19-norprogesterone Derivatives Research Articles

Evaluations of memory, anxiety, and the growth factor IGF-1R after post-surgical menopause treatment with a highly selective progestin

Progestogens are a key component of menopausal hormone therapies. While some progestogens can be detrimental to cognition, there is preclinical evidence that progestogens with a strong progesterone-receptor affinity benefit some molecular mechanisms believed to underlie cognitive function. Thus, a progestin that maximizes progesterone-receptor affinity and minimizes affinities to other receptors may be cognitively beneficial. We evaluated segesterone-acetate (SGA), a 19-norprogesterone derivative with a strong progesterone-receptor affinity and no androgenic or estrogenic-receptor activity, hypothesizing that it would enhance cognition. Middle-aged rats underwent Sham or Ovariectomy (Ovx) surgery followed by administration of medroxyprogesterone-acetate (MPA; used as a positive control as we have previously shown MPA-induced cognitive deficits), SGA (low or high dose), or vehicle (one Sham and one Ovx group). Spatial working and reference memory, delayed retention, and anxiety-like behavior were assessed, as were memory- and hormone- related protein assays within the frontal cortex, dorsal hippocampus, and entorhinal cortex. Low-dose SGA impaired spatial working memory, while high-dose SGA had a more extensive detrimental impact, negatively affecting spatial reference memory and delayed retention. Replicating previous findings, MPA impaired spatial reference memory and delayed retention. SGA, but not MPA, alleviated Ovx-induced anxiety-like behaviors. On two working memory measures, IGF-1R expression correlated with better working memory only in rats without hormone manipulation; any hormone manipulation or combination of hormone manipulations used herein altered this relationship. These findings suggest that SGA impairs spatial cognition after surgical menopause, and that surgical menopause with or without progestin administration disrupts relationships between a growth factor critical to neuroplasticity.

Estro-progestin and progestogen intake: What's the impact on hysteroscopic imaging?

In current literature there is no report aimed to evaluate the effects of exogenous steroids on hysteroscopic imaging. To evaluate the hysteroscopic features of endometrium in women undergoing female hormones administration. We reviewed video-records of hysteroscopies carried-out in women taking estro-progestins (EP), progestogen (P) and Hormonal Replacement Therapy (HRT). All women underwent biopsies resulting in atrophic, functional, or dysfunctional pathological reports. Description of hysteroscopic pictures related to each schedule of therapy. The study included 117 women. We evaluated 82, 24 and 11 women treated by EP, P and HRT, respectively. In EP users, imaging indistinguishable from physiological pictures was found when high oestrogen dosage and low-potency progestogen as 17-OH progesterone derivatives were administered. By enhancing progestogen potency with 19-norprogesterone and 19-nortestosterone derivatives we observed a promotion of progestogen differentiation such as polypoid-papillary pseudo-decidualisation, spiral artery differentiation, inhibition of gland-proliferation and endometrial atrophy. In P users we distinguished two patterns, depending on continuous or sequential schedules. Continuous therapy resulted in atrophic or proliferative-secretory features whereas sequential ones led to endometrial overgrowth reflecting stromal pseudo-decidualisation. Women undergoing HRT showed atrophic features in combined continuous and polypoid overgrowth in sequential schedules. In women taking Tibolone we found pictures ranging from atrophic to hyperplastic appearances. Exogenous steroids lead to significant endometrial moulding. Depending on schedule, hysteroscopic-view appears predictable and often showing overgrowths mimicking proliferative pathologies. In this case biopsy is recommended but in common practice physicians should gain awareness with hysteroscopic pictures induced from hormone administration. Systematic assessment of hysteroscopic pictures during estro-progestins intake.

