Progestational Potency Research Articles

Polarographic Investigation of Dienogest

Dienogest (DGN), is an orally administered synthetic progestin that has shown to have selective progesterone receptor (PR) agonistic activity and oral progestational potency on endometrium. In this paper, the investigation of electrochemical reduction of Dienogest on dropping mercury electrode (DME) is achieved and resulted in a reduction scheme that involves a two electron reduction of 3-keto-delta-4-group in the A-ring of the molecule. This observation is supported by comparison of the compound with model compounds of testosterone and norethisterone. In this study, electrochemical determination of the compound and its validation is also studied by differential pulse polarograhy (DPP). The results yielded good precision, accuracy and reproducibility. Calibration range was found as 2.00 × 10−6M to 1.00 × 10−4M, with LOD and LOQ values as 0.58 × 10−6M and 1.90 × 10−6M, respectively.

Cu (I) catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC): Synthesis of 17α-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19-nor-testosterone-17β-yl acetates targeting progestational and antipro-liferative activities

The progestational potency and selectivity of synthetic steroidal agonists can be enhanced by even larger chemical moieties at 17α-position of the steroid backbones. Hereby a series 5a-c and 6a-c of novel 17α-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19-nortestosterone-17β-yl acetates were designed and synthesized using click chemistry approach searching progestogenic derivatives with potential anticancer activity. Compounds 5a,b and 6a,c have affected to different extents the three histopatho-logical parameters considered for evaluation of their progestational activity. The compounds 5a,b and 6a,c showed modifications in rat uterus at 35.7–34.8 nM levels with privileged endometrial thickening effect and least change of uterine weight relative to NEA at 52.9 nM level. Up to 40 mg/kg dose compounds 5b and 6c were non-toxic. Molecular docking of the ligands in PR showed in the majority of cases a conformational fitting into the active site different from that of the reference steroid NEA. Compound 6b revealed about 46.4% growth inhibition of CNS cancer SNB-75 cell line, 56% growth inhibition of renal cancer A498 cell line and 56.7% growth inhibition of prostate cancer PC-3 cell line which was mediated by cell cycle arrest. Drugability of the screened compounds showed tolerated results after being challenged to diverse physicochemical parameters.

Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium

Dydrogesterone has a molecular structure closely related to that of natural progesterone, but it has enhanced oral availability compared with progesterone. The hormonal profile and the progestational potency of dydrogesterone has been determined in vitro, in vivo and in humans, in combination with estrogens or without. It showed varying affinity for progesterone-binding proteins in uterine tissue in vitro, depending on the species. It exerted a clear progestational response in the rabbit in vivo, although the potency was influenced somewhat by the route of administration. When used in hormone replacement therapy, 10 mg dydrogesterone given sequentially provides adequate protection against endometrial hyperplasia in postmenopausal women using 2 mg estradiol. Similarly, a dydrogesterone dose of 5 mg also protects the endometrium when continuously combined with 1 mg estradiol. Dydrogesterone also has beneficial effects in women with amenorrhea/oligomenorrhea, dysfunctional uterine bleeding and irregular cycles. In conclusion, having a similar profile to progesterone but with better oral availability, dydrogesterone has been used successfully to treat disorders related to absolute or relative progesterone deficiency.

