Testosterone combined with progestins

An overview of all studies using testosterone in combination with a progestin performed to date is given in Table 23.1.

23.4.1 Testosterone or 19-nortestosterone plus DMPA

19-Norethisterone (norethindrone), medroxyprogesterone acetate (MPA), depot-MPA (DMPA), 17-hydroxyprogesterone capronate and megestrol acetate have been used in clinical trials initiated by the WHO (1972-1983) and the Population Council (Schearer etal. 1978) (molecular structures in Figs. 23.1 and 23.2). The most favorable combination was the monthly intramuscular injection of 200 mg DMPA plus 200 mg testosterone enanthate or testosterone cypionate; this combination gave the best results in suppressing spermatogenesis and the incidence of untoward side

Table 23.1 Overview of studies on hormonal male contraception using testosterone either alone or in combination with progestins

Reference

Number of subjects

Ethnic origin

Androgen dose

Progestin dose

Azoospermia (n)

Severe oligozoospermia below 1 mill/ml (n)

Oligozoospermia below 3 mill/ml (n)

Testosterone alone

WHO 1990

271

mixed

TE 200 mg. i.m. / week

None

157

??

??

Handelsman etal. 1992

9

unknown

T-Pellets 1200 mg

None

5

4

0

Handelsman etal. 1996

10

unknown

T-Pellets 400 mg

None

0

0

0

Handelsman etal. 1996

10

unknown

T-Pellets 800 mg

None

4

0

0

Meriggiola etal. 1996

5

Caucasian

TE 100 mg. i.m. / week

None

5

0

0

Bebb etal. 1996

18

Caucasian

TE 100 mg. i.m. / week

None

6

4

1

WHO 1996

225

mixed

TE 200 mg. i.m. / week

None

157

29

8

Zhang etal. 1999

12

Chinese

TU 500 mg i.m./ 4 weeks

None

11

1

0

Zhang etal. 1999

12

Chinese

TU 1000 mg i.m./ 4 weeks

None

12

0

0

Kamischke etal. 2000b

14

Caucasian

TU 1000 mg i.m. / 6 weeks

None

7

4

1

McLachlan etal. 2002

5

unknown

TE 200 mg. i.m. / week

None

4= < 0.1 or

4

0

azoospermia

Gu etal. 2003

305

Chinese

TU 500 mg i.m./ 4 weeks

None

284

6

6

Depot medroyprogesterone acetate

Alvarez-Sanchez etal. 1977 8

Dominican

TE 250 mg. i.m. / week

DMPA 150 mg/4 weeks

4

3

1

Republic

Alvarez-Sanchez etal. 1977

' 10

Dominican

TE 250 mg. i.m. / week

DMPA 300 mg/4 weeks

7

2

0

Republic

Brenner etal. 1977

6

Caucasian

TE 200 mg. i.m. / week

DMPA 100 mg / 4 weeks

1

2

1

Brenner etal. 1977

3

Caucasian

TE 200 mg. i.m. / week

DMPA 150 mg/4 weeks

1

0

0

Frick etal. 1977

12

Caucasian

TE 250 mg. i.m. / week

DMPA 100 mg i.m. / 4 weeks

6

4

0

Frick etal. 1977

6

Caucasian

T-Propionate 4 rods

DMPA 100 mg i.m./4 weeks

2

0

0

Melo and Coutinho 1977

11

Brasilian

TE 200 mg. i.m. / week

DMPA 100-150 mg i.m/ 4

11= < 0.1 or

0

?

weeks

azoospermia

(cont.)

Severe Oligozoo-

Number of oligozoospermia spermia below

Reference subjects Ethnic origin Androgen dose Progestin dose Azoospermia (n) below 1 mill/ml (n) 3 mill/ml (n)

Severe Oligozoo-

Number of oligozoospermia spermia below

Reference subjects Ethnic origin Androgen dose Progestin dose Azoospermia (n) below 1 mill/ml (n) 3 mill/ml (n)

