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Gonadal soma-derived factor (gsdf) is a teleost- and gonad-specific growth factor involved in early germ cell development. The red spotted grouper, Epinephelus akaara, as a protogynous hermaphrodite, provides a novel model for understanding the mechanisms of sex determination and differentiation in teleosts. In the present study, a 2307-bp long gsdf gene was cloned from E. akaara and there was further analysis of its tissue distribution and gonadal patterns of gene expression during the female phase and sex change developmental stages. The cellular localization of gsdf at the late transitional developmental stage was also analyzed. In addition, the concentrations of serum sex steroid hormones (E2, 11-KT and DHP) were determined. The gsdf transcripts were exclusively localized in the gonad. During the female phase at an early developmental stage, when the ovotestis contained mainly oogonia and primary growth oocytes, the gsdf mRNA was relatively more abundant. The relative abundance of gsdf decreased, however, and the lesser amount was sustained with the advancement of oocyte development. During the transitional phase, the relative abundance of gsdf mRNA increased slightly at the early developmental stage and there were further increases in relative abundance in the late developmental stage, and the gsdf transcripts were observed in the Sertoli cells surrounding early developing spermatogonia. Among the sex steroids, 11-KT concentrations were positively correlated with amount of gsdf mRNA during sex change. These results suggest that gsdf could have roles in regulating pre-meiotic germ cell proliferation and be involved in sex change in E. akaara.

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The effect of progesterone (P) on pancreatic islet-cell proliferation and function of cyclic and pregnant rats was investigated in vivo. Silastic tubes containing P were inserted s.c. in cyclic rats for 7 or 14 days and in pregnant rats from day 7 to 14, from day 14 to 21 or from day 7 to 21 of pregnancy. 5-Bromo-2-deoxyuridine (BrdU) was infused during the last 24h of the treatment; the proportion of dividing islet-cells was determined in pancreatic sections, which were immunostained for BrdU. Islet-cell function was determined by measuring glucose and insulin response to a standard intravenous glucose challenge. P treatment increased P and 20alpha-dihydroprogesterone (20alpha-OHP) levels in cyclic rats; in pregnant rats, only the plasma levels of 20alpha-OHP were elevated. Both 7 and 14 days of P treatment stimulated islet-cell proliferation in cyclic rats. In pregnant rats, P treatment increased islet-cell proliferation on day 14, but not on day 21 after either 7 or 14 days of P treatment. P did not affect plasma lactogenic activity in pregnant rats; plasma concentrations of prolactin were decreased after 14 days of P treatment in cyclic rats, but were not affected in pregnant rats. P treatment had no effect on glucose tolerance and glucose-stimulated insulin secretion in any of the groups. It was concluded that: 1. in vivo P stimulates islet-cell proliferation, but does not affect islet-cell function, 2. the stimulatory effects of P are indirect and possibly mediated by the P metabolite 20alpha-OHP and 3. at the end of gestation, stimulation of islet-cell proliferation is inhibited by some factor, which is not identical to P.

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Concentrations of endogenous steroids and their glucuronide conjugates fluctuated during early development in steelhead trout Oncorhynchus mykiss. Whole body content of sex steroids and steroid glucuronides of both bisexual and gynogenetic (all female) steelhead trout were quantified by radioimmunoassay. Concentrations of 17beta-estradiol (E2) and cortisol increased 2-4 days before hatch. Two days after hatch, 11-ketotestosterone (11KT) increased in concentrations in both gynogenetic and bisexual populations, and 11KT glucuronide concentrations increased in the gynogenetic population. Testosterone (T) and E2 concentrations were at their lowest at 39 days postfertilization (dpf) for T and 39 and 61 dpf for E2. Changes in levels of steroid glucuronides were not consistently parallel to free steroids through time. T-, E2-, and 17alpha, 20beta dihydroxyprogesterone glucuronides declined slower than their free forms. Based on fluctuating concentrations of all steroid glucuronides, both populations of fish demonstrated an ability to form glucuronide conjugates of all steroids at the embryonic stage. The changes in levels of both free steroids and their glucuronides during early development of the trout indicate that steroid metabolism is active during development. This study also implicates steroid metabolism as an integral part of embryonic and postembryonic development.

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The objective of the present study was to investigate luteal function in cynomolgus monkeys (n = 32), aged 15-20 years with blood lead levels (BLLs) in the range of < 3.0 micrograms dl-1 (control, n = 20), 10-15 micrograms dl-1 (low, n = 7) and 25-30 micrograms dl-1 (moderate, n = 5). Sampling was performed daily beginning with day 10 of the menstrual cycle and concluding on the first day of the subsequent menstrual cycle. Circulating levels of oestradiol (E2), progesterone (P4) and 20 alpha-hydroxyprogesterone (20-OHP) were normalized to the day of the ovulatory E2 surge. The area under the concentration curve (AUC) for P4 was significantly lower in monkeys with moderate BLLs compared to the control group (P = 0.04). The number of days for which circulating levels of P4 were greater than 1.0 ng ml-1 were also significantly fewer (P = 0.03) in monkeys with moderate BLLs compared to controls. There was no statistical evidence of a lead effect on circulating levels of E2, 20-OHP or menstrual cycle characteristics. These data suggest that chronic lead exposure suppresses corpora luteal production of P4 in the monkey at circulating BLLs lower than previously reported and relevant to humans with occupational exposure to lead.

