ment: iccr’s contribution to male contraceptionment: iccr’s contribution to male contraception...
TRANSCRIPT
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
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)
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)
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)
Clinical trials for hormonal male contraception 1972 – 2011
- 60 surrogate trials counting sperm - 8 real contraceptive efficacy trials - 71 reviews
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
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
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
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)
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
enanthate implants
undecanoate
buciclate
OHCH3
CH3
O
Testosterone
19-Nortestosterone
The search for long-acting testosterone preparations
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
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)
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
FE 679
Germany 2004
Nether- lands 1975 China 1993
O
OCO(CH2)9CH3
Testosterone undecanoate FH 118
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)
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
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
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
(Lyster & Duncan [Upjohn] Acta endocrinol 43: 399 - 411, 1963)
„Anabolic, androgenic and myotropic activi- ties of derivatives of 7α-methyl-19-nortesto- sterone“
20 µg MENT / day ------ 100 µg TP / day (Lyster & Duncan (Upjohn) Acta endocrinol 43: 399 - 411, 1963)
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
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
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
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
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
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)
FE565
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
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)
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)
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)
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)
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)
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
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
• 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
The End