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The relationship between the hypothalamo-pituitary-gonadal (HPG) axis and the hypothalamo-pituitary-adrenal (HPA) axis has been well documented in the rat. In most cases, a negative coupling was observed and an inhibitory effect of the HPA axis upon the HPG was shown. In the female rat, a marked circadian rhythm of corticosterone plasma values is observed during each day of the estrous cycle, with maximal values around 08:00 p.m. The preovulatory luteinizing hormone (LH) surge also occurs at 08:00 p.m. on the day of proestrus. Here we measured circadian variations of plasma cortisol in humans in relation with the time of initiation of the preovulatory LH surge. Blood samples were taken at 08:00 a.m., 12:00 a.m., 04:00 p.m., 08:00 p.m., 12:00 p.m., and 04:00 a.m. from 19 subjects for 4 consecutive days, once 17β-estradiol (E₂) values reached 125 pg/ml (days 7–10 of the menstrual cycle). Serum E₂ and LH determinations were performed by microparticle enzyme immunoassays. Serum progesterone and plasma cortisol determinations were made using RIA methods. For plasma cortisol values, a marked circadian rhythm, with 2- to 3-fold higher values during the morning than during the afternoon, was almost identical before, during and after the LH surge. However, values were generally higher during the follicular phase than during the luteal phase. Maximum cortisol values occurred between 04:00 and 08:00 a.m. and minimal cortisol values between 04:00 and 08:00 p.m. Initiation of the LH surge (50% over the mean of previous values) occurred at 04:00 a.m. (20% of the cases) or at 08:00 a.m. (80% of the cases). There was a strong coupling between the onset of the surge and the acrophase of the cortisol circadian rhythm: maximal cortisol plasma values were seen at 04:00 a.m. when the LH preovulatory surge started at 04:00 a.m. and 08:00 a.m. when it started at 08:00 a.m. The present results show that the positive coupling documented in the female rat between the HPA and the HPG axis at the time of preovulatory LH surge is also present during the menstrual cycle in the human.

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The purpose of these experiments was to determine the reversibility of a-chaconine and a-solanine inhibition of human plasma butyrylcholinesterase (BuChE). For the substrate a-naphthylacetate, optimal assay conditions were 0.50 M sodium phosphate buffer and a substrate concentration of 3-5 X 10~4 M. Dibucaine (1 X 10~5 M) indicated the usual phenotype for all subjects; achaconine and a-solanine at 2.88 X 10~6 M inhibited BuChE about 70 and 50%, respectively. One-and 24-hr incubations at 1 X 10~! M with a-chaconine, a-solanine, paraoxon, eserine, and ethanol yielded reversible inhibition with dilution except for paraoxon. Twenty-four-hour dialyses of incubations showed no inhibition except for paraoxon. PAGE enzyme activity gels of 1-and 24-hr incubations also showed no inhibition except for paraoxon. aChaconine and a-solanine are reversible inhibitors of human butyrylcholinesterase. At estimated tissue levels, a-chaconine, a-solanine, and solanidine inhibited BuChE 10-86%. In assays which combined a-chaconine, a-solanine, and solanidine, inhibition of BuChE was less than additive. No inhibition of albumin a-naphthylacetate esterase (an arylesterase) was noted with any inhibitor. The importance of these data to adverse toxicological effects of potato alkaloids is diSCUSSed. C 1996 SodMy of Toxicology.Potatoes, consumed by humans for at least 2000 years (Spoerke, 1994;Ugent, 1970), contain the steroidal alkaloids, a-chaconine, a-solanine, and solanidine. The toxicology of these known butyryl-and acetylcholinesterase inhibitors (Harris and Whittaker, 1962;Orgell, 1963) has been reviewed

Letrozole is a targeted aromatase inhibitor which has primarily been used in post-menopausal women with breast cancer. Recently, it has been utilized in infertile pre-menopausal women because of its ability to enhance FSH production for ovulation induction. However, the ovarian follicle’s response to FSH is only a part of the endocrine events occurring in a developing follicle. The health of the small antral follicles is driven primarily by androgens, which contribute to granulosa cell mitosis, sensitivity to FSH, and resistance to atresia. In contrast, elevated androgens in the late antral to pre-ovulatory follicle have a negative impact on follicle health and lead to atresia and cystic follicle formation. This ovarian physiologic data suggests that current applications of letrozole to infertility may be squandering some of the primary benefits available in using letrozole to promote follicle development. Four applications of letrozole to infertility that have appeared in the medical literature are reviewed. Androgen-related benefits are reviewed and various questions put forward about how letrozole could be more effectively used to help patients in these settings.