Sex differences in the cerebroprotection by Nestorone intranasal delivery following stroke in mice

Our previous studies showed that intranasal delivery of progesterone offers a good bioavailability and neuroprotective efficacy after experimental stroke. We have also demonstrated that progesterone receptors (PR) are essential for cerebroprotection by endogenous progesterone and by progesterone treatment. The identification of PR as a potential drug target for stroke therapy opens new therapeutic indications for selective synthetic progestins. Nestorone® (16-methylene-17α-acetoxy-19-nor-pregn-4-ene-3, 20-dione, also known as segesterone acetate) is a 19-norprogesterone derivative that more potently targets PR than progesterone. The objective of this study was to evaluate the cerebroprotective efficiency of intranasal administration of Nestorone after middle cerebral occlusion (MCAO) in mice. We show here that intranasal administration is a very efficient route to achieve a preferential delivery of Nestorone to the brain and confers a slow elimination and a sustained bioavailability. Furthermore, intranasal administration of Nestorone (at 0.08 mg/kg) improved the functional outcomes and decreased the ischemic lesion in male but not in female mice at 48 h post MCAO. Use of PRNesCre mice, selectively lacking expression of PR in neural cells, and their control PRloxP/loxP littermates showed that the cerebroprotective effects of Nestorone in male mice depended on neural PR as they were not observed in PRNesCre mice. Our findings show that intranasal delivery of Nestorone may be an efficient strategy to promote recovery after stroke in males and confirm the key role of PR in cerebroprotection. Furthermore, they point to sex differences in the response to Nestorone treatment and emphasize the necessity to include males and females in experimental studies.

Bone turnover markers in women participating in a dose-finding trial of a contraceptive vaginal ring releasing Nestorone and estradiol

ObjectiveTo evaluate changes in the bone turnover markers CTx and P1NP during 6 months' use of novel continuous contraceptive vaginal rings delivering Nestorone (NES) 200 mcg/day and three doses of estradiol (E2) (10, 20, and 40 mcg/day). Study designThis randomized trial enrolled 189 women who used two consecutive vaginal rings over 180 days. Frequent blood sampling permitted analysis of NES, E2, CTx and P1NP concentrations. The bone-turnover marker analyses included only women with complete sampling and excluded women with characteristics that might interfere with accurate measurement of bone markers such as afternoon sampling, poor ring compliance or recent pregnancy. We evaluated the change from baseline to 6 months in CTx and P1NP, stratified by ring dose and by average circulating E2 concentrations. ResultsOne hundred fifty-one women completed the study, and 82 women had complete data available for the bone marker analyses; the three dosage groups were balanced with regard to baseline characteristics. E2 concentrations remained low throughout treatment, regardless of which dose ring the participant used. Individual CTx changes from baseline averaged 27±56% (p<.01). Similarly, individual P1NP changes averaged 11±33% (p=.04). These increases were within the premenopausal reference ranges, and unrelated to treatment dose or to circulating E2 concentrations. ConclusionsThe low E2 dose of these rings was associated with low E2 concentrations and modest increases in serum bone turnover makers. Because we have only 6-month bone turnover markers and no direct evidence of bone loss or bone density change, these results must be interpreted with caution. ImplicationsNestorone, a 19-norprogesterone derivative, leads to complete ovarian suppression, which should yield excellent contraceptive effectiveness. To prevent potential adverse effects on bone, the NES contraceptive ring should be combined with higher doses of E2 than were assessed in this study.

