Leonard J. Lerner

Peritoneal fluid and serum steroids in infertility patients

Peritoneal fluid and serum were collected from 78 patients at the time of laparoscopy. Twenty-two were fertile controls (CTL), and 56 were infertility patients, who were subdivided into three main groups: endometriosis (EMS), pelvic adhesions (ADH), and ovarian dysfunction (OvDF). Based on control group data, biochemical criteria indicative of the presence of a stigma, S(+), were established: (1) serum progesterone (P) greater than or equal to 2 ng/ml, (2) peritoneal fluid P greater than or equal to 50 ng/ml, and (3) peritoneal fluid/serum ratio of P greater than or equal to 3. Direct visualization by laparoscopy showed that 21% CTL, 75% EMS, 69% ADH, and 56% OvDF subjects had luteinized unruptured follicle (LUF) syndrome. Biochemical criteria, however, demonstrated only 7% CTL, 37% EMS, 23% ADH, and 56% OvDF subjects had LUF. Peritoneal fluid estradiol (E2) and P concentrations and total content were significantly lower in LUF than in non-LUF patients, whereas serum E2 and P concentrations were not different between the two groups. Values for testosterone and androstenedione in peritoneal fluid and serum were similar between these two groups. Endometrial dating in LUF versus non-LUF patients were also similar. The usual indicators of ovulation, i.e., serum P, endometrial dating, and basal body temperature, failed to identify LUF. The diagnosis of LUF can be best made by P assay of peritoneal fluid and serum.

A-norprogesterone, an androgen antagonist.

Summary A-norprogesterone antagonizes testosterone induced accessory sex organ hypertrophy in the immature castrate male rat and comb growth stimulation in the chick. Growth of the ventral prostate, seminal vesicles, adrenals and thyroids of intact rats and the chick comb in animals not treated with androgen were significnatly reduced by administration of this compound. A-norprogesterone is not androgenic, estrogenic, anti-estrogenic, progestational or anti-progestational under the experimental conditions described.

Biological Activities of 16α, 17α Dihydroxyprogesterone Derivatives

Summary The 16α, 17α acetophenane (P-DHP) and acetone (A-DHP) derivatives of 16α, 17α-dihydroxyprogesterone (DHP) and their 6α-methyl, 6β-methyl, 6α-fluoro and 6β-fluoro analogues were assayed for parenteral and oral progestational activity. P-DHP and A-DHP are equal in parenteral activity, each being about twice as potent as progesterone. P-DHP is strongly active orally, being 1 to 2 times as active as nore-thisterone, whereas A-DHP has only weak oral activity. Parenteral activity of P-DHP or A-DHP was not altered by 6-methylation. Oral activity of 6β-methyl-P-DHP was similar to P-DHP but both 6α and 6β-methyl-A-DHP were more potent orally than A-DHP. 6α fluorination had little or no enhancing effect on either parent compound when parenterally administered but did reduce oral potency. 6β fluorination made both parent steroids inactive by either route of administration. P-DHP and A-DHP have longer duration of activity than progesterone, moderate progestational effects still being present 25 days and 20 days, respectively, following a single 10 mg intramuscular injection. P-DHP is devoid of inherent androgenic, anti-androgenic, estrogenic, anti-DCA or corticoid activities.

COMPARISON OF ANTI-GRANULOMA, THYMOLYTIC AND GLUCOCORTICOID ACTIVITIES OF ANTI-INFLAMMATORY STEROIDS.

Summary A series of 15 corticoids was assayed for anti-granuloma, thymolytic and liver glycogen deposition activities in adrenalectomized male rats. The order of relative potency for the majority of the steroids was similar in the three bioassays. Exceptions were 6α-chloro-9α-fluoro-16α-hydroxyprednisolone acetonide acetate and 6α-fluoro-16α-methylprednisolone which had greater relative potencies in the anti-granuloma and thymolytic assays, and 9α-fluoro-16α-hydroxyprednisolone acetonide which had a greater relative potency in the liver glycogen deposition assay.

Correlation of Anti-Inflammatory Activity with Inhibition of Prostaglandin Synthesis Activity of Nonsteroidal Anti-Estrogens and Estrogens

Summary Diethylstilbestrol, clomiphene, ethamoxytriphetol and triparanol were 0.18, 1.0, 0.02 and 0.01 times as potent in the in vitro inhibition of prostaglandin synthe-tase, respectively as was indomethacin. In the in vivo carrageenan-induced rat paw edema studies, diethylstilbestrol was more potent as an anti-inflammatory agent than was clomiphene, and ethamoxytriphetol and triparanol were only marginally effective. The most potent of the compounds tested was indomethacin. The results reported demonstrate that the nonsteroidal anti-inflammatory agents and the nonsteroidal estrogens and anti-estrogens share the property of inhibition of prostaglandin synthetase. The authors thank Mr. Giovanni Ghinzone for assisting in the prostaglandin synthetase assays; Dr. Domenica Selva for assisting in the anti-inflammation studies; and Miss Maria Carla San Pietro for typing the manuscript.

