19-nortestosterone Derivatives Research Articles

Oral contraceptives and the liver.

This paper is a general review of recorded adverse effects of oral contraceptives on the liver. An attempt is made to emphasize metabolic aspects which could explain the physiopathology. Thrombosis of the hepatic veins is not considered as this complication is thought to be related to other venous thrombosis. Between 1955 and 1970 about 300 cases of jaundice were reported among an estimated 12 million women using oral contraceptives. High incidences were reported in Sweden (1 in 4000) and Chile. Elsewhere 1 in 10000 cases were average. Jaundice has usually come in the first 3 months of oral contraceptive use. Digestive disorders and pruritis precede it. Adverse effects have disappeared on stopping the drug. The jaundice has been of mixed cholestatic and cytotoxic type with serum bilirubin rarely exceeding 10 mg per 100 ml and usually of the conjugated form. Alkaline phosphatase is moderately increased. Serum transaminase levels may rise to 100 or 200 Reitman-Frankel units or more remain high longer than serum bilirubin but may subside even if hormone therapy is continued. Serum choesterol rarely is increased. Flocculation tests are usually negative and the prothrombin time is normal. The histological appearance is that of intrahepatic cholestasis with canalicular and hepatocellular bile stasis. Lesions seen under the electrong microscope are not specific. Bromsulphalein (BSP) retention is frequently found and depends upon the dose of hormone used. These changes resemble those observed in pregnant women and recurrent jaundice of pregnancy is frequently noted in the past history of women with oral contraceptive jaundice. Pregnancy jaundice is considered to be an individual reaction to the secretion of placental hormones similar to the estrogen and progesterone administered in contraceptives. There may be hereditary disposition. On the whole the estrogens or their metabolites are responsible for cholestasis. There is a relationship between the chemical structure of the estrogens and their cholestatic effect. Only estrone and 17-alpha-ethinyl-substituted estrogens seem to definitely reduce bile flow. The progestogens used in oral contraceptives are either derivatives of 19-nortestosterone or derivatives of progesterone which are metabolized mainly in the liver. On the whole oral contraceptives do not cause severe liver disturbance and the abnormalities they do cause do not generally have any clinical consequences. Contraindications are not clear. They should not be used in women with previous recurrent jaundice or pruritus in pregnancy and a period of 6 months after infectious hepatitis is recommended before starting oral contraceptives. They also should not be used when there is preexisting chronic liver disease.

The effects of some progestational steroids on pubertal ovulation in the rat

Fifteen progestational steroids, including many of the compounds which are currently employed clinically as components of oral contraceptive preparations, were tested for ability to suppress pubertal ovulation in the rat. All of the compounds tested, except ethynodiol diacetate, inhibited initial ovulation. The steroids tested could be divided into two groups based upon their effects on uterine weight. The pregnanes and dimethisterone decreased uterine weight, while the nortestosterone derivatives increased the weight of the uterus. Compound effects on ovarian weight and body weight gain are also reported.

Developments in steroidal hormonal contraception.

The steroidal contraceptive agents in widest use are the estrogens ethynyloestradiol and its 3-methyl ether. The synthetic progesterones used in oral contraceptives are derivatives of 19-nortestosterone or 17 alpha hydroxyprogesterone. The estrogens suppress ovulation possibly by interfering with the preovulatory luteinizing hormone (LH) peak. The progesterones exert their effect on the cervix endometrium and fallopian tubes. They cause histological changes in the endometrium which probably interfere with endometrial secretions. The use of contraceptives alters the balance of endogenous hormones in the user by changing the hypothalamic-pituitary-gonadal feedback hormone. Toxic effects include the temporary minor side effects which may effect acceptance and longer term effects such as hepatic function thromboembolism and carbohydrate metabolism.

Oestrogens and thromboembolism.

