Oral Progestogen Combined with Testosterone as a Potential Male Contraceptive: Additive Effects between Desogestrel and Testosterone Enanthate in Suppression of Spermatogenesis, Pituitary-Testicular Axis, and Lipid Metabolism¹

Abstract

The effects of a synthetic oral progestogen, desogestrel (DSG), administered with low dose testosterone (T) were investigated to determine the optimal combination for suppression of gonadotropins and spermatogenesis to targets compatible with effective male contraception. Twenty-four healthy male volunteers (33.2 +/- 0.9 yr) were randomly assigned to 3 groups (n = 8) to receive: 1) 300 microg DSG orally daily and 100 mg T enanthate, i.m., weekly; 2) 300 microg DSG and 50 mg T enanthate; or 3) 150 microg DSG and 100 mg T enanthate for 24 weeks. To investigate the individual contribution to the combined action, DSG was administered alone for the first 3 weeks, and T enanthate was added on day 22. After 24-week treatment, sperm density in 78% (18 of 23) of the subjects became azoospermic, whereas 91.7% (22 of 24) and 95.8% (23 of 24) suppressed to less than 1 million/mL and less than 3 million/mL, respectively. The 300 microg DSG with 50 mg T enanthate combination induced azoospermia in 8 of 8 subjects, and the suppression of sperm density was significantly greater than that in the 300 microg DSG/100 mg T enanthate group, but was not different from that in the 150 microg DSG/100 mg T enanthate group. DSG (300 or 150 microg daily) alone in the first 3 weeks suppressed LH, FSH, and T to 60.6%, 48.0%, and 35.4%, respectively, of the baseline. Addition of T enanthate (50 and 100 mg weekly) raised plasma T to the physiological range and induced a further fall in LH and FSH to the limits of assay detection. There was no consistent difference in mean LH and FSH levels among the three groups during treatment or recovery, except that FSH remained detectable in a higher proportion of samples from the group receiving 300 microg DSG with 50 mg T enanthate. Total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol decreased by 9.3 +/- 1.7%, 10.3 +/- 2.6%, and 7.7 +/- 2.8%, respectively, during treatment with DSG alone with no difference between 300 and 150 microg. Addition of T enanthate (both 50 and 100 mg weekly) induced a further fall only in high density lipoprotein cholesterol to 22.6 +/- 3.7% from the baseline. In summary, the combined actions of oral DSG with low doses of T enanthate were highly effective in suppressing pituitary-testicular functions in adult men. The optimal regimen for inducing azoospermia was 300 microg DSG daily with 50 mg T enanthate weekly. Oral DSG exerted discernible effects on lipid metabolism. We conclude that the combination of oral progestogens with low dose T is a promising approach to achieve effective reversible male contraception.

Hormonal Contraception in Men

“…Some weight gain was reported in both groups and a significant fall in HDL-C occurred in the Caucasian group but not in the Chinese subjects [50]. Weight gain has been reported in a previous similar study [19], but not in another [47]. These two studies reported a similar degree of spermatogenic suppression, with 150µg desogestrel daily and 100mg T enanthate im weekly, proving the most effective dosage combination in the former, and 300µg desogestrel and 50mg T enanthate inducing azoospermia in 8 out of 8 subjects in the latter.…”

“…When administered alone in men it suppressed LH, FSH and testosterone levels within 3 days, reaching a nadir at 14 days [47]. The degree of suppression achieved was greater with 300µg than with 150µg [47] but was not improved upon by the administration of a higher dose of 450µg daily [48]. A short-term dose finding study in which subjects received a single dose of 300mg of testosterone in combination with 75µg, 150µg or 300µg of desogestrel daily for 8 weeks (10 subjects per group) found that gonadotrophins fell rapidly in all groups, some men becoming azoospermic particularly in the 300µg group despite the short duration of the study [49].…”

“…Desogestrel has less androgenic properties that other progestogens [46] and has been widely used in the combined oral contraceptive in women. When administered alone in men it suppressed LH, FSH and testosterone levels within 3 days, reaching a nadir at 14 days [47]. The degree of suppression achieved was greater with 300µg than with 150µg [47] but was not improved upon by the administration of a higher dose of 450µg daily [48].…”

Barriers in Male Contraception: Literature Review

“…sadece testosteron yama ile çalışmıştır. 17,31,32 Yama ile çalışan Büchter ve ark.nın çalışmalarında ise tek bir testosteron yamanın yanı sıra oral levonorgestrel (250, 500 µg/gün) ya da oral desogestrel (300 µg/gün) kombinasyonu kullanılmıştır. 30 Bu çalışmalar istenilen sonucu vermeyince Hair ve ark.…”

“…15 TU ve TE'nin kas kaybı, kolesterol düzeylerinde değişim, kilo artışı, sivilce, libidoda azalma, prostat bezi, kas yoğunluğunda azalma, psikolojik değişimlere yol açması, yöntemlerin geri dönüşlerinin sağlanamaması, transdermal testosteron patch'lerin dermatite neden olması, yönteme ilişkin yapılan çalışma sonuçlarının başarısız olması, oral, intramusküler (İM) enjeksiyonlar, implantlar, flasterler, jellerin çoğunda etkinliğin başlaması için en az 1-1,5 ay sürenin geçmesi, geri dönüşleri için ise en az 3,5-5 ay süreye ihtiyaç duyulması testosteron ile birlikte progesteron ve GnRH analoğunun günlük enjeksiyon uygulanması nedeni ile gönüllülerin çalışmadan ayrılması ve uygulanma güçlüğü yeni kontrasepsiyon çalışmalarının sürdürülmesini engellemektedir. 1,22,27,[30][31][32][33][34]…”