Faundes etal. 1981

10

Dominican

TE 500 mg i.m. / week

DMPA 150 mg/4 weeks

8

1

0

Republic

Fhcketal. 1982

4

Caucasian

TE 500 mg/4 weeks

150 mg/4 weeks

4

0

0

Frick etal. 1982

5

Caucasian

TE 250 mg/2 weeks

75 mg/2 weeks

5

0

0

WHO 1993

45

Indonesian

19-Nortestosterone 200 mg

DMPA 250 mg i.m./ 6 weeks

44

1

0

i.m. / 3 weeks

WHO 1993

45

Indonesian

TE 200 mg i.m. / 3 weeks

DMPA 250 mg i.m./ 6 weeks

43

2

0

Knuth etal. 1989

12

Caucasian

19-Nortestosterone 200 mg

DMPA 250 mg i.m./ 6 weeks

8

3

1

i.m. / 3 weeks

Wu and Aitken 1989

10

Caucasian

TE 250 mg i.m. / week

DMPA 200 mg/4 weeks

6

0

4

Pangkahila 1991

10

Indonesian

TE 100 mg i.m. / week

DMPA 100 mg / 4 weeks

10

0

0

Pangkahila 1991

10

Indonesian

TE 250 mg i.m. / week

DMPA 200 mg/4 weeks

10

0

0

Handelsman etal. 1996

10

unknown

T-Pellets 800 mg

DMPA once 300 mg i.m.

9

0

1

McLachlan etal. 2002

5

unknown

TE 200 mg i.m. / week

DMPA once 300 mg i.m.

5 = < 0,1 or

5

0

azoospermia

Turner et al. 2003

53

unknown

T-Pellets 800 mg/ 16 weeks

DMPA 300 mg i.m. /12 weeks

49

2

0

Levonorgestrel

Fogh etal. 1980

5

Caucasian

TE 200 mg / 4 weeks

LNG 250 |xg p.o. / day

1

?

1

Fogh etal. 1980

5

Caucasian

TE 200 mg i.m. / 4 weeks

LNG 500 |xg p.o. / day

2

?

?