It is suggested that research linking combined oral contraceptives with thromboembolism fails to specifically incriminate estrogens rather than progestogens as the responsible agent. Dosage may be a relevant factor. One study (Daniel Campbell and Turnbull) found that a regimen of diethylstilbestrol in doses of 30-60 mg daily for 3 days followed by 20 mg daily for a final 3 days significantly increased the risk of embolism in the puerperium. This is a total dosage of 150-240 mg over 6 days while a total of only 75 mg over a period of 9 days is recommended by another authority (Martindale) for suppresion of lactation. 1 mg of diethylstilbestrol has been quoted as being equivalent in potency to .05 mg of ethinylestradiol and contraceptive use of the latter drug for 6 days would total only .60 mg. Studies reporting adverse effects of the pill on glucose metabolism and blood chemistry were based almost exclusively on combined oral contraceptives containing 19 nortestosterone derivatives which are known to have certain androgenic and anabolic properties. Conclusions drawn about combined oral contraceptives inaccurately determine the relative effects of their components.

Oral contraceptives and thyroid function tests: the role of progestogens.

8 young women and 23 geriatric patients treated with progestogen estrogen and oral contraceptives (OCs) at different time periods were studied to elucidate the effect of OCs on thyroid indices. The progestogens were derivatives of 19-nortestosterone and 17-alpha-acetoxyprogesterone and the amount given was equal to or less than that present in the OCs. Protein bound iodine triiodothyronine resin uptake and electrophoretic index were studied. All 3 parameters demonstrated considerable deviation from pretreatment levels which are characteristic for estrogen intake e.g. hig PBI and EI low uptake. With the exception of norethynodred no progestogens induced a response resembling the action of estrogen. No progestogens exerted a synergistic effect on estrogen when taken in combination. It is concluded that estrogen is the only component in OCs causing different thyroid function test results.

Studies of the so-called virilizing effects of steroids in female rat fetuses.

Twelve compounds, composed of C18, C19 and C21 steroids, were studied for their effect upon the differentiation of the secondary sexual structures in female rat fetuses. It was shown that androgens, estrogens and steroids with anti-estrogenic activity behave differently. Compounds with androgenic and/or estrogenic side-effects behave partly as androgens and/or as estrogens; as, for example, C17-alkylated derivatives of 19-nortestosterone. Changes induced by pregnane derivatives are related to the antiestrogenic potency of the steroid. Substitutionfor the neutralized endogenous estrogen by exogenous estradiol prevents the changes caused by steroids with the anti-estrogenic activity. Thus, the combination of MAP with estradiol inhibited completely changes usually observed in female rat fetuses when MAP is given alone. Alterations induced by TP are only partly inhibited by the administration of estradiol. The classification of steroids according to their principal effects and by their antihormonal properties...

Effectiveness of topical application of a number of progestins

Assay of progestins using topical applications have shown Chlormadinone (6-chloro-17-hydroxypregna-4,6-diene-3,20-dione, acetate), Provera (17-hydroxy-6α-methylpregn-4-ene-3,20-dione, acetate), 19-norprogesterone (19-norpregn-4-ene-3,20-dione), a number of progesterone (pregn-4-ene-3,20-dione)' and 19-nortestosterone (17β-hydroxyester-4-en-3-one) derivatives to be highly effective in progestational and antiovulation tests in rabbits. A more limited examination of progestins in antiluteinization, ovulation facilitation or deciduoma production in rats showed 19-norprogesterone, Provera, Chlormadinone, and norethindroe (17-hydroxy-19-nor-α-pregn-4-en-20-yn-3-one) to be effective in all instances where tested. Norethindrone and 19-norprogesterone were the most effective compounds tested topically for implantation and maintenance of pregnancy in ovariectomized hamsters. Both Chlormadinone and Provera were completely ineffective at all doses tested topically in hamsters, corresponding to the very low potency of these compounds by subcutaneous injection in the same assay procedure. Progesterone exhibited reduced activity in all assay procedures when applied topically.

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.

Fluoresence of some 17α-substituted steroids in concentrated HCl

Several testosterone and 19-nortestosterone derivatives fluoresced intensely when dissolved in 37% HCl and subjected to U.V. light. Free testosterone did not fluoresce in HCl, nor did 17β-estradiol, estrone, progesterone, hydrocortisone, DOC or corticosterone. Fluorescence of 17α-methyltestosterone (MT) was unstable and a linear relationship of concentration to fluoresence was only achieved by prior treatment of the HCl reagent with an excess of non-fluorescent steroid (testosterone) or of ascorbic acid. The method can easily detect as little as 0.001 μg MT/ml concentrated HCl containing ascorbic acid. HCl-induced fluorescence may offer a practical approach to the assay of blood levels of certain 17α-alkyl or alkynyl testosterone and 19-nortestosterone derivatives.