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Ovarian cells of pregnant rats were cultured with synthetic progestins (R5020, R2323), dexamethasone and RU486. Progesterone and 20 alpha-hydroxy-pregn-4-en-3-one (20 alpha-dihydroprogesterone) in the medium were measured by specific radioimmunoassay. Both R5020 and R2323 increased concentrations of these intrinsic progestins. RU486 decreased concentrations of progesterone, however, the addition of R5020 or R2323 counteracted this action. Immature hypophysectomized rats treated with pregnant mare serum gonadotropin (PMS) and human chorionic gonadotropin (hCG) were administered with RU486; the serum levels of progesterone and 20 alpha-dihydroprogesterone tended to decrease. R5020 and R2323 inhibited the effect of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), whereas RU486 did not. Inhibition of the cholesterol side chain cleavage enzyme (CSCC) by RU486 was more marked than that by R5020 or R2323. These results show that RU486 decreases progesterone synthesis in cultured ovarian cells. A part of the mechanism may involve an inhibition of CSCC.

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The progesterone antagonists, mifepristone (RU-38,486) and onapristone (ZK-98,299), given as 2 mg daily, did not markedly affect lactation in rats. Both litter growth and time spent by 10-pup litters attached to their mothers were similar in antagonist-treated mothers and in solvent-treated controls. The progesterone antagonists did not affect the steroid content in corpora lutea remaining from the preceding pregnancy. Corpora lutea formed after post-partum ovulation also showed nearly normal function throughout the first 17 days of lactation. It is concluded that progesterone itself plays no role in the initiation or maintenance of luteal function when prolactin secretion is governed through an action independent of the ovaries, as through suckling. Antagonist-treated rats ovulated around Day 13 of lactation despite suckling. This ovulation was not associated with a decrease of progesterone production by the corpora lutea formed after post-partum ovulation. Apparently, elimination of progesterone action may protect corpora lutea from luteolysis. The latter finding indicates a possible role of progesterone in luteolysis and deserves further analysis.

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Both placenta and prolactin are required for maintenance of gestation in rabbit. This study was undertaken to characterize the influence of placenta on uterus and mammary gland using the virgin pseudopregnant rabbit as a model system. Homogenates of 20-day rabbit placenta were found to stimulate increased growth of uterine and mammary tissue in pseudopregnant rabbits. Essentially, all of this uterine growth occurred in endometrium and represented growth of both stromal and epithelial cell types. After fractionation by successive extraction of rabbit placenta with acetone and bicarbonate, both extracts were found to stimulate uterine and mammary growth in pseudo-pregnant rabbits when measured on day 20 of pseudopregnancy after 13 days of treatment at extract doses equivalent to that found in 0.1 gram of placenta. Approximately 75% of this stimulatory activity is found in the acetone extract and the remainder appears in the aqueous extract. The extracts stimulate a maximum 90% increase in uterine growth and 400% increase in mammary pad area. Both activities exhibit logarithmic response characteristics, yet significant changes in serum 17 beta estradiol, progesterone, 20 alpha dihydroxyprogesterone and prolactin did not occur. These observations suggest the presence of an unidentified factor in rabbit placenta which has a non-ovarian mediated stimulatory activity on endometrial and mammary growth.

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The kinetics of the responses of plasma testosterone (T) its precursors and estrogens to a single injection of human chorionic gonadotropin (hCG) was studied in 9 46 XY subjects affected with one of 4 inborn errors of testicular biosynthesis. In the adults (n = 4), the kinetics and profile of the hormonal responses to hCG were qualitatively comparable to those previously described in normal adult men, and the profile of response characteristic of the hCG-induced steroidogenic desensitization was observed, suggesting that the 17,20 desmolase blockade induced by hCG is superimposed to the inborn enzymatic defect. In the prepubertal patients (n = 5), testicular desensitization was not observed, as in prepubertal controls. However, T precursors, each marker of a given enzymatic blockade, significantly rose several fold 2-5 days after the hCG injection, while they do not in normal children. The results also show that an hCG test is necessary for a clear-cut diagnosis of a given enzymatic block in children, but is not in adults. The single hCG injection protocol used in this study offers a sophisticated way of a qualitative analysis of the testicular secretory products, but is not a must.

