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Oestradiol-induced spermatogenesis requires a functional androgen receptor
Patrick Lim1, Charles M Allan, Amanda J Notini
1Andrology Laboratory, ANZAC Research Institute, Concord Hospital and University of Sydney, Australia.
Abstract:
Spermatogenesis requires androgen but, paradoxically, oestradiol (E2) treatment stimulates spermatogenic development in gonadotrophin- and androgen-deficient hypogonadal (hpg) mice. The mechanisms of E2-induced spermatogenesis were investigated by determining intratesticular E2 levels and testis cell populations in E2-treated hpg male mice, and E2 spermatogenic actions were determined in androgen receptor-knockout (ARKO) mice. Despite increased serum E2 concentrations (150-300 pmol L(-1)), intratesticular E2 concentrations declined fivefold (P < 0.001) in E2-treated v. untreated hpg male mice. Serum FSH reached 40% of normal and total testicular numbers of known FSH-responsive Sertoli, spermatogonia and meiotic spermatocyte populations were significantly (P < 0.001) elevated 1.7-, 4- and 13-fold, respectively. However, E2 administration also increased androgen-dependent pachytene spermatocytes and post-meiotic spermatids to levels comparable with testosterone-treated hpg testes. Selective investigation of androgen receptor involvement used E2-treated ARKO mice, which were found to exhibit increased (1.6-fold; P < 0.05) intratesticular E2 concentrations and suppression of the elevated serum gonadotrophins, although FSH remained twofold higher than normal. However, testis size and total Sertoli, spermatogonia and spermatocyte numbers were not increased in E2-treated ARKO male mice. Therefore, E2-stimulated murine spermatogenic development occurs with markedly suppressed and not elevated intratesticular E2 levels and displays an absolute requirement for functional androgen receptors. We propose that this paradoxical E2 spermatogenic response is explained by predominantly extratesticular E2 actions, increasing FSH to combine with residual androgen activity in hpg testes to stimulate pre- to post-meiotic development.
Insights
Estradiol (E2) stimulates spermatogenesis in hypogonadal mice by increasing follicle-stimulating hormone (FSH) and requiring androgen receptors. This occurs despite lower intratesticular E2, suggesting extratesticular actions are key for male fertility.
Area of Science:
- Reproductive Endocrinology
- Spermatogenesis Research
- Hormonal Regulation of Male Fertility
Background:
- Spermatogenesis, the process of sperm production, is known to require androgens.
- Paradoxically, estradiol (E2) has been observed to stimulate spermatogenic development in certain models.
- Hypogonadal (hpg) mice, deficient in gonadotropins and androgens, provide a model to study these hormonal effects.
Purpose of the Study:
- To investigate the mechanisms underlying estradiol (E2)-induced spermatogenesis in hypogonadal (hpg) mice.
- To determine the role of intratesticular E2 levels and testis cell populations in E2-stimulated spermatogenesis.
- To elucidate the involvement of androgen receptors in E2's spermatogenic actions using androgen receptor-knockout (ARKO) mice.
Main Methods:
- Measurement of serum and intratesticular E2 concentrations in E2-treated hpg mice.
- Analysis of testis cell populations (Sertoli, spermatogonia, spermatocytes, spermatids) in treated and control groups.
- Evaluation of E2's effects in E2-treated ARKO mice to assess androgen receptor dependency.
Main Results:
- E2 treatment in hpg mice led to decreased intratesticular E2 but increased serum FSH and elevated Sertoli, spermatogonia, and meiotic spermatocyte populations.
- E2 also increased androgen-dependent spermatocytes and spermatids to levels comparable with testosterone treatment.
- In E2-treated ARKO mice, testis size and germ cell numbers did not increase, despite elevated intratesticular E2 and suppressed gonadotropins, confirming the need for functional androgen receptors.
Conclusions:
- Estradiol (E2)-stimulated spermatogenesis in hpg mice occurs with suppressed intratesticular E2 and requires functional androgen receptors.
- The findings suggest E2 primarily acts extratesticularly to boost FSH, which then, with residual androgens, promotes spermatogenic development.
- This highlights a complex interplay between E2, FSH, and androgens in regulating male reproductive function.
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