Experimental Studies on the Steroid Aromatization

Estrogen has been well known for many years, but the entire route of its biosynthesis has not yet been sufficiently understood. It has been recently reported by Ryan that a conversion experiment was made to obtain Estrogens from some steroids in vitro by using placental aromatizing enzyme system.The principal target was the possibility of conversion of 19-Norsteroids to Estrogen. These 19-Norsteroids are of great interest as a potent progestin.Quantitative measurement of Estrogens was performed by a modified Engel's method. The ex-traction from the tissue was done by acetone. Additional washing with toluene proved more effective in cleaning out the substrate as well as in removing the impurities.Stimmel's almina column chromatography method was perfomed for the purified fractionation of EstrogenHydroquinone Kober reaction also was used for colorimetric determinaton, according to Brown's mdthod.It was learned empirically during the course of such experiments that the quality of sulfuric acid could bring about a diversity in results.Identification of steroids was made by the use of paper chromatography and its hydroquin one-Kober chromogen spectrum.The optimal pH of the reaction was about 7.0, and the optimal enzyme concentration was prepared by homogenizing the placental tissue with its 1/3 volume 0.25 Mol sucrose solution, containing 0.04 Mol nicotinamide and 0.05 Mol phosphate buffer ; the maximal amount of Estrogens was obtained after 2 hours incubation with 500/2g of substrate.Calculation of the Estorogen amounts was made according to the following equation ;CE- (S2-B2) - (So-Bo) where abbreviations CE stand for Estrogen corrected, S with 500μg of substrate, B blank without substrate, 0 and 2 indicating 0 and 2 hours of incubation period, respectively.The interconversion from Estradiol to Estrone was only demonstrable and no other interconversions were observed. Comparatively large amounts of conversion to Estrogen was observed from Androgens such as Testosterone, Δ4-Androstenedine, Dehydro-epiandrosterone, whereby the conversion ratio was almost identical in every sample. The conversion of 19-Norsteroid to Estrogen occured only from 19-Nortestosterone and not from its derivatives, including Ethinyl-nortestosterone and Methyl-nor-testosterone.Conversion ratio in the case of 19-Nortestosterone was calculated to be about 20% of that of Testosterone. Further experiments were undertaken with Ethinyl-estradiol as the substrate, and we observed no appreciable conversion to Estrogen. Likewise, conversion of Testosterone derivatives to Estrogen was not demonstrable.Of the tentative schema of conversion process from 19-Nortestosterone derivatives to Estrogen, many experiments were done, but only one route from 19-Nortestosterone to Estrone (or Estradiol) was observed and no other routes could be demonstrated.<BE> From these results, it was concluded, that the side chain of 17-position blocked the aromatization in some way. If conversion of 19-Nortestosterone derivatives to Estrogen occurs in vivo, some mechanisms other than that found in the case of Androgen in vitro seem to play a role in the conversion.

A comparative study of the metabolic fate of testosterone, 17α-methyl-testosterone, 19-nor-testos-terone, 7α-methyl-19-nor-testosterone and 17α-methyl-estr-5(10)-ene-17β-ol-3-one in normal males

Single doses of 150 mg each of five different testosterone and nor-testosterone derivatives were given to four normal male subjects and urinary excretions of 17-ketosteroids, 17-hydroxycorticoids, hydroxy steroids and phenolsteroids by Brown's method in basal urine and two 24 h post-treatment urines were measured. The conversions to Zimmerman chromogens, phenolsteroids, and hydroxysteroids were compared from the point of view of total percentage recovery of metabolites and of the rapidity of excretion. The three 17α-methylated steroids studied were metabolised to Zimmerman positive chromogens in a small but constant percentage. Testosterone and nor-testosterone had equivalent conversions to 17-ketosteroids, but the metabolites of the nor-derivatives were excreted more rapidly. The percentage recovery of metabolites appeared distinctly greater if the steroid could be easily metabolized to 17-ketosteroids. There was no phenolsteroid increase found after methyl-testosterone administration and only a small amount in one of the four subjects after testosterone. The 19-nor-steroids, on the contrary, gave rise to significant amounts. Nor-testosterone gave a strong increase in the estrone fraction. 17α-methyl-estr-5(10) ene-17β-ol-3-one and 17α-methyl-19-nor-testosterone gave increases in the estriol fraction, the former being the more potent precursor of the two.