Bebb etal. 1996

18

Caucasian

TE 100 mg i.m. / week

LNG 500 |xg p.o. / day

12

2

3

Anawalt etal. 1999

18

Caucasian

TE 100 mg i.m. / week

LNG 125 (xg p.o. / day

11

5

1

Anawalt etal. 1999

18

Caucasian

TE 100 mg i.m. / week

LNG 250 |xg p.o. / day

14

2

0

Ersheng etal. 1999

16

Chinese

TU 250 mg i.m./ 4 weeks

Sino-Implant 2 rods

6

0

1

Kamischke etal. 2000b

14

Caucasian

TU 1000 mg i.m. / 6 weeks

LNG 250 |xg p.o. / day

8

4

2

Gaw Gonzalo et al. 2002

20

Mixed

Testoderm TTS 2 patches /

Norplant II 4 rods

7

5

2

day

Gaw Gonzalo et al. 2002

15

Mixed

Testoderm TTS 2 patches /

LNG 125 (jLg p.o. / day

5

1

1

day

Gaw Gonzalo et al. 2002

14

Mixed

TE 100 mg i.m. / week

Norplant II 4 rods

13

1

0

Pollánen et al. 2001

5

Caucasian

DHT-Gel 250 mg / day

LNG 30 |xg p.o./day

0

0

1

Pollánen et al. 2001

5

Caucasian

DHT-Gel 250 mg / day

lardelle (LNG) 1 rod

0

0

0

Pollánen et al. 2001

8

Caucasian

DHT-Gel 500mg/day

lardelle (LNG) 2 rods

0

0

0

Pollánen et al. 2001

7

Caucasian

DHT-Gel 250mg/ day

lardelle (LNG) 4 rods

0

0

0

Norethisterone

Kamischke et al. 2001

14

Caucasian

TU 1000 mg i.m. / 6 weeks

NETE 200 mg / 6 weeks

13

0

0

Kamischke et al. 2002

14

Caucasian

TU 1000 mg i.m. / 6 weeks

NETE 200 mg / 6 weeks

13

1

0

Kamischke et al. 2002

14

Caucasian

TU 1000 mg i.m. / 6 weeks

NETE 400 mg / 6 weeks

13

1

0

Kamischke et al. 2002

14

Caucasian

TU 1000 mg i.m. / 6 weeks

NETA 10 mg p.o. / day

12

2

0

Cyproterone acetate

Meriggiola etal. 1996

5

Caucasian

TE 100 mg i.m. / week

CPA 50 mg p.o/day

3

0

1

Meriggiola etal. 1996

5

Caucasian

TE 100 mg i.m. / week

CPA 100 mg p.o/day

5

0

0

Meriggiola etal. 1998

5

Caucasian

TE 100 mg i.m. / week

CPA 12.5 mg p.o/day

3

2

0

Meriggiola etal. 1998

5

Caucasian

TE 100 mg i.m. / week

CPA 25 mg p.o/day

5

0

0

Meriggiola etal. 2002b

9

Caucasian

TE 100 mg i.m. / week

CPA 5 mg p.o/day

6

3

0

Meriggiola etal. 2002b

7

Caucasian

TE 200 mg i.m. / week

CPA 5 mg p.o/day

0

4

2

Desogestrel or etonorgestrel

Wu etal. 1999

8

Caucasian

TE 50 mg i.m. / week

DSG 300 |xg p.o. / day

8

0

0

Wu etal. 1999

7

Caucasian

TE 100 mg i.m. / week

DSG 150 (xg p.o. / day

4

3

0

Wu etal. 1999

8

Caucasian

TE 100 mg i.m. / week

DSG 300 |xg p.o. / day

6

0

1

Anawalt etal. 2000

7

Caucasian

TE 50 mg i.m. / week

DSG 150 (xg p.o. / day

4

1

0

Anawalt etal. 2000

8

Caucasian

TE 100 mg i.m. / week

DSG 150 (JLg p.o. / day

8

0

0

Anawalt etal. 2000

8

Caucasian

TE 100 mg i.m. / week

DSG 300 jjtg p.o. / day

7

1

0

Kinniburgh etal. 2001

8

Caucasian

T-Pellets 400 mg / 12 weeks

DSG 150 jjtg p.o. / day

6

2

0

Kinniburgh etal. 2001

7

Caucasian

T-Pellets 400 mg / 12 weeks

DSG 150 jjtg p.o. / day

5

1

0

Anderson etal. 2002b

9

Black

T-Pellets 400 mg / 12 weeks

DSG 150 jjtg p.o. / day

9

0

Reference

Number of subjects

Ethnic origin

Androgen dose

Progestin dose

Azoospermia (n)

Severe oligozoospermia below 1 mill/ml (n)

Oligozoospermia below 3 mill/ml (n)

