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The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation. Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson's Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.

The effect of androgens on the conversion of estradiol (E2) and estrone (E1) from estrone-3-sulfate (E1-S) was studied in explants of normal human term placentas. Explants incubated in medium supplemented with 2.0 microM E1-S showed that 50 microM dihydrotestosterone (DHT) stimulated E2 production 15-fold above control values after 0.5h, but neither 50 microM methyltestosterone (MT) nor 50 microM diethylstilbestrol (DES) had any effect. HCG (5.0 i.u./ml), alone or in combination with one of the androgens, did not influence the E2 production. When the explants were incubated in medium with 0.25 microM E1-S (the average concentration reported for late pregnancy plasma), DHT (0.5-50 microM) caused a dose- and time-dependent increase in E2 production, while E1 production and the combined accumulation of E2 and E1 were slightly inhibited by all doses of DHT during the 0.5-4h incubation. When E1 (0.1 microM) was used as substrate, DHT caused a dramatic dose- and time-dependent shift in the E1-E2 equilibrium towards E2. The results indicate that during late pregnancy, a particular class of androgens may increase the production of the more bioactive E2 from the circulating E1-S; the mode of action may be an enhanced conversion of E1 to E2.

A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinylestradiol (EE) was administered orally at 36 hours after the detection of the luteinizing hormone peak and again at 48 hours in 12 healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17 alpha-hydroxyprogesterone, and estradiol (E2) in control (placebo) and treatment cycles. Five subjects showed no significant change in the levels of these steroids but had a shortened luteal phase. The treatment significantly decreased both P and E2 levels in three subjects, while two subjects showed diminished E2 levels only. The remaining two subjects had lower P levels and fluctuating E2 patterns. Endometrial biopsies from both study cycles indicated asynchronous development of the epithelial and stromal components in the treatment cycle. These findings (abnormal luteal phase steroid levels and duration and outphased endometrial development) indicate that corpus luteum function was variously affected by the action of norgestrel-EE treatment.

A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinylestradiol was administered orally at 18 hours after the detection of luteinizing hormone rise and again at 30 hours in five healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17 alpha-hydroxyprogesterone, and estradiol (E2) measured in a control (placebo) cycle with those in two consecutive treatment cycles. Treatment did not alter the steroid levels in one subject. P was suppressed in one or both treatment cycles of four subjects. E2 was suppressed in both treatment cycles of one subject and produced widely fluctuating patterns in another. The hormonal patterns in the two consecutive treatment cycles of the same individual were similar in all but one instance, where only the P level in the second treatment cycle was diminished. These results showed that this treatment can elicit steroidogenic responses of varying degrees and duration. The contraceptive action may lie in the altered P and/or E2 level at certain points in the menstrual cycle.