Estrogen Antagonisms: Effects of a Series of 19-Nortestosterone Derivatives on Vaginal Changes Induced by Estrone

Summary19-Nortestosterone derivatives are antagonists of estrone in vaginal smear as well as uterine growth tests. Structure-activity relationships among these materials are largely the same in bot...

Effects of Oral 19-Nortestosterone Derivative (Nilevar) on Growth of Premature Infants

In the past, several hormones have been investigated with the hope of finding a drug which would stimulate the growth of premature infants. Injections of chorionic gonadotropin by Giuffrida, 1 in 1936, produced no effect. In 1938, Moncrieff 2 found no significant response to thyroid extracts. Estrogens have been tried 3-5 and were found to produce no constant effect. Testosterone compounds presented more promising possibilities in the early studies of Shelton 6,7 and Earle 8 ; however, later studies by Hardy and Wilkins, 9 Seitchik and Agerty, 10 and Reilly and Earle 11 found this steroid to be of no value in promoting growth of premature infants. Currently, the prevailing opinion is that no hormonal agent has proved to be of value in accelerating the rate of growth in premature infants. Recently, a new anabolic compound, 17-α-ethyl-17-hydroxynorandrostenone (Nilevar), has been synthesized. Structurally its similarity to testosterone may be represented as shown in

A myotrophic agent and gonadotrophin inhibitor, 19-nortestosterone-17-benzoate.

19-Nortestosterone-17-benzoate, a new ester of 19-nortestostcrone, has been ompared with testosterone propionate for several biological activities. Testosterone propionate and 19-nortestosterone-17-bcnzoate are myotrophic and suppress production or release of pituitary gonadotrophins. Unlike testosterone propionate, the 19-nortestosterone derivative elicits these responses in doses which do not stimulate growth of seminal vesicles and ventral prostate in rats. The uterotrophic, anti-estrogenic and progestational potenciesof the 2 androgens are similar. 19-Nortestosterone-17-benzoate is devoid of estrogenic ativity. A 6- week study in intact and castrate male and female rats demonstrate that the biologic properties of 19-nortestosterone-17-benzoate are typical of those of an androgen. This steroid was orally inactive at the dose tested.

Comparative pharmacological and clinical activity of 19-nortestosterone and 17-hydroxyprogesterone derivatives in man.

Studies on a comparison of the biological activity of 19-nortestosterone and 17-hydroxyprogesterone derivatives were presented. Pituitary inhibiting androgenic and anabolic effects induced by progestational steroids in parabiotic rats were presented. Initial studies with parabiotic rats showed that these compounds produce hypertrophy of secondary male sex glands and an increase in levator ani muscle weight. The female parabiont underwent marked precocious sexual maturation. In comparing levator ani weights the 17-ethyl and 17-methyl nortestosterones were the only compounds with marked anabolic activity. Progestational steroids were rated as good to excellent in inhibition of human ovulation and in the treatment of dysmenorrhea. It was found that 17-methyl-19-nortestosterone appeared to be undesirably androgenic in many women while 17-ethyl-19-nortestosterone showed good anabolic activity with minimal androgenic effects.

Progesterone-like activity of a series of 19-nortestosterones.

Summary1. Progestational activity of a series of 17-substituted 19-nortestosterone derivatives was investigated using both intrauterine and systemic assays in rabbits. Several of the substances studied possessed a high order of progestational activity. This activity was not related to either androgenic or anabolic potency of these compounds. Of the compounds studied 17-butenyl appeared to be the most potent, possessing about 10 times and 2 1/2 times the activity of progesterone in intrauterine and systemic assays, respectively. 2. Progesterone-like activity of these 19-nortestosterones was further demonstrated by the ability of some members of the series to maintain pregnancy in ovariectomized rabbits.