Anderson et al. 2002b

11

Mixed

T-Pellets 400 mg / 12 weeks

DSG 150 (jig p.o. / day

9

0

1

Anderson et al. 2002b

8

Black

T-Pellets 400 mg / 12 weeks

DSG 300 |xg p.o. / day

8

0

0

Anderson et al. 2002b

12

Mixed

T-Pellets 400 mg / 12 weeks

DSG 300 |xg p.o. / day

8

0

0

Anderson et al. 2002a

14

Caucasian

T-Pellets 400 mg / 12 weeks

Implanon (ENG) 1 rod

9

1

3

Anderson et al. 2002a

14

Caucasian

T-Pellets 400 mg / 12 weeks

Implanon (ENG) 2 rods

9

4

0

Kinniburgh etal. 2002b

15

Caucasian

T-Pellets 400 mg / 12 weeks

DSG 300 |xg p.o. / day

15

0

0

Kinniburgh etal. 2002b

18

Asian

T-Pellets 400 mg / 12 weeks

DSG 300 |xg p.o/day

18

0

0

Kinniburgh etal. 2002b

18

Asian

T-Pellets 400 mg / 12 weeks

DSG 150 (jig p.o. / day

11

2

2

Kinniburgh etal. 2002b

13

Caucasian

T-Pellets 400 mg / 12 weeks

DSG 150 (jig p.o. / day

11

2

0

Self-applicable

Nieschlag etal. 1978

7

Caucasian

Andriol 240 mg p.o. / day

None

1

0

0

Guerin and Rollet. 1988

13

Caucasian

Andriol 160 mg p.o. / day

NETA 10 mg p.o./day

7

2

3

Guerin and Rollet. 1988

5

Caucasian

T gel 250 mg / day

NETA 5 mg p.o. / day

4

1

0

Guerin and Rollet. 1988

5

Caucasian

T gel 250 mg / day

NETA 10 mg p.o. / day

5

0

0

Guerin and Rollet. 1988

8

Caucasian

T gel 250 mg / day

MPA 20 mg p.o. / day

5

0

1

Meriggiola etal. 1997

8

Caucasian

Andriol 80 mg p.o. /day

CPA 12.5 mg p.o./ day

1

3

2

Hair etal. 1999

4

Caucasian

Andropatch 2 patches / day

DSG 75 (jig p.o / day

0

1

0

Hair etal. 1999

6

Caucasian

Andropatch 2 patches / day

DSG 150 (jig p.o,/ day

3

0

0

Hair etal. 1999

7

Caucasian

Andropatch 2 patches / day

DSG 300 |xg p.o. / day

4

1

0

Buchter etal. 2000

12

Caucasian

Testoderm TTS 2 patches /

LNG 250 |xg p.o. later

2

3

0

day

500 |xg

Gaw Gonzalo et al. 2002

19

Mixed

Testoderm TTS 2 patches /

None

5

0

1

day

Pollanen etal. 2002

2

Caucasian

DHT-Gel 250 mg / day

None

0

0

Testosterone ch3Oh

19-Nor- CH3

testosterone.

19-Nor- ch3

ethisterone oh oh c=HC

c=HC

CH2CN

Dienogest

CH2CN

Dienogest t

Desogestrel

Etonogestrel h3c ^ OH

Etonogestrel h3c ^ OH

Levonorgestrel

Fig. 23.2 Progestins derived from 19-nortestosterone tested in hormonal male contraception.

effects was low.However, this combination did not produce azoospermia uniformly and its possible efficacy remained uncertain.

Since monotherapy with the long-acting androgen ester 19-nortestosterone-hexoxyphenylproprionate injected every three weeks resulted in effective suppression of spermatogenesis to azoospermia in about 70% of the volunteers (Schurmeyer etal. 1984) the possibility of even more complete suppression of spermatogenesis was tested (Knuth etal. 1989). Twelve volunteers were injected weekly with 200 mg 19-nortestosterone hexoxyphenylpropionate, followed by injections with the same dose every three weeks up to week 15. In addition, the volunteers were injected with 250 mg DMPA in weeks 0, 6 and 9. Azoospermia was achieved in eight of twelve volunteers during the study course, while in three of the remaining four volunteers, spermatogenesis was suppressed to single sperm, and, in one volunteer, to a sperm concentration of 1.4 mill/ml.

The promising results prompted the WHO Task Force on the Regulation of Male Fertility to launch a large-scale multicenter trial in five centers in Indonesia, comparing the effectiveness of testosterone enanthate, or 19-nortestosterone hexyoxyphenylpropionate, in combination with DMPA (WHO 1993). Surprisingly,

43/45 and 44/45 subjects in the testosterone and the 19-nortestosterone groups respectively suppressed to azoospermia. Unfortunately, this study had failed to include groups treated with the androgens alone, so that it remained unclear whether the azoospermia rates of 97% and 98% were due to the combined treatment or could also be achieved by the androgens alone.

The latter possibility appears likely in the light of the ethnic differences between Caucasian and East Asian men described above. Although ultimately effective, the disadvantage remains that it took almost 20 weeks to reach azoospermia or the lowest sperm counts in these volunteers. Thus, more rapid onset of sperm suppression is required.

A recent study using either 200 mg testosterone enanthate given alone in weekly intramuscular injections or in combination with an injection of 300 mg DMPA showed that the suppression rate was not greater when DMPA was added (McLachlan et al. 2002). However, when subcutaneous testosterone implants of 200 mg were applied every 4 or 6 months in combination with 300 mg DMPA given every three months, 51/53 men achieved azoospermia or suppression below 1 x 106 sperm/ml. During a twelve-month efficacy phase with otherwise unprotected intercourse no pregnancy occurred (35.5 person years) (Turner etal. 2003). The differences between the studies highlight the fact that obviously the kinetics of testosterone are very important, since the implants produce very stable serum levels and the testosterone enanthate injections cause high peaks and troughs. Although the combination of an implant with an injection every three months may not be ideal, this study is the first to demonstrate the contraceptive efficacy of a testosterone + progestin combination.

Recovery to baseline semen parameters appears to be rather slow in studies employing DMPA. This may be due to secondary depots of this progestin formed in the subcutaneous and abdominal fat and requires special attention should studies be extended over several years.

23.4.2 Testosterone plus levonorgestrel

Levonorgestrel has been widely used for contraception in females either orally or as an implant and has proved safe and effective. Although early studies combining 0.5 mg levonorgestrel given orally with testosterone enanthate were not very encouraging (Fogh et al. 1980), more recent trials comparing testosterone enanthate (100 mg/week) alone with testosterone enanthate in combination with 0.5 mg levonorgestrel given orally showed that the combination resulted in more pronounced suppression of spermatogenesis than testosterone enanthate alone (Bebb etal. 1996).

Encouraged by the renewed interest in levonorgestrel we conducted a trial combining oral levonorgestrel with a transdermal testosterone patch applied to the trunk

(Buchter et al. 1999). The advantage of such a combination is that it is completely self-administered and thus independent of medical personnel. Unfortunately the results were disappointing, as suppression of spermatogenesis was insufficient. We presume that the testosterone dose absorbed from the transdermal systems was too low and often impeded by inadequate adhesiveness to the skin of the systems (Buchter etal. 1999). The study again emphasizes the need for steady serum testosterone levels to suppress gonadotropins, even when co-administered with a potent gestagen.

Similarly it was shown that the combination of 0.5 mg levonorgestrel given orally with transdermal DHT was quite ineffective, nor did the combination of transdermal DHT with levonorgestrel implants lead to sufficient suppression of spermatogenesis (Pollanen etal. 2001).

Finally, when the long-acting testosterone preparation testosterone undecanoate (in castor oil) given at six weeks intervals was combinedwith oral levonorgestrel, the progestin did not enhance the effect of testosterone undecanoate alone (Kamischke et al. 2000). However, when levonorgestrel was administered in 4 capsules delivering about 160 |xg levonorgestrel (Norplant II = Jadelle)/per day together with weekly injections of 100 mg testosterone enanthate, 93% of the subjects achieved azoospermia and all suppressed to oligozoospermia below 1 x 106/ml sperm (Gaw Gonzalo et al. 2002). As effective as this combination may be, it brings us back to weekly testosterone injections, making the approach impractical for general use. The combination of levonorgestrel implants with long-acting testosterone preparations (ideally also implants) might be a solution and requires investigation.

23.4.3 Testosterone plus cyproterone acetate

Animal studies and studies in sexual delinquents have shown that the antiandro-gen cyproterone acetate, which can be considered a potent progestin, suppresses spermatogenesis, an effect exerted through suppression of pituitary gonadotropin secretion. In clinical trials using 5 to 20 mg cyproterone acetate per day for up to 16 weeks, sperm counts and motility were reduced markedly (Fogh et al. 1979; Moltz et al. 1980; Wang and Yeung 1980). Thus, cyproterone acetate appeared to be a possibility for male fertility control. However, decreases in serum testosterone levels to below normal were also observed. Some of the volunteers complained of fatigue, lassitude and decrease in libido and potency attributable to the diminished testosterone levels.

When later cyproterone acetate was combined with testosterone enanthate injections at even higher doses of 50 and 100 mg, it effectively suppressed spermatogenesis (Meriggiola etal. 1996),but even whenlower doses of cyproterone acetate were administered, antiandrogenic effects prevailed and the volunteers showeddecreased red blood, preventing this antiandrogenic gestagen from being an attractive combination for male contraception (Meriggiola etal. 1998). Although the attempt to create a male pill by co-administration of oral testosterone undecanoate with oral cyproterone acetate led to suppression of spermatogenesis, it had to be discontinued because of a decrease in hemoglobin and hematocrit caused by the antiandrogen (Meriggiola etal. 1997).

23.4.4 Testosterone plus 19-norethisterone

19-noresthisterone, one of the earliest progestins derived from testosterone (Djerassi etal. 1954), is characterized by some undesirable androgenicity when given to women, but might be of advantage when administered to men. An early study with only few volunteers using a combination of orally effective 19-norethisterone acetate with either a transdermal testosterone gel or oral testosterone undecanoate led to azoospermia in all volunteers (Guerin and Rollet 1988). Considering its properties and these promising results, it was surprising that it took another ten years to investigate the use of 19-norethisterone more systematically.

