The midcycle surge of LH and FSH is critical for final oocyte maturation and ovulation. In normal women, this gonadotropin surge follows a gradual increase in estradiol levels (E) and is concomitant with a small increase in progesterone (P) levels. However, whether sex steroids alone are sufficient to induce the complex neuroendocrine interactions underlying this switch from negative to positive feedback is unknown. In this study, physiological midcycle levels of E, with and without periovulatory levels of P (E+P and E, respectively) were infused into 18 normally cycling women in their early to midfollicular phases. The resulting sex-steroid-induced gonadotropin responses were then compared with 118 spontaneous midcycle surges in 81 normal women. The sex steroid levels achieved by the infusions were within the normal ranges for the spontaneous midcycle surge. However, neither women who received E alone nor those who received E+P had LH responses that achieved those of spontaneous LH surges in the normal menstrual cycle (NMC) [82.7 +/- 16.23 IU/L E (mean +/- SEM), 69.7 +/- 12.01 IU/L E+P vs. 121.7 +/- 6.23 IU/L NMC, P < 0.05 E and P < 0.005 E+P vs. NMC]. In contrast, peak FSH levels evoked by E and P matched the spontaneous FSH peaks (19.0 +/- 2.1 IU/L E, 24.5 +/- 4.0 IU/L E+P vs. 23.3 +/- 0.9 IU/L NMC, P = 0.07 E and P = 0.71 E+P vs. NMC). In conclusion, sex steroids alone do not seem to be sufficient to stimulate the normal midcycle LH surge. We hypothesize that other ovarian factors, which are missing in the midfollicular phase, are required for the generation of the normal midcycle surge of LH.

Dysfunction of the hypothalamic-pituitary axis presenting as hypogonadotropic amenorrhea is a common sequelae of treatment for cranial tumors with surgery and/or radiation. We hypothesized that the site of the defect in this condition is hypothalamic, rather than pituitary, in the majority of patients. Nine women with acquired hypogonadotropic hypogonadism after treatment with transphenoidal pituitary surgery (n = 3), transphenoidal surgery plus conventional radiotherapy (XRT; n = 1), hypothalamic surgery plus XRT (n = 2), or XRT with or without noncentral nervous system surgery (n = 3) underwent assessment of endogenous pulsatile LH secretion and a standard GnRH test followed by iv administration of a physiological replacement regimen of exogenous GnRH. A total of 25 cycles were completed at doses of 75 or 100 ng/kg.bolus. Ovulation occurred in 78% of patients, with all ovulatory patients who desired fertility becoming pregnant. The hormonal responses in these cycles did not differ from the patterns of sex steroids and gonadotropins in normal women. The response to pulsatile GnRH was not influenced by GH deficiency or PRL abnormalities. Of the two patients who failed to ovulate, there was no evidence of folliculogenesis in one, whereas the second consistently developed follicles, but proved incapable of mounting a LH surge despite adequate preovulatory estradiol levels. Both patients had a history of pituitary radiation and surgery. There was no consistent relationship between the results of GnRH testing and the pattern of pulsatile LH secretion. However, the only patient who failed to achieve folliculogenesis was the only patient without a FSH response to GnRH testing and an apulsatile baseline study. Hypothalamic GnRH deficiency is the etiology of hypogonadism in the majority of patients after treatment with hypothalamic or pituitary surgery or cranial irradiation. Therefore, exogenous pulsatile GnRH represents a physiological replacement therapy that completely restores normal gonadotropin dynamics, resulting in ovulation and fertility.

vices-a problem identified by Francke more than 30 years ago as inherent to pharmacy practice in supermarkets andchain drugstores." Francke statedin 1968,"The dispensing function of the pharmacist,while importantand evenvital, is essentially a superficial practice of the profession which,by itself,does not require knowledge or skills sufficiently basic to meritprofessional recognition ... .''6 The goal in commemorating the 40th anniversary of TheAnnals has been to reflecton the change in the focus of the profession from primarilydispensingfunctions to the provision of complete and personalized pharmacotherapy services, as envisioned by Francke, to complement the traditional services (Figure 1).

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