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Synthesis by hamster corpora lutea (CL) in vitro and serum levels of progesterone (P4), 17 alpha-hydroxyprogesterone (17OHP) and 20 alpha-dihydroprogesterone (20DHP) were assessed for different days of pregnancy (Day 1=day of sperm; Day 16=day of delivery). Highest serum levels of the progestins were observed on Day 14 (P4=33 ng/ml; 17OHP=2 ng/ml; 20DHP=3 ng/ml), followed by precipitous declines on Day 16. The highest in vitro levels of luteal P4 and 17OHP were attained on Days 2-6 (production rates of P4=9-30 ng/mg CL/h; 17OHP=0.6-1.5 ng/mg CL/h), and dropped gradually thereafter. In contrast, the production rate of luteal 20DHP was extremely low on Days 2-8 but abruptly increased on Day 10 and was maintained through Day 14 (4-8 ng/mg CL/h). The in vitro production rates of all 3 progestins dropped abruptly on Day 16. Thus, in the pregnant hamster on the day of parturition (Day 16) there was good agreement between in vivo and in vitro levels of the progestins, contrary to the situation in the rat, where on Day 22 the CL in vitro produce large quantities of P4 and 20DHP while the serum levels are very low (Taya and Greenwald, 1981). Addition of 25 ng/ml of ovine LH to the incubation media containing hamster CL increased production rates of P4 (18-55 ng/mg CL/h) and 17OHP (1.5-2.4 ng/mg CL/h) on Days 2, 4 and 14 of pregnancy but the CL were refractory to this dose of LH from Days 6 to 12. The production rate of luteal 20DHP ws never stimulated by the addition of 25 ng LH. These results indicate that P4 is the principal progestin in the pregnant hamster with 17OHP and 20DHP as minor metabolites. The latter 2 progestins have been measured for the first time in the pregnant hamster and the levels are very low in comparison to the pregnant rat.

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Ovarian and luteal blood flow rates were measured at different stages of luteal development in anaesthetized rats using 15 +/- 5 micron radioactive microspheres. Ovulations were induced by injection of 8 IU of PMSG at 28 days of age. Steroid concentrations in peripheral plasma were determined using radioimmunoassays. The highest luteal blood flow was found in the youngest corpora lutea and decreased gradually with luteal age. Luteal flow on days 13 and 14 was significantly lower than that of days 2, 4, and 6. Ovarian stromal blood flow remained unchanged throughout the lifespan of the lupus luteum. Peripheral progesterone concentrations rose significantly on days 4, 6, and 8 with a maximum on day 8, as compared to day 2, and fell significantly after day 8. The levels of 20 alpha-OH-progesterone increased sharply on day 10, indicating that functional luteolysis. The progesterone levels fell significantly between day 8 and 10 without a concomitant significant decline in luteal blood flow. Since a fall in progesterone production seem sto precede a drop in luteal blood flow, the initiation of luteolysis does not appear to be caused by a vascular mechanism.

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The effect of Trichosanthin (TCS), a protein obtained from the roots of Trichosanthis kirilowii, alone or in combination with prostaglandin-F2 alpha (PGF2 alpha; Tromethamine salt) on the termination of pregnancy in rabbits was investigated. Intraperitoneal injection of 1 or 2 mg TCS/10-day pregnant rabbits neither altered the serum progesterone (delta 4P) level nor interrupted pregnancy. Doses of 0.5 or 0.25 mg PGF2 alpha incorporated in a Silastic-PVP tube and inserted intravaginally, terminated pregnancy within 72 h of treatment in 75 and 16% of the treated does, respectively. By contrast, does treated on day-10 of pregnancy with a combination of a non-effective dose of TCS (1 mg) and a sub-effective dose of PGF2 alpha (0.25 mg) terminated pregnancy in all the treated animals as no live embryos were found within 3 days of treatment. Pregnancy interruption was associated with a significant reduction of serum delta 4P and delta 4P/20 alpha-dihydroprogesterone (20 alpha-DHP) ratio. The present study indicates that TCS and PGF2 alpha act synergistically, rendering the termination of 10-day pregnancy possible in the rabbit. It was also noted that pregnancy cannot be maintained when the serum delta 4 P level drops below 4 ng/ml and delta 4P/20 alpha-DHP falls lower than 0.6 in the 10-day pregnant rabbit.

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PIP: This review addresses itself to the question of why science has yet to develop a safe, effective, and long-acting fertility control agent (for women), and attempts to define the attributes of such an agent while dealing with the limitations and unsolved problems presently at hand. Special emphasis is placed on the problems of long-term safety, efficacy, and adverse reactions. After a discussion using medroxyprogesterone acetate and norethisterone enanthate as examples of the state of present technology, the following theoretically new options for agent development are presented: 1) new schedules of administration for old agents, i.e., previously developed agents; 2) development of new compounds; 3) development of new formulations; and 4) development of new delivery systems.^ieng

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The dynamics of estradiol, estrone, 17 alpha-hydroxyprogesterone, progesterone and 20 alpha-dihydroprogesterone were investigated in the blood plasma of the pavian (papio, hamadryas) with regard to the menstrual cycle and in comparison with the human. Furthermore results were presented about the basal temperature, the fern phenomenon and the development of the sex-skin in the pavian.

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