Creativity and individuality in matters of hormonal contraception

The relevance of the discussion about therapeutic and preventive effects of combined oral contraceptives is caused to the fact that their impact is quite often the primary motivation for the appointment and intake the drugs. “Therapeutic portrait” of the hormonal contraceptive is mainly determined by component of progestin. Knowledge and ability to use the variety of pharmacological effects, metabolic characteristics of progestins and application regimens of combined oral contraceptives allows to achieve the maximum benefit from the appointment of the drug and increases the number of adherents of hormonal contraception among patients and doctors. The authors reveal the possibility of a creative approach to the appointment of combined oral contraceptives on the example of the combination of 30 mcg of ethinyl estradiol and 2 mg of dienogest, which unites the positive properties of 19-nor progestins and progesterone derivatives. A feature of dienogest is high selectivity for the progesterone receptors, absence of estrogenic, anti-estrogenic and androgenic properties, metabolic neutrality, slight suppression of gonadotropin secretion, pronounced anti-proliferative effect on the endometrium. This allows to recommend the preparation containing 2 mg of dienogest and 30 mcg of ethinyl estradiol for contraception of conditionally healthy women during the whole reproductive period, without fear to cause hormonal or metabolic disorders, weight gain, decrease of libido. Non-contraceptive benefits of this combination make it preferable for women who suffer from dysmenorrhea, endometriosis, acne, chronic abnormal uterine bleedings. The decision to choose one or another of drugs is taken individually in each case, taking in attention the severity of clinical manifestations, concomitant somatic and gynecological pathology, previous experience and expectations of patients. However, great importance in the formation of adherence to therapy, particularly in respect of long-term use of schemes, has a price of hormonal contraceptive. The absence of any significant differences in the profiles of the solubility and bioavailability of the generic zhastinda (Alvogen) and original drug allows to reckon them as bioequivalent and makes dienogest in combination with ethinyl estradiol the most available drug for the consumer.

Reprint of Pharmacological profile of progestins

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several newprogestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17α-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone® is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.

Reprint of Classification and pharmacology of progestins

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17α-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Structure–activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay

The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure–activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for individual steroids by their progestin bioactivity. 17α-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17β-substituents were strong progestins but generally weak androgens. 17α-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17α-ethynyl group of each of these progestins produces 17α-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17α-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.

Routes of delivery for progesterone and progestins

The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies.

Pharmacological profile of progestins

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17α-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone ® is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.

Classification and pharmacology of progestins

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17α-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Development of the selective progesterone receptor modulator CDB-2914 for clinical indications

CDB-2914 (17 α-acetoxy-11 β-[4- N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) is a 19-norprogesterone derivative that acts as an antagonist in progesterone-responsive tissues. It binds to progesterone receptors A and B with high affinity. After oral dosing in humans, CDB-2914 serum levels peak at 60–90 min. CDB-2914 binds to serum proteins and is cleared slowly. Doses of 1, 10 and 50 mg exhibit proportional increases in peak serum levels, but serum levels from higher doses, 100 and 200 mg, are not dose-dependent, suggesting saturation of carrier sites. The biological effects of CDB-2914 vary according to time of the menstrual cycle that the drug is given. In the mid-follicular phase, CDB-2914 (50 mg) inhibits follicular development and delays ovulation and menses. At 100 mg, in some cases the original follicle ceases development and a new follicle is recruited. Endometrial maturation is delayed at all doses tested (10, 50, 100 mg). Given at mid-luteal phase, there was a dose-dependent effect on menses, with higher doses (100–200 mg) resulting in earlier menses. On average, CDB-2914 tends to lengthen the menstrual cycle by ∼1–2 days although the amount of delay varies with timing in the menstrual cycle and dose.

Propriétés antigonadotropes d'un progestatif norprégnane : l'exemple du nomégestrol acétate

The antigonadotropic activity of progestins, progesterone and 19-norprogesterone derivatives, is generally used in clinical practice to treat hyperestrogenic symptoms and to provide a contraceptive effect in women with intolerance to exogenous estrogens. Our purpose was to review data from clinical pharmacological trials and from efficacy and/or safety clinical studies on progestin antigonadotropic properties with the example of nomegestrol acetate administered at the dose of 5 mg daily during 20 or 21 days per cycle. The antigonadotropic effect was shown by the effect on gonadotropins: in normally cycling premenopausal women, gonadotropin ovulatory peak was constantly inhibited, LH secretion was decreased and FSH increase at the end of the control cycle was inhibited by nomegestrol acetate ( n = 5). Moreover, LH basal levels, LH response to exogenous GnRH and aeras under the curves (AUC) of LH pulsatile profile were decreased in the treated cycle ( n = 11) compared to the control cycle. For both LH and FSH, the basal levels, the response to GnRH and the AUC of pulsatile profile were decreased by nomegestrol acetate compared to placebo in postmenopausal women; moreover, the frequency but not the amplitude of LH pulses was decreased. Depending on the woman's ovarian functional status, the effects of nomegestrol acetate on FSH were divergent (FSH increased before menopause and decreased at postmenopause), perhaps due to experimental conditions or a direct effect on the ovary. In postmenopausal women, the action of nomegestrol acetate on gonadotropin secretion was not modified by flutamide, a pure antiandrogen; this suggests that the antigonagotropic activity of the progestin is not mediated through the androgen receptor and it acts probably through the progesterone receptor. This antigonadotropic effect had an impact on ovarian function: in premenopausal women on nomegestrol acetate ( n = 21), progesterone secretion was inhibited attesting to the absence of corpus luteum, the pre-ovulatory peak of estradiol was inhibited and plasma estradiol concentrations were decreased. The antigonadotropic activity of nomegestrol acetate results in reinforcement of its antiestrogenic activity, particurlarly on the endometrium and enables to treat the frequent clinical hyperestrogenic symptoms of the perimenopause without negative metabolic or hemostatic effects. In the efficacy and/or safety studies, no pregnancy was observed with nomegestrol acetate administered in antigonadotropic sequence, during 1355 treated cycles and the hormonal data ( n = 205) were in agreement with the antigonadotropic effects of the progestin demonstrated in the clinical pharmacological studies. Furthermore, at the same dose and sequence, nomegestrol acetate, in addition to its inhibitory effect on ovulation, induces changes in the endometrium rendering it unable to implantation and in the cervical mucus to rendering it hostile to spermatozoa migration. However, it must be emphasized that data from experimental conditions required for the calculation of the Pearl Index are not available and therefore there is no legal claim for “contraception”.

Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women.

This study aimed to assess the changes in vertebral bone mineral density (BMD) after cessation of hormone replacement therapy (HRT) in postmenopausal women who had been treated on a long-term basis. Fifty healthy postmenopausal women who had been followed both during the course of HRT and after cessation of treatment in our menopause clinic were included in this study. All women had started HRT within the first 3 years after the postmenopause and had received HRT (either 1.5 mg/day of 17 beta-estradiol given percutaneously or 50 micrograms/day of 17 beta-estradiol given as a transdermal patch, combined in all women with natural progesterone or a 19-norprogesterone derivative) for a mean 5 +/- 2.4 years. In all women, vertebral BMD was assessed during the course of HRT up to the last 6 months before estrogen withdrawal, then at least once within the first 18 months after cessation of treatment. Of the initial population, 30 women were additionally reviewed later on and up to 8 years after cessation of treatment (mean duration of follow-up for the whole population: 3.9 +/- 1.7 years). Rates of changes in vertebral BMD were compared with those determined in a group of healthy untreated women who had been followed within the first years of postmenopause during the same time period as the study population. In the study group, bone loss was found to accelerate within the first 2 years after HRT withdrawal and the annual rate of loss was identical to that which occurs within the first 2 years of postmenopause in untreated women (-1.64% +/- 1.3% vs -1.52 +/- 0.9%, NS). Beyond this first 2-year time period, the annual rate of bone loss decreased as a function of time following cessation of treatment, as was observed following the menopause in untreated women (between 3 and 5 years: -0.83% + 1.35% in the study group vs -0.70% +/- 0.8% in the control group, NS). On average, 3 years after cessation of HRT mean vertebral BMD when expressed as a Z-score was significantly higher (-0.13 vs -0.89, p < 0.01) than at baseline, before HRT was started, which suggested a lasting beneficial effect on bone mass. However, even though our findings do not support the hypothesis that bone loss might continue to be accelerated several years after cessation of treatment we cannot fully address the question as to whether any residual benefit on bone mass over a longer period of time may be observed. In conclusion, the pattern of bone loss observed after cessation of estrogen therapy was found to be comparable to that which occurs in younger women within the first years after the menopause. Such a pattern needs to be kept in mind when the decision to stop HRT is taken, especially in women who were given HRT to prevent osteoporosis. The issue of assessing their risk of fracture several years after cessation of treatment thus needs to be addressed.

