A prodrug design for improved oral absorption and reduced hepatic interaction.

A series of estradiol-17-ß esters of N-(p-sulfomylbenzamide)-amino acids were prepared and evaluated for systemic and hepatic estrogenic activity after oral administration in ovariectomized rats. The alkyl substitution at nitrogen of amino acids such as proline or N-methyl-alanine produced compounds that exhibit potent oral activity. The proline analog (EC508) was further evaluated along with 17ß-estradiol (E2) and ethinyl-estradiol (EE) and compared their effects on the uterus, angiotensin and HDL-cholesterol after oral administration to ovariectomized female rats. Orally administered EC508 produced systemic estrogenic activity 10 times greater than EE and a 100 times higher activity than E2 with no influence on levels of angiotensin and HDL-cholesterol, whereas EE and E2 reduced the HDL-cholesterol and increased the angiotensine plasma levels. EC508 might offer significant advantages in indications like fertility control and HRT based on its high oral bioavailability and lack of hepatic estrogenicity.

Synthesis and biological evaluation of 11' imidazolyl antiprogestins and mesoprogestins.

Antiprogestins with a 4' para imidazolylphenyl moiety were synthesized and their biochemical interactions with the progesterone and glucocorticoid receptor were investigated. Depending on the substitution pattern at the 17 position partial progesterone receptor (PR)-agonistic derivatives like compounds EC339 and EC336 or pure antagonists like compound EC317 were obtained. EC317 was investigated in vivo and found to be significantly more potent than RU 486 in cycling and pregnant guinea pigs. For testing the biological action progesterone receptor modulators (PRM), guinea pigs appears as a specific model when compare to pregnant human uterus. This model correlates to human conditions such as softening and widening of the cervix, the elevation of the uterine responsiveness to prostaglandins and oxytocin, and finally to induction of labor. The use of non-pregnant guinea pigs permitted the simultaneous assessment of PR-agonistic and PR-antagonistic properties and their physiological interactions with uterine and vaginal environment. These can histologically be presumed from the presence of estrogen or progesterone dominance in the genital tract tissues. The ovarian histology indicated the effects on ovulation. Corpora lutea in guinea pigs further reflects inhibitory effects of the progesterone-dependent uterine prostaglandin secretion. PRMs are initially synthesized as analogues of RU 486. They represent a heterogeneous group of compounds with different ratios of PR-agonistic and-antagonistic properties. PR-agonistic properties may be essential for uterine anti-proliferative effects. In various clinical studies these were also attributed to RU 486 or Ulipristal [1,2]. Adjusted PR-agonistic PRMs (EC312, EC313) [3] may be more effective in achieving a mitotically resting endometrium and superior uterine tumor inhibition. For the use in termination of pregnancy, progesterone-inhibitory effects are essentially needed. Even minor PR-agonistic properties compromise the therapeutic goals. Pure PR-antagonists, as EC317, clearly exceeded the gold standard RU 486 with respect to labor inducing effects. Mechanistically it is surprising that both types of compound may be potent inhibitors of ovulation.

Synthesis and biological evaluation of partially fluorinated antiprogestins and mesoprogestins.

A series of antiprogestins have been synthesized by partially fluorinating the steroid molecule in positions relevant for receptor binding. By introducing fluorine at the exo-methylene of the 17 spirofuran ring, we obtained partial agonists (mesoprogestins) with significant applications for antiproliferative and antiovulatory treatment strategies in gynecological therapy such as uterine fibroids, endometriosis and heavy menstrual bleeding. Compared to the standard drug RU486, our synthesized compounds exhibited considerable dissociation between antiprogestational and antiglucocorticoid PR receptors. Furthermore, our studies have shown that pure antiprogestins can be generated by partially fluorinating the 17 propenyl and propynl group or by substituting the 4' acetyl phenyl group in the 11 position using trifluromethyl group.

Structure-based design, synthesis and in vitro characterization of potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors based on 2-substitutions of estrone and D-homo-estrone.

In search for specific drugs against steroid-dependent cancers we have developed a novel set of potent inhibitors of steroidogenic human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1). The X-ray structure of 17beta-HSD 1 in complex with estradiol served as basis for the design of the inhibitors. 2-Substituted estrone and D-homo-estrone derivatives were synthesized and tested for 17beta-HSD 1 inhibition. The best 17beta-HSD 1 inhibitor, 2-phenethyl-D-homo-estrone, revealed an IC(50) of 15 nM in vitro. The inhibitory potency of compounds is comparable or better to that of previously described inhibitors. An interaction within the cofactor binding site is not necessary to obtain this high binding affinity for substances developed.

A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.

OBJECTIVE: To determine efficacy and safety of asoprisnil in patients with leiomyomata. DESIGN: Phase 2, multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Twenty-eight sites in the United States and 1 in Canada. PATIENT(S): One hundred twenty-nine women with leiomyomata. INTERVENTION(S): Asoprisnil (5, 10, or 25 mg) or placebo orally daily for 12 weeks. MAIN OUTCOME MEASURE(S): Uterine bleeding changes by using daily bleeding diaries, hemoglobin concentrations, dominant leiomyoma and uterus volume measured sonographically, patient-reported symptoms related to bloating and pelvic pressure, endometrial thickness and morphology, hormonal parameters, and standard safety measures. RESULT(S): Asoprisnil suppressed uterine bleeding in 28%, 64%, and 83% of subjects at 5, 10, and 25 mg, respectively, and reduced leiomyoma and uterine volumes. Median percentage decrease from baseline in leiomyoma volume was statistically significant at 25 mg compared with placebo after 4 and 8 weeks of treatment; by week 12, leiomyoma volume was reduced by 36%. There was a significant reduction in bloating with the two highest doses and in pelvic pressure with 25 mg by week 12. Asoprisnil was associated with follicular-phase estrogen concentration and minimal hypoestrogenic symptoms. CONCLUSION(S): After 12-week treatment, asoprisnil controlled uterine bleeding while reducing leiomyoma volume and the associated pressure symptoms. Asoprisnil was well tolerated.

Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs).

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.

Inhibitory effects of fluorine-substituted estrogens on the activity of 17beta-hydroxysteroid dehydrogenases.

In search for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (h17beta-HSD1) a specific group of steroids with interesting properties including novel compounds was investigated. