Some Biological Activities of 17-Ethynyl and 17-Alkyl Derivatives of 17-Hydroxyestrenones

Abstract

The natural hormone, progesterone, has long served as the standard for the production of endometrial changes in the uterus. In 1944 Allen and Ehrenstein' reported that norprogesterone was more active than the natural hormone, a finding that has since been confirmed by Tullner and Hertz2 Recently it has also been demonstrated that the nor derivative of ethynyltestosterone is more potent as a progestational agent than the methylated parent compound, both in animals and man.3, Studies in this laboratory have encompassed a wide variety of steroid structures. Particular attention has been paid to the study of 17-substituted derivatives of 17-hydroxyestrenones with the double bond in either the 5(10) or the 4(5) position. In the series with the double bond in the 5(10) position, the most interesting substance has been norethynodrel, which shows a mixture of both estrogenic and progestational a~tivities.~ With the double bond in the 4(5) position, estrogenic activity is absent and more nearly pure progestational effects are obtained. However, some of this latter group also have androgenic and anabolic activities.6 Inasmuch as the properties in these two series do differ, the endocrine effects of the A6(lU) compound, norethynodrel, will be discussed first, and the progestational activity of the A4(6) steroids second. MethodsProgesteronelike activity, Clauberg assay.7 Immature female rabbits weighing about 1 kg. were treated for 6 days with 5 fig. of estradiol daily. Starting on the following day they received the test compound in oil, subcutaneously, daily for the next 5 days. On the day after the last injection they were sacrificed and the uteri were fixed for later histological study. Sections of the uterus were graded from 1 to 4 on the basis of glandular development.* Further studies were conducted using the technique described by McGinty et aL9 I n this assay the compound in oil was injected into a segment of the uterus in the ovariectomized rabbit, previously primed with estrogen. Uterine sections were examined histologically and graded as above. Estrogenic activity was determined by the uterine weight technique of Rubin et in immature mice and by the vaginal smear technique of Allen and Doisy17 employing castrated rats and scoring according to the method of Biggers and C1aringbold.l' Norethynodrel Norethynodrel has four main properties: (1) It is progestational under certain conditions; (2) it has estrogenic activity; (3) it can inhibit the pro-516 Progesteronelike activity, intrauterine assay. Estrogenic activity. Saunders & Drill: 17-Ethynyl and 17-Alkyl Derivatives 517 CH 111 C FIGURE 1. Structural formula of norethynodrel.duction or release of pituitary gonadotropin; and (4) during treatment it prevents conception.Detailed data illustrating the biological activities of the pure compound, 17a-ethynyl-17hydroxy-5 (lO)-estren-3-one, called norethynodrel, are presented below.The condition of the uterus of an estrogen-primed control rabbit in the Clauberg assay is shown in FIGURE 2. Glandular crypts are lacking. ...

Effects of Norethynodrel and Mestranol on Pituitary Luteinizing Hormone in the Female Rat

“…The uterotrophic effect of this dose of norethynodrel was also negligible (Table 1 ) and it was found ineffective in altering the ovarian sensitivity to gonadotrophins (Saunders & Drill, 1958;Eckstein & Mandl, 1962). Thus, although this dose has been found incapable of exerting a signifi¬ cant peripheral action, the present study suggests that it is effective in increasing hypophysial lh stores.…”

The Influence of Norethynodrel on the Hypophysis

“…Blaquier (3 ) reported a reduction in basophils. Similar disagreement exists regarding the influence of norethynodrel on pituitary weight, no change (1,(3)(4)(5) and an increase ( 2 ) having been reported. However, the extensive evidence that norethynodrel stimulates the secretion of prolactin (6)(7)(8)(9)(10) and, depending on the dose level, either elevates the gland content of luteinizing hormone (LH) (11,12) or reduces the content ,of total gonadotropin (5) indicates that significant alteration in pituitary cytology is to be expected.…”

“…However, the extensive evidence that norethynodrel stimulates the secretion of prolactin (6)(7)(8)(9)(10) and, depending on the dose level, either elevates the gland content of luteinizing hormone (LH) (11,12) or reduces the content ,of total gonadotropin (5) indicates that significant alteration in pituitary cytology is to be expected. Determination of the pituitary cytological response to norethynodrel is of special interest because it has both progestational and estrogenic (4) properties and little is known about the combined action of naturally occurring progestins and estrogens on pituitary cells.…”

Effects of Progestogenic Substances on the Uterine Secretion of Spayed Rats Primed with Oestradiol

“…1957;Edgren et a i, 1966], On the other hand, an estrogen-like activity of some representatives of this group such as norethynodrel. norethisterone [Saunders and D rill, 1958] and lynestrenol [Desaulles and Krahenbuhl, 1964] has been demon strated by the vaginal-smear technique in rats treated both orally and parenterally, or by their influence on the weight of the uterus of mice treated s.c. [Pincus et al, 1956], Moreover, in contrast to an only slight 'phenolic conversion' of orally-administered norethynodrel [Arai et a i, 1962] and of parenterally-given norethisterone and d.l-norgestrel [Kamyab et al, 1967] in rabbits, in rats a direct metabolization of norethynodrel into I7u-ethynyloestradiol could be demonstrated [Martin et al, 1970],…”