In a pharmacokinetic study single injections of 200 mg 19-norethisterone enan-thate led to a marked suppression of the gonadotropins (FSH for 29 days), testosterone, SHBG and sperm (Kamischke etal. 2000a). When testosterone undecanoate became available in the form of intramuscular depot injections it was combined with noresthisterone enanthate and volunteers achieved azoospermia or severe oligozoospermia in all but one. The additive effect to testosterone undecanoate alone was striking. An injected dose of 200 mg 19-norethisterone enanthate every 6 weeks was as effective as 400 mg, so that 200 mg appears to be a useful dose. Although 19-noresthisterone acetate 10 mg given orally daily in combination with intramuscular testosterone undecanoate is as effective as injected noresthisterone enanthate, the combination of the twosteroids in one injection appears quite attractive (Kamischke et al. 2000b; 2001; 2002b). The effectiveness of various combinations is shown in Figure 23.3. Larger-scale trials should now be performed in order to test the contraceptive efficacy of this combination.

23.4.5 Testosterone plus desogestrel or etonogestrel

Orally administered desogestrel, a levonorgestrel derivative, was evaluated in clinical trials using 300 |xg/day combined with weekly injections of 50 or 100 mg testosterone enanthate for 24 weeks. A third group received 150 |xg/day desogestrel and 100 mg testosterone enanthate per week intramuscularly. While the group receiving 50 mg testosterone enanthate showed complete suppression of spermatogenesis i.e. azoospermia, the other groups achieved only incomplete suppression. In the most effective group, total serum testosterone levels were found in the range of the lower limit of normal men and this may explain the volunteers complaints of decreased sex drive, depression, fatigue and nocturnal sweating (Wu etal. 1999).

Fig. 23.3 Effectiveness of various testosterone (T) and progestin combinations in terms of suppression of spermatogenesis (data from BUchter etal. 1999; Kamischke etal. 2000; 2001; 2002b). TTS = transdermal T, LNG = Levonorgestrel, TU = T undecanoate intramuscular, NETE = norethisterone enanthate intramuscular, NETA = norethisterone acetate.

Fig. 23.3 Effectiveness of various testosterone (T) and progestin combinations in terms of suppression of spermatogenesis (data from BUchter etal. 1999; Kamischke etal. 2000; 2001; 2002b). TTS = transdermal T, LNG = Levonorgestrel, TU = T undecanoate intramuscular, NETE = norethisterone enanthate intramuscular, NETA = norethisterone acetate.

In a two-center study in Edinburgh and Shanghai testosterone pellets (400 mg every 3 months) were combined with either 150 or 300 |xg desogestrel/day orally (Kinniburgh et al. 2002a). Azoospermia was achieved in all 33/33 men receiving the 300 |xg desogestrel dose. Disregarding the fact that a combination of an implant with an oral pill might not offer a highly attractive option, these results are quite promising.

This group continued their investigations using etonogestrel, the active metabolite of orally active desogestrel, as an implant which was recently licensed for use as a female contraceptive (Implanon). 28 men received one or two etonogestrel implants which provide contraceptive protection in females for three years, but the implants were removed from the volunteers after six months. In addition, they received 400 mg testosterone pellets at the beginning of the study and after three months. Nine men in each group achieved azoospermia and in the group with 2 implants sperm counts fell to 0.1 x 106/ml in 13/14 men (Anderson etal. 2002).

23.4.6 Testosterone plus dienogest

The latest progestin to be tested for male contraceptive purposes is the orally effective dienogest. This is another 19-norprogestin in which position 17 is not substituted by the common ethinyl group, but by a cyanomethyl group and a double bond is introduced in ring B. When given at2,5or10 mg doses over 21 days, 10 mg resulted in a suppression of gonadotropins comparable to 10 mg of cyproterone acetate. Semen parameters were not affected, as one would expect with this short application period (Meriggiola et al. 2002a). As dienogest displays only mild antiandrogenic activity, this substance may be a possible candidate for future trials.

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