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School of Biomedical Sciences (F.J.P.E.), University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, United Kingdom; Zeneca Pharmaceuticals Central Toxicology Laboratory (A.N.B.), Alderley Park, Macclesfield, SK10 4TJ, United Kingdom; Department Anatomy (J.B.K.), Monash University, Clayton, Victoria 3168, Australia; and Department Anatomy (A.S.C., H.F.), University of Cambridge, Cambridge CB2 3DY, United Kingdom
Address all correspondence and requests for reprints to: Dr. Francis J. P. Ebling, School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, United Kingdom. E-mail: fran.ebling{at}nottingham.ac.uk
Abnormal sperm production and reduced fertility have been reported in
transgenic male mice lacking the 
-subtype of the estrogen receptor
(ER) or aromatase. The aim of this study was to investigate the role
of estrogen in male reproductive function, by determining the effect of
estradiol on testicular function in hypogonadal (hpg)
mice congenitally lacking gonadotropin; and thus, sex steroid
production. hpg mice were treated, at 2–3 months of
age, with slow-release estradiol implants, which achieved circulating
estradiol concentrations of approximately 40 pg/ml. Treatment for 35
days reliably induced a 4- to 6-fold increase in testicular weight,
compared with the vestigial testes in the untreated or
cholesterol-treated controls. The degree of testicular growth after 35
days was similar to that in hpg mice receiving an
intrahypothalamic graft of preoptic area tissue taken from neonatal
mice on the day of birth, a procedure known to induce testicular
development in hpg mice by activation of the pituitary
gland. Histological analysis revealed that the testes contained
elongated spermatids after 35 days of estradiol treatment, whereas germ
cell development never progressed beyond the pachytene stage in control
hpg mice. Treatment for 70 days induced full
qualitatively normal spermatogenesis in hpg mice. Testis
weight increased 5-fold, reflecting a 5-fold increase in total
seminiferous tubule volume and a 4- to 5-fold increase in the total
volume of the seminiferous epithelium. In all experiments,
spermatogenesis proceeded in the absence of measurable androgen
concentrations, but circulating FSH concentrations were slightly (but
significantly) elevated, relative to cholesterol-treated control
hpg mice. This stimulatory action of estradiol on FSH
secretion was unexpected, particularly because identical estradiol
treatments significantly decreased serum FSH levels in wild-type
littermates. These results indicate that estrogens may play a role in
spermatogenesis, via stimulatory effects on FSH secretion. An
alternative or complementary explanation, given the recent
identification of estrogen receptors (ER and ERß) and aromatase
within various cell types in the testis, is that estrogens exert
paracrine actions within the testis to promote spermatogenesis. The
identification of effects of estradiol on testicular function provides
a conceptual basis to reexamine the speculative link between increased
exposure to environmental estrogens and reduced fertility in man.
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