Transdermal Contraceptive Patches

Many contraceptive methods have been developed for fertility regulation, either reversible or irreversible, in males and females. Oral contraceptives have been considered the most popular form of reversible contraception. However, they must be taken consistently, on a daily basis for 21 or 28 days of each menstrual cycle, in order to achieve the maximal outcomes of contraception. Moreover, their contraceptive efficacy has been reportedly affected by their interactions with many drug products taken concurrently for other conditions. To resolve the dilemma of daily compliance and the risk of potential interactions with drugs taken orally, several non-traditional delivery systems have been developed to permit contraceptive agents and their combinations to be administered via a non-oral route, and also at a lesser frequency of administration, so as to enhance treatment compliance, maximize therapeutic outcomes, and minimize adverse effects. One typical example is the successful development of the ethinylestradiol/norelgestromin patch for achieving contraception in females via transdermal delivery. With topical application on intact skin, each patch delivers a combination of norelgestromin and ethinylestradiol for a week. With a treatment schedule of 3 weeks with a patch on and 1 week without a patch for each menstrual cycle, the ethinylestradiol/norelgestromin patch has achieved a clinical efficacy that is considered bioequivalent to oral contraceptives (with an unintended pregnancy rate of 0.8% per woman-year for the patch versus 0.1% per woman-year for the combined oral contraceptive).Stimulated by the marketing success of the ethinylestradiol/norelgestromin transdermal contraceptive patch, and a growing recognition of the therapeutic benefits realized by delivering an orally inactive progestin via a transdermal route, other transdermal drug delivery systems (DDS), such as transdermal gels and a metered-dose transdermal spray system, have also been developed. Further transdermal contraceptive patches have also been developed. One of these is similar to the ethinylestradiol/norelgestromin patch, in that it is fabricated from an adhesive polymer matrix diffusion-controlled DDS; however, it has a two times smaller patch size (to minimize localized reactions at the application site). This was made possible by substituting norelgestromin with a more potent progestin called gestodene, that has a higher skin permeation rate. The other transdermal patch that has been developed employs a microreservoir partition-controlled delivery system, to provide dual-controlled delivery of estradiol (a natural estrogen) and levonorgestrel (another potent synthetic progestin) at constant rates (zero-order kinetics). Clinical studies have demonstrated that these two new patch systems may be attractive alternative forms of contraception, since ovulation inhibition has been achieved in all subjects who wear the transdermal patch for 3 weeks, replacing it on a weekly basis.A transdermal gel has been formulated to contain elcometrine, which has a progestational potency that is 100 times that of progesterone but is orally inactive, in an alcoholic solution. Preliminary clinical studies have indicated that suppression of ovulation was achieved in the majority of subjects receiving daily application of the transdermal gel. To address the problems associated with the dosing accuracy of the transdermal gel, due to difficulty controlling the area and size of the application site, the feasibility of delivering the transdermal gel from a metered-dose transdermal spray system is currently under evaluation by the Population Council.

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC(50) value of 0.02 nm) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.

91140949 The impact of different doses of estrogen and progestin on mood and sexual behavior in postmenopausal women

This study investigated the effects of various doses of estrogen and progestin on psychological functioning and sexual behavior of 48 healthy, naturally menopausal women. Subjects were tested before treatment and then randomly assigned to 1 of 4 cyclic sequential hormone regimens for 1 yr. Groups A and C received 0.625 or 1.25 mg conjugated equine estrogen (CEE), respectively, for days 1-25 and 5 mg medroxyprogesterone acetate from days 15-25. Groups B and D were given 0.625 or 1.25 mg CEE, respectively, from days 1-25 and placebo from days 15-25. The higher dose of CEE induced supraphysiological levels of plasma estrone. Plasma testosterone levels were lower in group A when blood was sampled during days 18-20 at a time when they were ingesting both 0.625 mg CEE and 5 mg medroxyprogesterone acetate (P < 0.05), although these decreases were perhaps too trivial to have affected sexual behavior as was hypothesized. Women in group A also had more negative moods and more psychological symptomatology during treatment compared to those in jjroup D who were receiving 1.25 mg CEE and placebo (P < 0.0 L). Regardless of group, sexual desire and arousal were higher during the first 2 weeks of the treatment cycle than during wi;ek 4 when no hormones were being ingested (P < 0.05). Thesu findings demonstrate that the effects of progestin on the cential nervous system are reflected by an increase in psychological, exclusive of sexual, symptomatology and are attenuated by a higher estrogen/progestin dose ratio. (J Clin Endocrinol Metab 72: 336-343,1991) T INCREASING tendency to treat postmenopausal women with estrogen-progestin replacement regimens has prompted numerous anecdotal reports of adverse progestational effects on mood, sexuality, and physical symptoms. The observation that progestins have sedative and hypnotic properties in humans was first reported by Selye in 1942 (1). Since then, it has been established that progestins have potent anaesthetic properties and that the administration of large doses to humans induces dizziness, drowsiness (2), and deep sleep (3). 17a-Hydroxyprogesterone derivatives possess high progestational potency and exert antiandrogenic effects (4). In addition, progestins decrease brain excitability, thereby raising the electroshock seizure threshold (5), whereas estrogens have the opposite effect on brain electrical activity (6). These two steroid hormones also exert contrary effects on monoamine oxidase (MAO), the enzyme that catabolizes the neurotransmitter serotonin. Whereas estrogen decreases MAO activity in the amygReceived July 5,1990. Address all correspondence and requests for reprints to: Dr. B. B. Sherwin, Department of Psychology, McGill University, 1205 Docteur Penfield Avenue, Montreal, Quebec, Canada H3A 1B1. * This work was supported by Ayerst, McKenna, and Harrison, Inc., Canada, and Grant MA-8707 from the Medical Research Council of Canada (to B.B.S.). dala and hypothalamus (7), progestins increase it (8). Thus, with respect to postmenopausal replacement therapy, it was hypothesized :hat the influence of these two sex steroids on behavior might depend on the relative doses of each as well as the specific compounds administered. The major goals of the present study were to investigate the clinical effects of adding a 17-hydroxyprogesterone derivative, medroxyprogesterone acetate (MPA), to various doses of conjugated equine estrogen (CEE) on mood and sexual behavior of postmenopausal women within the context of a prospective experimental design. Materials and Methods

