In the present study we investigated the effects of infantile/prepubertal chronic oestrogen treatment, chemical sympathectomy with guanethidine and combined sympathectomy and chronic oestrogen treatment on developing sensory nerves of the rat uterus. Changes in sensory innervation were assessed quantitatively on uterine cryostat tissue sections stained for calcitonin gene-related peptide (CGRP). Uterine levels of NGF protein, using immunohistochemistry and ELISA, and mRNA, using Northern blots and in situ hybridization, were also measured. Finally, levels of TrkA NGF receptor in sensory neurons of T13 and L1 dorsal root ganglia (DRG), which supply the uterus, were assessed using densitometric immunohistochemistry. These studies showed that: (1) chronic oestrogen treatment led to an 83% reduction in the intercept density of CGRP-immunoreactive nerves; (2) sympathectomy had no effect on the density of uterine sensory nerves or on the pattern of oestrogen-induced changes; (3) NGF mRNA and protein increased following sympathectomy or chronic oestrogen treatment; and (4) oestrogen produced increased intensity of labelling (28%) for TrkA receptors in small-diameter sensory neurons, but decreased labelling (13%) in medium-sized neurons, which represent the large majority of the DRG neurons supplying the upper part of the uterine horn. Contrary to expectations, increased levels of NGF after sympathectomy and oestrogen treatment did not lead to increased sensory innervation of the uterus. The possibility that alterations in neuronal levels of TrkA contribute to the lack of response of uterine sensory nerves to the oestrogen-induced increase in NGF levels is discussed.

The female reproductive tract undergoes remarkable functional and structural changes associated with cycling, conception and pregnancy, and it is likely advantageous to both individual and species to alter relationships between reproductive tissues and innervation. For several decades, it has been appreciated that the mammalian uterus undergoes massive sympathetic axon depletion in late pregnancy, possibly representing an adaptation to promote smooth muscle quiescence and sustained blood flow. Innervation to other structures such as cervix and vagina also undergo pregnancy-related changes in innervation that may facilitate parturition. These tissues provide highly tractable models for examining cellular and molecular mechanisms underlying peripheral nervous system plasticity. Studies show that estrogen elicits rapid degeneration of sympathetic terminal axons in myometrium, which regenerate under low-estrogen conditions. Degeneration is mediated by the target tissue: under estrogen's influence, the myometrium produces proteins repulsive to sympathetic axons including BDNF, neurotrimin, semaphorins, and pro-NGF, and extracellular matrix components are remodeled. Interestingly, nerve depletion does not involve diminished levels of classical sympathetic neurotrophins that promote axon growth. Estrogen also affects sympathetic neuron neurotrophin receptor expression in ways that appear to favor pro-degenerative effects of the target tissue. In contrast to the uterus, estrogen depletes vaginal autonomic and nociceptive axons, with the latter driven in part by estrogen-induced suppression BMP4 synthesis. These findings illustrate that hormonally mediated physiological plasticity is a highly complex phenomenon involving multiple, predominantly repulsive target-derived factors acting in concert to achieve rapid and selective reductions in innervation.

The developing noradrenaline-containing (NA-C) sympathetic nerves of the rat uterus were analyzed following acute and chronic treatment with oestrogen. Histochemical methods were used in association with nerve density measurements and biochemical assays. For comparative purposes, noradrenaline (NA) levels were measured in the urinary bladder and right auricle following chronic oestrogen treatment. Acute treatment was performed by s.c. administration of a single dose of 40 micrograms oestradiol cypionate on the 25th day of age. Chronic treatment consisted of four doses of 10 micrograms oestradiol on days 10, 15, 20 and 25 of postnatal development. Both acute- and chronic-treated animals were killed at 28 days of age. The main biochemical findings were the following: (a) both acute and chronic oestrogen treatment increased the weight of the uterine horn, parametrial tissue and uterine cervix; (b) in the uterine horn, the total content of NA was reduced following both oestrogen treatments. However, the degree of reduction was greater after chronic treatment; (c) in the parametrial tissue, the NA levels were reduced only after chronic treatment; (d) in the cervix, the NA total content was increased after both treatments; (e) in the urinary bladder, there was a parallel increase between organ growth and NA content following chronic oestrogen treatment; (e) in the auricle neither the tissue weight nor the total content of NA were changed by chronic estrogen treatment. Histochemical studies showed that: (a) acute treatment with one single dose of oestradiol, provoked a marked reduction in the density of NA-C nerves associated with the myometrial and parametrial smooth muscle, without affecting the innervation of blood vessels; (b) following chronic treatment, the only fibers we were able to recognize were those associated with blood vessels. These fibers were thinner and less intensely fluorescent than in controls. Results are interpreted considering the differential sensitivity of uterine nerves to sex hormones. A possible involvement of oestrogen in changes of noradrenergic innervation of the uterus following puberty is discussed.

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