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Maintenance of Spermatogenesis by the Activated Human (Asp567Gly) FSH Receptor During Testicular Regression Due to Hormonal Withdrawal¹

Andrology Laboratory, University of Sydney, ANZAC Research Institute, Concord Hospital, Sydney, New South Wales 2139, Australia

ABSTRACT

The first activating mutation of the FSH receptor (FSHR*D567G) was identified in a gonadotropin-deficient hypophysectomized man who exhibited persistent spermatogenesis and fertility with only androgen replacement. We have determined the ability of FSHR* activity to maintain spermatogenesis and/or steroidogenesis during gonadotropin and androgen deprivation in mature transgenic FSHR* mice (Tg(Abpa-FSHR*D567G)1Cmal), hereafter referred to as Tg-FSHR* mice. Testes of untreated adult Tg-FSHR* males were equivalent in weight to nontransgenic controls but exhibited increased total Sertoli cell (24%) and spermatogonia (34%) numbers and nonsignificantly elevated spermatocyte-spermatid numbers (13%–17%). During sustained GNRH1 agonist treatment that markedly reduced (96%–98%) serum LH and testosterone (T) and decreased serum FSH (68%–72%), the testes of GNRH1 agonist-treated Tg-FSHR* mice remained significantly larger than treated nontransgenic controls. After 4 wk of gonadotropin suppression, Sertoli cell numbers were reduced in Tg-FSHR* testes to levels comparable with nontransgenic testes, whereas spermatogonia numbers were maintained at higher levels relative to nontransgenic testes. However, after 8 wk of GNRH1 agonist treatment, the total spermatogonia, spermatocyte, or postmeiotic spermatid numbers were reduced to equivalent levels in Tg-FSHR* and nontransgenic mice. FSHR* effects were further examined in gonadotropin-deficient hypogonadal Gnrh1^hpg/Gnrh1^hpg (Gnrh1^–/–) mice during testicular regression following withdrawal of T after maximal T-stimulated spermatogenesis. After 6 wk of T withdrawal, spermatogonia, spermatocyte, and postmeiotic spermatid numbers in Tg-FSHR* Gnrh1^–/– testes decreased to levels found in untreated Tg-FSHR* Gnrh1^–/– testes. Basal serum T levels in untreated Tg-FSHR* Gnrh1^–/– males were 2-fold higher than Gnrh1^–/– controls, but following T treatment/withdrawal, serum T and epididymal weights declined to basal levels found in nontransgenic Gnrh1^–/– mice. Therefore, FSHR* was unable to sustain circulating T or androgen-dependent epididymal size or postmeiotic spermatogenic development. We conclude that FSHR* activity enhances Sertoli and spermatogenic development in normal testes but has limited ability to maintain spermatogenesis during gonadotropin deficiency, in which the testicular response provided by the FSHR*D567G mutation resembled typical FSH-mediated but not steroidogenic activity.

follicle-stimulating hormone receptor, Sertoli cells, spermatogenesis, testis, testosterone

¹ Supported in part by a National Health & Medical Research Council project grant.

² Correspondence: Charles M. Allan, Andrology Laboratory, ANZAC Research Institute, Concord Hospital, Sydney NSW 2139, Australia. FAX: 61 2 9767 9101; charles{at}anzac.edu.au