The Next Generation of Oral Contraceptives in Clinical Practice: Chairman's Summary

Oral contraceptives with low-dose formulations have mitigated cardiovascular (CV) disease risk. High-density lipoprotein (HDL) had cardioprotective properties whereas low-density lipoprotein (LDL) is positively correlated with high risk. Half of the women have a lipid problem by the age of 30. The benefits of early lipid modification will accrue later in life because of reduced CV morbidity and mortality. The evolution of OCs improved the benefit-to-risk ratio. The risk of venous thromboembolic events has dropped by lowering the dose of estrogen to 30 or 35 mcg. Beta 1 and 2 agonists to H2 receptor blockers are a promising solution to the problem of OC-related CV risk. Norgestimate a selective new progestin has strong progestational potency and antiovulatory activity. 250 mcg norgestimate (NGM) was combined with 35 mcg ethinyl estradiol (EE) in a new formulation NGM/EE and compared to a norgestrel (NG) containing compound Lo/Ovral (NG/EE). The effect of NGM/EE on ovulation suppression was equivalent to NG/EE. The LDL/HDL ratio changed as a result of the increase of HDL in NGM/EE patients and the rise of LDL in NG/EE patients. NGM/EE positively affected lipid parameters increasing HDL levels with a concomitant improvement of the LDL/HDL ratio. Obstetricians and gynecologists have the duty of assessing cardiovascular risk for the sake of the long-term health of women. Effects of lipid-lowering OCs on cardiovascular morbidity and morality are still a long way off from exact quantification. Thus the progestational selectivity of norgestimate will be a valuable alternative by obviating problems associated with oral contraception.

Determination of progestational potency: a review.

Determination of progestational potency: a review.

Comparative metabolism of 17α‐ethynyl steroids used in oral contraceptives

The metabolism of mestranol, ethynylestradiol, norethynodrel, norethindrone, ethynodiol diacetate, lynestrenol, and norgestrel is reviewed. The estrogenic components of the oral contraceptives, mestranol or ethynylestradiol, have nearly identical metabolic pathways since mestranol is rapidly and almost completely converted to ethynylestradiol The major fraction of the drugs plus metabolites is excreted in the urine as conjugated materials. All of the 17beta-ethynyl progestins reviewed follow similar metabolic paths. For three of these, norethynodrel, ethynodiol diacetate and lynestrenol, a principal metabolite is norethindrone. Biotransformation to more polar metabolites and conjugation proceed rapidly for these three precursor drugs and norethindrone. Norgestrel follows metabolic paths similar to those of norethindrone. However, the ethyl moiety at the C-13 position appears to slow the metabolism of this steroid so that biotransformation to more polar metabolites and the conjugation of these steroids does not proceed as rapidly as that of the other progestins. The high progestational potency of norgestrel may be attributed to this slow rate of biotransformation. Some of the pharmacokinetic parameters derived from the research reports reviewed here are summarized. The compounds appear to be readily absorbed, and they and their metabolites are excreted to a greater extent in the urine than in the feces.