Changes in the metabolism of PGE1 and PGF2α in rat placenta during pregnancy

Abstract The metabolism of PGE1 and PGF2α were studied in an in vitro system using placentae from 11-day pregnant rats. PGE1 was metabolized faster than PGF2α. The same system was employed to study the quantitative metabolism of these prostaglandins at various stages of pregnancy in the rat. Results of these investigations showed that metabolism became maximal between days 9–12 and between days 15–22 of gestation. On days 12–15 of pregnancy, metabolism decreased, and was at its lowest point on day 14. Maximum prostaglandin metabolism during the sensitive period of days 9–12 of gestation may act as a protective device against the detrimental effects of prostaglandin. Possible correlation of prostaglandin regulation with hormonal balance is discussed.

PHLORETIN, A WEAK ESTROGEN AND ESTROGEN ANTAGONIST.

Summary Phloretin is a very weak estrogen. It induces a uterotrophic effect in immature mice and in ovariectomized rats. Estradiol benzoate-induced uterine growth in the mouse and vaginal cornification in the castrate female rat are partially inhibited by concurrent treatment with large doses of phloretin. This compound is a weak inhibitor of pituitary gonadotrophins in parabiotic female rats and in intact immature male rats. Administration of phloretin to female rats on days 1–4 after mating decreased the number of pregnancies by 40%.

Effect of day of pregnancy and pregnancy terminating agents on prostaglandin synthesis and metabolism and histamine metabolism in the rat utero-placental fetal complex and lung

Abstract Synthesis and metabolism of prostaglandins (PG) in the rat placenta during the first two-thirds of pregnancy is low with the exception of a large peak of activity on day 11. During the last third of pregnancy placenta PG-synthesis is low but PG-metabolism increases sharply. In contrast, uterine PG synthesis is low during the first two-thirds of gestation but increases during the remainder of pregnancy, peaking at parturition. Uterine PG-metabolism is low throughout pregnancy. Fluctuation in sex steroid levels during pregnancy may be related to changes in PG-synthesis and metabolism. Maintenance of vital functions in pregnancy may require timed changes in prostaglandin as well as hormonal balance. The non-hormonal non-prostaglandin compounds L-10503 (2-(3-methoxyphenyl)-5,6-dihydro -s-triazole [5,1-a]-isoquinoline) and L-11204 (2-(3-ethoxyphenyl)-5,6-dihydro-s-triazole [5,1-a]-isoquinoline) which terminate pregnancy after blastocyst implantation in the uterus, inhibits PG-metabolism. Administration of these compounds to rats on day 9 of gestation reduces PG-metabolism in the placenta, uterus and lungs whereas treatment on pregnancy days 13 or 15 decreases PG-metabolism only in the maternal and fetal lungs. PG-synthesis is not affected under these conditions. Male and non-pregnant female rats treated with L-10503 and 24 h later given [ 3 H]-PGF 2α . or [ 3 H]-PGE 1 , have a reduced ability to metabolize PG as measured in plasma. L-11204 administered on day 9 of pregnancy increased placental, uterine and fetal histamine. Placental histaminase was also increased by this treatment. Alteration of PG and/or histamine metabolism may be involved in the anti-fertility activity of these novel compounds.

Effects of Prostaglandins PGE2 and PGF2a on the Adenyl Cyclase Activity of Various Segments of the Immature Rabbit Oviduct and Uterus

Summary Immature rabbit oviducts and uteri incubated in the presence of PGE2 showed increases in the percent conversion of 3H-nucleotides to 3H-cAMP. The different segments of the oviduct had similar adenyl cyclase activities in the absence of prostaglandin. In the presence of PGE2, however the degrees of response varied. The adenyl cyclase activities of oviductal ampulla, oviductal isthmus, uterotubal junction and uterus were 2, 3, 4, and 2 times those of their controls, respectively. Addition of theophylline to the incubation mixture enhanced the level of cAMP formation and the response to PGE2·PGF2α , at a concentration (10 μg/ml) that produced a maximal response for PGE2, did not significantly alter the adenyl cyclase activity in any area of the oviduct or uterus. Isoproterenol increased and oxytocin decreased adenyl cyclase activity in the immature rabbit uterus.

Effects of prostaglandin E2 and DL204 IT, an inhibitor of prostaglandin degradation, on ovulation and ovum transport in the hamster

The effects of 2(3-ethoxyphenyl)-5,6-dihydro-s-triazole-[5,1-a]isoquinoline (L-11204 or DL 204 IT and PGE2 on ovulation and ova transport were studied. DI 204 IT was administered in doses of 0.2-25 mg/kg s.c. on the day of estrus. A smal reduction in ovulating follicles was observed 96 hours later, but only at the 5 mg/kg dose level. At all dose levels, however, DL 204 IT caused a dose-related reduction in the number of ova in the oviducts. PGE2 at a total dose of 2 mg/animal s.c., administered in 4 divided doses over the second and third day of the cycle did not affect ovulation or ova transport. PGE2 plus DL 204 IT (5 mg/kg), however, completely blocked ovulation in all but one animal. That animal had one ovulated follicle and a single ova was recovered from its oviduct.