Like the female of many species, the female guinea-pig, when injected with androgen, is easily induced to display male-like sexual behaviour1. High progesterone levels, however, resulting from pregnancy, pseudopregnancy or exogenous sources will protect the female from this ‘induced masculinization’ 2,3. These findings raise questions as to possible effects of progesterone on normal males. Will progesterone or synthetic progestagens inhibit masculine sexual behaviour in the male as well as in the androgen-treated female? How do the effects of progestagen treatment compare with those of castration? These questions are of practical, as well as theoretical, interest in view of present-day tests of progesterone and progesterone-like substances as male contraceptives4. With non-standardized indices of behaviour some reports indeed indicate that progesterone can affect sexual performance4,5.
To answer these questions, sixty-one mature male guinea-pigs 6-12 months old kept in individual cages were observed and tested with an oestrous female for a 10-min period each week. Observations were continued through three 10-week periods constituting respectively a control phase, an experimental phase, and a recovery phase.
During the control phase, all subjects were tested and handled in a similar fashion in order to obtain a base line of sexual performance for each animal. The experimental phase made it possible to observe the immediate effects of the various treatments. To prepare for this phase (within 6h subsequent to the tenth test of the control phase), animals were assigned to one of six groups. Animals assigned to three of these groups were castrated. Beginning the following day, each subject in group 1 (progesterone-intact) was given two 25mg injections of progesterone in cotton seed oil with 10mg injections daily thereafter throughout the experimental phase; group 2 (MPA-intact) was given the same dosage of the synthetic progestagen ‘Depo-provera’, a brand of medroxyprogesterone acetate (MPA); group 3 (progesterone-castrate) was given the same dosage of progesterone; group 4 (progesterone-TP-castrate) was given the same dosage of progesterone with the simultaneous addition of 5mg of the androgen testosterone propionate (TP) on the first day and 1mg daily thereafter. This dosage of TP has been shown to be sufficient to maintain precastration levels of sexual activity in male guinea-pigs6 and permits consideration of behavioural effects due to the interactions of hormones in known proportions. This would not be possible in intact animals with individually varying androgen output. Groups 5 and 6 served as intact and castrate controls respectively. Animals in these groups were given two initial 0.5ml. and subsequent 0.2ml. daily injections of cotton seed oil, the injection vehicle. Tests during the recovery phase indicated the nature and duration of post-treatment behaviour characteristics. During this phase all injections of progesterone and MPA were discontinued and the castrate groups (3, 4 and 6) received replacement dosages of testosterone propionate, 5mg on the first day and 1mg daily thereafter. The intact groups (1, 2 and 5) received equivalent dosages of the injection vehicle. Injectates were uniformly prepared to contain 50mg hormone/ml. oil. All injections were given intramuscularly daily and administered alternately into the right and left gluteal and hamstring regions.
The behaviour characteristics recorded included sniffing, nuzzling, mounting, intromission and ejaculation. Each of these components contributed a weighted value to a total sex score. (These behaviour components and scoring procedures have already been described elsewhere6,7.)
The differences among the groups were statistically significant. During the experimental phase all groups except control-intacts showed marked and significant declines in sexual activity (Table 1). For most groups, an immediate decrease was evident. Between the final test of the control phase and the first test of the experimental phase (an interval of 1 week; 100mg of progestagen) the sex score of the control-castrate group declined from 4.7 to 1.7, that of the progesterone-castrate group from 5.2 to 1.4, that of the progesterone-TP-castrate group from 4.7 to 1.8, and that of the intact group receiving MPA declined from 5.2 to 1.4. The progesterone-intact group dropped less, but significantly, from 6.3 to 3.4. At the end of the following week return toward control levels was seen, but after that, through the remainder of the experimental phase all groups except the control-intact showed a downward trend in their level of sexual activity.
|N||Control phase||Experimental phase||Recovery phase||Phase I versus Phase II||Phase II versus Phase III|
Progesterone and TP-castrate
Over-all findings from intact and castrate control groups were as expected; no significant effects due to the placebo were seen in intact animals, but castration significantly reduced sexual activity. In the critical experimental groups it was obvious that both progesterone and the synthetic progestagen, MPA, are capable of inhibiting normal masculine sexual behaviour to an extent comparable with castration. The effect of castration and progesterone combined produced the largest drop in activity but this was not statistically more injurious to libido than was either treatment alone. The results gained with the castrate group receiving simultaneously androgen and progesterone showed that 1mg of testosterone daily was generally insufficient to overcome the inhibiting effect of 10mg of progesterone daily.