Studies on the activities of steroidogenic enzymes in corpora lutea of early pregnant rats treated with abortifacient drugs (author's transl)

The major role of the corpus luteum is biosynthesis of progesterone. Luteal function has been investigated by following plasma progesterone concentrations and by studying ultrastructural and histochemical changes in corpora lutea. Recently, changes in enzyme activities concerned with formation and degradation of progesterone are taken into investigation in order to understand the regulation of luteal function. In rat ovaries, progestational potency of ovarian secretions has been regulated by the activity of 20 alpha-hydroxysteroid dehydrgoenase (20 alpha-HSD), Which catabolizes progesterone to 20 alpha-hydroxypregn-4-en-3-one, progestatinally inert steroid. In regressing corpora lutea, extensive conversion of progesterone to 20 alpha-hydroxypregn-4-en-3-one occurred with a marked increase in 20 alpha-HSD activity as well as a decrease in plasma progesterone concentrations. On the other hand, histochemical studies of glucose-6-phosphate dehydrogenase (G 6 PDH) and delta5-3beta-hydroxysteroid dehydrogenase (3 beta-HSD) have been investigated without any remarkable changes in corporalutea at their early stages of luteolysis. In the present study the activities of steroidogenic enzymes in corpora lutea of pregnant rats are measured after treatment with a variety of abortifacient drugs, and compared with those in corpora lutea of 1 day post partum rats which showed changes characteristic of spontaneous luteolysis. On days 7 to 9 of pregnancy, Wistar-strain pregnant rats were injected with either prostaglandin F2alpha (PGF2alpha), aminoglutethimide or clomiphene citrate (clomid). Animals were sacrificed 15 to 63 hrs. after the last injection, and implantation sites were inspected. Ovaries were removed, and corpora lutea dissected free, weighed and homogenized. The homogenate was centrifuged at 105,000g for 60 min. The supernatant solution was assayed for the activities of G 6 PDH, 6-phosphogluconate dehydrogenase (6 PGDH), malic enzyme, ATP citrate lysase, 20 alpha-HSD and pyruvate kinase. The pellet fraction was re-homogenized, and centrifugated 2,000 g for 5 min. The supernatant solution was used for the assay of 3 beta-HSD. Complete fetal resorption was observed in all rats treated with PGF2alpha, while 7 out of 15 rats (47%) treated with both PGF2alpha and LH-RH maintained pregnancy. In intact rats after treatment with both drugs, lutein cells showed ultrastructures characteristic for luteolysis, although the degree of luteolysis was greatly diminished compared with PGF2alpha-treated ones. In agreement with these ultrastructural findings, 20alpha-HSD activity in corpora lutea was maintained at a rather low level in intact rats, while it was increased moderately in aborted ones after treatment with both drugs. In PGF2alpha-treated rats, G 6 PDH activity increased to 140% and malic enzyme activity decreased to 27% of the activity in control rats. In aminoglutethimide-treated rats, the activites of G 6 PDH and malic enzyme were decreased, while 2-alpha-HSD activity was maintained at a low level...

Synthesis and biological activity of 17-esters of 6-dehydro-16-methylene-17 -hydroxyprogesterones.

Synthesis and biological activity of 17-esters of 6-dehydro-16-methylene-17 alpha-hydroxyprogesterone are presented. A systematic study of the influence of the alteration of halogen at 6 and the acyl group at 17 on the progestational and antiandrogenic activities of the resulting structures is described. A convenient general method for synthesis of all of the members of the generic family from the precursors in common is described. It is believed that 6-chloro-16-methylene-17 alpha-hydroxy-4,6-pregnadiene 17-acetate, because of its structural similarity to chlormadinone acetate and its high progestational potency, will perform as a contraceptive at perhaps a lower dose than that of chlormadinone acetate.

Progestational potency of chlormadinone acetate in the immature beagle bitch: Preliminary report

Chlormadinone acetate (CAP) and norethindrone (NET) were administered orally to immature, estradiol benzoate-primed beagle bitches. The progestational activity of these compounds was compared by measuring uterine/body weight ratios and by scoring uterine morphological responses. On the basis of uterine/body weight ratios, CAP was 225 times more potent as a gestogen than was NET. By McPhailtype scoring the potency of CAP was 62 times that of NET and by a comparative method ranking uterine morphological responses the relative progestational potency of CAP to NET was 82. It has been reported that CAP has about 5 times the progestational potency of NET in man. The present study demonstrates that there is a marked interspecies difference in the relation of these two compounds. The importance of establishing pharmacologically analogous doses (PAD) before initiating toxicity studies in experimental animals is emphasized.

