3 The sertoli cell

Using a new experimental model for studying the hormonal induction of spermatogenesis, the hpg mouse, which has congenital functional gonadotropin deficiency due to a major deletion in the GnRH gene, we investigated the roles of testosterone (T) and dihydrotestosterone (DHT) in the initiation of spermatogenesis. Weanling homozygous hpg male mice were implanted subdermally with SILASTIC brand implants of varying lengths (0-2 cm) filled with T or DHT, using phenotypically normal (N/N or N/hpg) and untreated hpg/hpg mice as positive and negative controls. After 8 weeks, both T and DHT equally stimulated (approximately 14-fold) testis size and induced qualitatively complete spermatogenesis despite low intratesticular androgen levels and undetectable circulating FSH. Stereological quantitation of Sertoli and germ cells demonstrated a dose-dependent rise in the absolute numbers of all germ cell types induced by both T and DHT. At maximal androgen doses, germ cell numbers expressed per Sertoli cell and homogenization-resistant elongated spermatids expressed per mg testis were increased to more than 80% of non-hpg control values. An in vitro fertilization assay confirmed that both T and DHT induced quantitatively normal fertilizing capacity of the sperm in hpg males. We conclude that androgens, acting through the androgen receptor without need for aromatization, initiate qualitatively complete spermatogenesis in the mouse, including fertile sperm despite low intratesticular androgen levels and the absence of blood FSH levels. The hpg mouse model is a useful new paradigm to study the molecular basis of the hormonal induction of spermatogenesis.

Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice.

A review of the chemistry and pharmacology of the date fruits (Phoenix dactylifera L.)

The terms blood-testis barrier (BTB) or blood-epididymis barrier (BEB), are often described as Sertoli cell-Sertoli cell tight junctions (TJs) or TJs between the epithelial cells in the epididymis, respectively. However, in reality, the BTB and BEB are much more complex than just the TJ. The focus of this minireview is to remind readers that the complete BTB and BEB are comprised of three components: anatomical, physiological, and immunological. The TJs form the anatomical (physical) barrier that restricts passage of molecules and cells from entering or exiting the lumen. The physiological barrier is comprised of transporters that regulate movement of substances in or out of the lumen, thus creating a microenvironment, which is critical for the proper development and maturation of germ cells. The immunological barrier limits access by the immune system and sequesters the majority of the autoantigenic germ cells. Combined with the overall immune-privilege of the testis, this suppresses detrimental immune responses against the autoantigenic germ cells. These three components on their own do not create a complete functional barrier; instead, it is the interaction between all three components that create a barrier of maximal competence.

The Blood-Testis and Blood-Epididymis Barriers Are More Than Just Their Tight Junctions

I. Introduction II. Neurohormones/Neuropeptides A. GH-releasing hormone (GHRH) B. Pituitary adenylate cyclase-activating peptide (PACAP) C. GnRH D. CRH E. Oxytocin (OT) F. Arginine vasopressin (AVP) G. TRH H. Somatostatin (SRIF) I. Opioids J. Substance-P (SP) K. Neuropeptide Y (NPY) III. Peptides Originally Identified in the Male Gonad A. Inhibin (INH) and activin (ACT) B. PModS IV. Growth Factors A. Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBs) B. Transforming growth factor-β (TGFβ) C. TGFα/EGF D. Fibroblast growth factor (FGF) E. Platelet-derived growth factor (PDGF) F. Nerve growth factor (NGF) G. Steel factor (SLF) H. Gastrin-releasing peptide (GRP) V. Immune Derived Cytokines A. Interleukins (ILs) B. Tumor necrosis factor-α (TNFα) VI. Vasoactive Peptides A. Endothelin (ET) B. Angiotensin-II (AT-II) C. Atrial natriuretic peptide (ANP) VII. Conclusions and Perspectives

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Gonadal Peptides as Mediators of Development and Functional Control of the Testis: An Integrated System with Hormones and Local Environment

In order to clarify further the role of FSH in the maintenance of spermatogenesis, adult rats were treated with purified human FSH (2 X 5 IU/day per rat), testosterone (1.5 cm silicone elastomer implant) or a combination of both hormones for 2 weeks following hypophysectomy. After hypophysectomy alone, no elongate spermatids were observed and the numbers of pachytene spermatocytes and round spermatids observed were reduced when compared with untreated controls. Testosterone supplementation alone qualitatively maintained the formation of elongate spermatids in most seminiferous tubules, whilst in FSH-treated rats increased numbers of round spermatids and pachytene spermatocytes were observed when compared with hypophysectomized animals. Formation of elongate spermatids, however, did not occur under FSH treatment alone. A combination of FSH and testosterone treatment maintained spermatogenesis in an almost quantitative fashion. Numbers of pachytene spermatocytes and round spermatids were maintained at about 80% of levels seen in intact control animals. Treatment with FSH or testosterone alone maintained testis weights at significantly higher levels than those seen in hypophysectomized controls (FSH, 0.79 +/- 0.05 g; testosterone, 0.81 +/- 0.07 g; hypophysectomized, 0.50 +/- 0.04 g). Animals treated with FSH and testosterone showed testis weights 20% below control values (1.22 +/- 0.05 vs 1.51 +/- 0.06 g; P less than 0.05). No increases in intratesticular or intratubular androgen concentrations or in testosterone: dihydrotestosterone ratios were observed in any of the hormone-treated groups when compared with hypophysectomized controls. In all hypophysectomized animals testicular androgen concentrations were reduced to less than 5% of control values. The results obtained in this study suggest that FSH is involved in the maintenance of spermatogenesis in the adult rat and that the effects of FSH are not mediated through changes in intratesticular androgens. Low levels of testosterone in combination with FSH can almost quantitatively maintain spermatogenesis in adult rats.