The decline in sexual behaviour scores generally reflects a decrease in incidence of the higher components of the male sexual pattern, that is, mounting, intromission and ejaculation. Ejaculation frequencies were most markedly affected.
In all experimental groups at least a 50 per cent reduction was found in the frequency of ejaculation. Groups injected with progesterone or medroxyprogesterone acetate experienced a decrease in ejaculations of more than 75 per cent.
During the recovery phase, the cessation of progestagen treatment, replacement therapy with TP, or both were followed by a significant return toward control phase levels of sexual behaviour (Table 1). In the progesterone-intact and the progesterone-castrate groups a rise toward normal levels of sexual activity was evident within a week. Cessation of treatment with MPA was not followed by a similar recovery until the last 3 weeks of the investigation. Thus, although both progesterone and MPA are capable of inhibiting male sexual activity, the effects of progesterone seems relatively slow to appear and quick to disappear, while the effects of MPA develop quickly and persist longer.
No group displayed as high a level of sexual performance during the recovery phase as it had during the control phase. This may not be unexpected for the progestagen-treated animals where a longer interval for recovery might be needed. Concerning the control males, Grunt and Young6, Antliff and Young8 and Jakubczak9 also previously noted a decrease in the sexual behaviour scores of normal guinea-pigs during long-term experiments. They suggested that this is possibly related to advancing age. Analysis and comparison of the components of the sexual pattern for the recovery period with those found during the control phase reveal that these differences are qualitative as well as quantitative. While the low frequency of mounting seen during the experimental phase returns toward control phase levels, the frequency of intromission and ejaculation remains low. These latter behaviour components have been shown to be more labile than mounting when tested in respect to such factors as age9 and castration and androgen therapy10,11. A differential sensitivity in the neural tissues mediating these behavioural patterns has been postulated.
Histological studies of the testes of the intact groups 1, 2 and 5 were conducted within a week following the end of the recovery phase. In addition, the last day of the experimental phase, testes were removed from 3 sets of 2 males each, treated in a manner identical to the three intact group. Thus comparisons of gonads immediately after the experimental treatment and after recovery were possible without disturbing the actual experimental animals during the test sequence.
The testes of males treated with progesterone for 10 weeks showed few histological differences from controls. Nevertheless, the mean weight of the testes obtained from the progesterone-treated males was 2.79g while that from the control males was 3.99g. A substantial decrease in testes weight due to progesterone has also been reported for humans4. Despite this weight loss, as in humans,4 the tubular contents and interstitial cells appear unaffected by therapy except for a decrease in the absolute number of mature sperm. This is in contrast to findings in the rabbit5 and ram12, where general disorganization and degeneration of tubule contents have been reported.
Testes from males treated for 10 weeks with MPA, on the other hand, are severely affected. The mean weight of the testes from this group was 1.25g; less than half that of the controls. Under the microscope these testes showed general disorganization of the tubules and a lack of mature spermatozoa. Occasional tubules were spared, however, and all stages of spermatogenesis could be seen. Mature spermatozoa could be found in the epididymides of all animals. Following the recovery phase of 10 weeks no significant differences in testis weight or histological appearance were discernible between the groups. Ericsson and Dutt12 report similar effects of MPA on the ram testis.
These data indicate that progesterone and MPA are both capable of temporarily reducing the level of sexual performance in the male guinea-pig. It is not clear from these results where these progesterones act to bring about this inhibition. The seeming lack of serious effect of progesterone on the testes found in these experiments (and reported elsewhere for humans4) implies that we are dealing either with a pituitary feed-back problem or a direct nervous system effect. Additional experiments will be needed to clarify this point.
In view of its ability to inhibit androgen-induced masculine behaviour in the progesterone-rich female2,3 as well as in the male, progesterone is thus seen to be capable of affecting sexuality in both sexes so that androgen is ineffective in its role of activating the neural tissues mediating masculine sexual behaviour patterns. With recent findings13-15, confirming the unique part played by androgen in the differentiation of the hypothalamus with respect to structuring both male and female sexual behaviour, it is perhaps not surprising that a single hormone, progesterone, is capable of antagonizing an androgenic action in both sexes.
Progesterone, testosterone propionate and ‘Depo-provera’ were supplied through the generosity of Dr. S.S. Stubbs of the Upjohn Company, Kalamazoo, Michigan. Appreciation is extended to Barbara Tullis, Herbert Cook and Milton Palanker for assistance at various times during the course of this study.
This investigation was supported by a U.S. Public Health Service research grant from the National Institutes of Health.