Progesterone catabolism in the rat ovary: a regulatory mechanism for progestational potency during pregnancy.

Changes in rat ovarian 20α-OH-SDH3 and G-6-PDH activities as well as their intraglandular distribution during pregnancy, at parturition and during lactation have been determined concurrently with measurements of the peripheral blood and uterine tissue levels of progesterone and 20α-OH-P. In addition, effects of gonadotrophic hormones, hypophysectomy, placental dislocation and hysterectomy on the regulation of these enzyme activities have been examined. 20α-OH-SDH activity and 20α-OH-P concentrations decreased during early pregnancy as progesterone concentrations rose to a peak. At midgestation, day 7–12, a second rise in plasma progesterone occurred accompanied by an increase in 20α-OH-P. No increase in 20α-OH-SDH was evident at this time. Between days 19 and 21 progesterone levels dropped sharply coincident with a rapid rise in ovarian 20α-OH-SDH and peripheral 20α-OH-P concentration. A high positive correlation existed between plasma 20α-OH-P concentrations and ovarian 20α-OH-SDH activities. Uterine and placental steroid concentrations reflected the fluctuations seen in plasma steroid levels; however, progesterone, not 20α-OH-P, appeared to be preferentially accumulated in uterine tissue. Involuting corpora lutea present during early pregnancy gave an intense histochemical reaction for both 20α-OH-SDH and G-6-PDH, but only G-6-PDH was present in corpora lutea of pregnancy, thecal cells and interstitial tissue. At midpregnancy G-6-PDH distribution was unaltered except for its disappearance from involuting corpora lutea. 20α-OH-SDH was not detectable histochemically during midgestation. On day 19 20α-OH-SDH activity developed in small loci distributed randomly in some corpora lutea of pregnancy and became uniformly distributed within all corpora by day 21. Enzyme activity increased logarithmically during this period. Hypophysectomy did not alter the rate of enzyme increase, but delayed the time of initiation about 4 hr. Luteinizing hormones (LH and HCG) administered at midpregnancy as well as total placental dislocation and hysterectomy increase 20α-OH-SDH and G-6-PDH activities. LtH administration following hysterectomy inhibited the increases in enzyme activity. Ovarian 20α-OH-SDH in suckling mothers was only 50% of that in mothers deprived of their litters. It is concluded that progesterone catabolism to 20α-OH-P constitutes a normal regulatory mechanism for reducing the progestational potency of rat ovarian secretions during pregnancy, that ovarian 20α-OH-SDH and G-6-PDH activities are under gonadotrophic hormone regulation, and that increased 20α-OH-SDH activity provides an index of the luteolytic process. (Endocrinology82: 844, 1968)

Structure-function relationships of various steroids relative to induction of a specific oviduct protein (Avidin).

Progesterone induces the synthesis of the specific protein avidin in the oviducts of chicks which have received prior estrogenic stimulation. This system permits the examination of structure-function relationships of various steroids relative to their capacity to induce synthesis of a specific physiological protein. No absolute structural requirements could be elucidated, but activity in this system correlated best with the progestational potency of the steroids tested. The marked ability of the nonprogestational, antiestrogenic compound, allopregnane- 21-ol-3,20-dione, to stimulate avidin synthesis and the known antiestrogenic activity of potent progestins would allow for the possibility that induction capacity may best parallel antiestrogenic potency. (Endocrinology81: 677, 1967)

Estrogen antagonisms: relationship between estrogen antagonistic and progestational potencies of delta-4-3-oxosteroids.

The progestational (Clauberg) and anti-estrogenic (mouse vaginal smear) potencies of various A-3-oxosteroids are compared. The ratio anti-estrogenic potency/ progestational potency varies from 0.1 to 85, indicating that there is no necessary correlation between these parameters of steroid action.

