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In view of the growing number of postmenopausal women using estrogen replacement therapy for the prevention of acute and chronic consequences of hypoestrogenism, any possible associations between hormone therapy and manifestations of gynecologic cancer are an issue of increasing importance. We reviewed the published literature to evaluate the impact of estrogen replacement therapy on the occurrence of gynecologic malignancies including breast cancer. The tumor growth of ovarian, cervical, vaginal, and vulvar neoplasias is not fundamentally influenced by hormone therapy. However, long-term replacement therapy may be associated with an increased incidence of endometrial hyperplasia and even of neoplasia. This increased risk is related to the duration and cumulative dose of estrogen therapy. Addition of progestin probably reduces the risk of endometrial cancer to that observed in the general population. With regard to the relationship between hormone replacement therapy and the incidence of breast cancer, available epidemiologic data are contradictory. While therapy of less than 5 years appears not to be associated with an increased risk, long-term use may be related to a small but significant increase in the risk of developing breast cancer. It is important to note that the cyclic addition of a progestin to estrogen replacement does not affect this risk. After discontinuation of hormone replacement the increased relative risk returns to that of non-users. In conclusion, when considering estrogen replacement therapy for a postmenopausal woman, a slightly increased risk of developing breast cancer and the need to add progestin for protection of the endome-trium need to be mentioned. Bearing this in mind, the benefits of estrogen therapy in terms of a better quality of life and perhaps of a disease-free prolongation of life justify a wide use of hormonal preparations.

Using probes for rat neural nitric oxide synthase (NOS) mRNA and GnRH mRNA, we performed in situ hybridization to survey NOS mRNA distribution within the hypothalamus of the male and female rat and sought evidence for its expression in GnRH neurons. The NOS cRNA probe was radiolabelled with 35S, and a digoxigenin-labeled rat GnRH cRNA probe was used for double-label studies. NOS mRNA was localized in discrete hypothalamic areas, in grain clusters suggestive of individual neurons. NOS mRNA-positive cells were located mainly in the supraoptic and paraventricular nucleus, particularly overlying the magnocellular division. Rostrally, cells expressing NOS mRNA were especially prominent in the diagonal band of Broca, in a distribution very similar to GnRH neurons. Nevertheless, only one of 370 cells labeled for GnRH mRNA appeared to be positive for NOS mRNA. We conclude that NOS mRNA is located prominently in regions where CRH, AVP and oxytocin cells are located. NOS mRNA-positive cells are located in close proximity to GnRH neurons, but rarely do such neurons express NOS mRNA.

To investigate the effects of acute hyperprolactinemia on the 24 h LH pulsatile pattern, 11 women in the early follicular phase (EF, days 3 and 4) and 8 postmenopausal women (PMW) were studied before and during administration of metoclopramide, a dopamine receptor antagonist. Sequential 24 h infusions of either metoclopramide (MCP, 30 micrograms/kg/h) or normal saline were conducted and pulsatile LH activity assessed for 48 hrs. In both EF women and PMW, a prompt (within 90 min, p less than 0.001) and sustained (greater than 45 micrograms/L, p less than 0.001) release of PRL was induced by MCP infusions. MCP-induced hyperprolactinemia failed to modify the LH pulsatile activity in both EF women and PMW. These observations suggest that acute hyperprolactinemia due to dopaminergic blockade has no discernible effect on LH pulsatility and that the reduced LH pulse frequency observed in association with endogenous hyperprolactinemia may result from different neuroendocrine mechanism(s) and/or is time dependent.