Cardiovascular risk factors and combined estrogen-progestin replacement therapy: a placebo-controlled study with nomegestrol acetate and estradiol

To assess the effects of oral E2 replacement therapy combined with nomegestrol acetate, a 19-norprogesterone derivative, on cardiovascular risk factors. A double-blind randomized prospective study comparing the effect of a placebo and two oral E2-nomegestrol acetate combinations (1 mg-2.5 mg and 1.5 mg-3.75 mg) over a three-cycle trial. Department of Internal Medicine and Nutrition, Hotel-Dieu, Paris, France. Fifty-seven nonhysterectomized women with natural menopause. Blood pressure, renin substrate, glucose, total cholesterol, high-density and low-density lipoprotein cholesterol, triglycerides, apoproteins A1 and B, lipoprotein(a), antithrombin III, fibrinogen, plasminogen, prothrombin fragment 1 + 2, protein C, and total and free protein S. Both treatments significantly reduced menopausal complaints, total cholesterol, low-density lipoprotein cholesterol and lipoprotein(a). Treatment with the 1.5 mg-3.75 mg combination resulted in a significant increase in apolipoprotein A1. No significant change were observed in other parameters. Sequentially combined with oral E2 in hormone replacement therapy, nomegestrol acetate had favorable effects on plasma lipids and lipoproteins. This nonandrogenic progestin decreased lipoprotein(a) levels as observed previously with medroxyprogesterone acetate combined with conjugated equine estrogens.

Nomegestrol acetate, a clinically useful 19-norprogesterone derivative which lacks estrogenic activity

The estrogenic activity of various 19-norprogestin derivatives has been identified by several laboratories. We have previously hypothesized that the estrogenic activity of these compounds stems from the absence of a methyl group at the 19 position, as various progestins that have a methyl group at this position are not estrogens. To test this hypothesis more directly, we now compare the progestin megestrol acetate against its 19-nor analogue nomegestrol acetate. We also compare these compounds to known estrogens (estradiol, norgestrel, RU486) as well as compounds known to be devoid of estrogenic activity at concentrations as high as 10 −6 M (medroxyprogesterone acetate, R5020, ICI 182780). In growth assays using the MCF-7 and T47D:A18 human breast cancer cell lines, we find that only estradiol, norgestrel and RU486 stimulate proliferation, and this effect can be blocked by the pure antiestrogen ICI 182780. Furthermore, in transient transfection studies using a luciferase reporter construct containing three tandem copies of the Xenopus vitellogenin A 2 estrogen response element, estradiol, norgestrel and RU486 can stimulate transcription, while none of the other compounds act as estrogens. Transcriptional stimulation by the estrogenic compounds can be blocked by ICI 182780. Our results demonstrate that the lack of a 19-methyl is not the major determinant for estrogenic activity in 19-norprogestins. We suggest that the 17-hydroxyl group more accurately defines estrogenic action.

Orally active steroidal ovulation inhibitors in the adult estrus rabbit

Orally administered 19-norprogesterone derivatives and selected 3-deoxy steroids have been studied in a rabbit anti-ovulation test. Compared to norethisterone the 3-deoxy steroids lynestrenol, allyestrenol and ethylestrenol were 300, 33 and 100% effective. Removal of carbon 19 from the progesterone and 17α-acetoxyprogesterone resulted, in ten to twenty-fold, gains in activity. Two 6, 16α-dimethylated. C 21 steroids also exhibited, relatively high antl-ovulatory activity.