A new progestogen: The 18‐homologue of norethisterone

A new agent with progestational, anabolic, and antiestrogenic properties in man is the 18‐homologue of norethisterone. On clinical examination it proved to be more potent than norethisterone (17‐ethinyl‐19‐nortestosterone). The progestational potency was considered to be quite high since as little as 1.25 mg. given with 100 μg of ethinyl estradiol delayed the onset of menses in 100 per cent of the trials. Like norethisterone, anabolic and mildly androgenic characteristics were in proportion to doses. The drug was markedly antiestrogenic and readily neutralized the effect of endogenous estrogens on the vaginal mucosa of children with precocious puberty and of menopausal women with evidence of persistent estrogenic activity. Because of its multifaceted properties, the 18‐homologue of norethisterone may be useful in the management of endometriosis and also gynecomastia in adolescent males.

RELATIONSHIP BETWEEN PROGESTATIONAL ACTIVITY AND CHEMICAL STRUCTURE OF SYNTHETIC STEROIDS.

SUMMARY Forty-two synthetic steroids have been studied for which certain relationships between chemical structure and progestational activity could be established. Thus, unsaturation and esterification in pregnane derivatives enhances progestational potency. Of the 4-dehydro derivatives, the 6α-CH3 and the 6α-fluoro compounds were the most active. Progestational potency on oral administration was increased in the 4-hydroxy derivatives. In the group with the 1:4-dehydro configuration, the basic activity of the parent compound was increased only by the introduction of a 6α-chloro or fluoro group. The 4:6-dehydro derivative showed an increase in potency on oral administration of about the same extent on introduction of a 6-chloro, a 6-fluoro or a 6:16α-dimethyl group. Only in the group of pregnane derivatives did changes of the parent molecule lead to a considerable increase in potency to inhibit ovulation. Since the maintenance of pregnancy in spayed animals is a parameter of progestational activity, it is felt that the results in animals are difficult to compare with those in female patients.

EFFECT OF 7-ALPHA-METHYLATION ON BIOLOGICAL ACTIVITIES ON NORETHINDRONE.

SummaryA very substantial increase of oral gonadotropin inhibiting (34 X), pregnancy inhibiting (10 X) and uterotropic (24 X) potencies was observed for 7α-meth-y1-17 α-ethynyl-19-nortestosterone (U-13851) compared to 17-ethynyl-19-nortestosterone (norethindrone) even though progestational potency was not enhanced. Although anabolic and androgenic properties are greatly increased in some 7α-methyl derivatives of testosterone and 19-nortestosterone, U-13851 did not appear to produce a typical androgenic response in laboratory tests.The authors wish to express their appreciation to J. I. Northam for statistical analysis of data and to J. C. Cornette and A. D. Forbes for technical assistance.

Induction of rat ovarian 20α-hydroxysteroid dehydrogenase activity by gonadotrophic hormone administration

The increased activity of rat ovarian 20α-hydroxysteroid dehydrogenase observed during proestrus and estrus results in an increased secretion of the biologically weaker or impotent steroid, 20α-hydroxypregn-4-en-3-one, from the gland. The decreased activity of this enzyme during pseudopregnancy allows the progestational potency of the ovarian secretion to rise commensurate with the need. The present study, performed on hypophysectomized prepubertal female rats, was designed to study gonadotrophic hormone action responsible for regulation of 200-hydroxysteroid dehydrogenase and glucose-6-P dehydrogenase activities. Both enzyme activities correlate positively with the process of interstitial cell and thecal cell luteinization achieved either by HCG administration or by simultaneous administration of FSH and LH. Levels of glucose6-P debydrogenase normally present in immature or adult rats are in excess of those required for estrogen biogenesis.

3β-hydroxy-6α-methylpregn-4-en-20-one

The title compound has been synthesized by an established route and also by a sequence using the Serini reaction. This compound has about twice the progestational potency of progesterone by injection and is anti-estrogenic. 20-Ethylenedioxy-6α-methylpregn-4-en-3-one and 20-ethylenedioxy-6α-methylpregn-4-3β-ol acetate possess both anti-estrogenic and anti-androgenic activity in the testosterone-stimulated castrated mouse. 3β-Hydroxy-6α-methylpregn-4-en-20-one acetate was anti-androgenic when inuncted on the testosterone-stimulated chick comb.