormone concentrations in men receiving 2 etonogestrel implants either with testosterone (closed circles) or MENT implants (open circles) (Walton et al. J Androl 28: 679-688, 2007)
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F 2315
Sperm concentrations in 29 men receiving 2 etonogestrel implants either with testosterone (closed circles) or
MENT implants (open circles) (Walton et al. J Androl 28: 679-688, 2007)
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F 2316
Blood pressure in 29 men receiving 2 etonogestrel implants either with testosterone (closed circles) or
MENT implants (open circles) (Walton et al. J Androl 28: 679-688, 2007)
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Clinical trials using MENT Silastic implants for suppression of spermatogenesis
MENT applied to bonnet monkeys
MENT applied to 35 volunteers in 3 centres (Münster, Santiago de Chile, Santo Domingo)
Etonogestrel combined with MENT or testosterone implants in 29 volunteers (Edinburgh)
MENT plus levonorgestrel implants in 72 volunteers in 3 centres (Los Angeles, Münster, Santiago de Chile)
F 2326
(Ramachandra et al. 2002)
von Eckardstein et al. 2003
(Walton et al. 2007)
(Wang et al. in preparation)
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Development of MENT by the Population Council
1963 MENT first described by Lyster & Duncan (Upjohn)
1988 C.W. Bardin identifies MENT as suited for replacement therapy and male contraception
1990 RIA for MENT by Kumar et al.
1990- Pharmacology, modes of application and toxicology 1995 by Kumar & Sundaram since 1995 Clinical trials for treatment of hypogonadism since 2000 Clinical trials for male contraception 2001- MENT licensed to Schering AG: 2004 eF-MENT gel in phase I studies 2006 MENT back to Population Council for contraception
F 2325
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T undecanoate
T implant
T implant
T implant/MENT
T undecanoate
Transdermal T
MENT implant
NETA
DSG
DMPA
ETN
NETE
Oral MDP
LNG / DMPA
+
+
+
+
+
+
+
Most promising testosterone/progestin combinations
Paris
Münster / Bologna WHO-CONRAD Schering
Edinburgh / Organon / PopCcl
Popul. Council
F 1823
T undecanoate ETN + Schering-Organon
implants intramuscular oral
transdermal
Sydney / Melbourne
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• MENT has high androgenic potency (5 – 10 times T).
• Suited for long-lasting implants (one year and longer).
• However, implantation & removal require minor surgery.
• Needs to be combined with progestin for contraception in Caucasian men.
• No 5α-reduction i.e. little effect on prostate.
• At adequate doses bone mass is maintained.
• Minor effect on blood pressure needs to be resolved.
• MENT and eF-MENT has potential for substitution therapy.
• A male contraceptive is still a long way off.
MENT for male contraception: key messages
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The End