Differential effects of FSH and testosterone on the maintenance of spermatogenesis in the adult hypophysectomized rat

Synchronization of spermatogenesis would provide an ideal model for the investigation of stage-dependent changes in the secretion of paracrine factors. In vitamin A-deficient animals subsequently injected with vitamin A, over 80% of seminiferous tubules were synchronized within three to five stages of the seminiferous cycle. Following replenishment of vitamin A, spermatogenic stages IV-VI (35 days), VI-VIII (38 days), IX-XII (41 days), I-IV (45 days) and V-VII (48 days) were observed. Despite synchronization of spermatogenesis at all stages, spermatogenesis was markedly impaired when evaluated in a quantitative fashion. At all times evaluated, numbers of round spermatids were reduced compared with age-matched controls. Numbers of pachytene spermatocytes reached control values only after 45 days of vitamin A replenishment. Elongate spermatids were almost totally absent up to 41 days after vitamin A replenishment. Testicular and epididymal weights were also reduced, although testicular weights showed a significant recovery over the time-course of the study. Serum and pituitary concentrations of LH and FSH were raised at the commencement of the study, with serum gonadotrophins returning to control values 48 days after vitamin A replenishment. Both testicular and serum testosterone concentrations in treated animals tended to be higher than in the controls. Although synchronization of spermatogenesis was achieved, testicular testosterone concentrations did not reflect the stage-dependent cyclical changes observed in earlier studies. Testicular concentrations of testosterone were raised throughout the period of observation with the exception of animals synchronized around stages II-IV of the spermatogenic cycle. No correlation between the most frequent stages and intratesticular testosterone was found (r = 0.06, P greater than 0.1). Previous observations that testosterone concentrations are selectively increased at stages VII-VIII of the spermatogenic cycle are not supported by the present study.

Quantitative analysis of germ cell numbers and relation to intratesticular testosterone following vitamin A-induced synchronization of spermatogenesis in the rat.

Evidence derived predominantly from a series of in-vitro studies indicates that insulin-like growth factor-I (IGF-I) plays an important role as a paracrine and autocrine regulator within the testis. We investigated the effects of FSH substitution on spermatogenesis and testicular IGF-I content in rats treated with gonadotrophin-releasing hormone (GnRH) antagonist (ANT) and injected with ethane dimethane sulphonate (EDS), a Leydig cell toxin. FSH treatment partially prevented the marked decrease in intratesticular IGF-I in rats treated with only GnRH antagonist but not in GnRH antagonist+EDS-treated animals (controls, 191.0 +/- 4.5; ANT, 80.1 +/- 5.6; ANT+EDS, 81.6 +/- 3.4; ANT+EDS+FSH, 86.3 +/- 1.4; ANT+FSH, 137.7 + 7.3 (S.E.M.) ng/testis). Correlation analysis of testicular IGF-I content with the number of pachytene spermatocytes and round spermatids per cross-section revealed r values of 0.77 and 0.74 respectively (P < 0.001). We then analysed the same parameters in GnRH antagonist-treated rats which, in addition, received daily injections of the anti-androgen flutamide, in order to investigate the potential role of testosterone, as opposed to other Leydig cell products, in the regulation of spermatogenesis and testicular IGF-I. FSH treatment prevented regression of spermatogenesis in rats treated with GnRH antagonist alone but not in GnRH antagonist- and flutamide-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of FSH and testosterone on intratesticular insulin-like growth factor-I and specific germ cell populations in rats treated with gonadotrophin-releasing hormone antagonist

J. M. S. Bartlett

Papers

Differential effects of FSH and testosterone on the maintenance of spermatogenesis in the adult hypophysectomized rat

Quantitative analysis of germ cell numbers and relation to intratesticular testosterone following vitamin A-induced synchronization of spermatogenesis in the rat.

Effects of FSH and testosterone on intratesticular insulin-like growth factor-I and specific germ cell populations in rats treated with gonadotrophin-releasing hormone antagonist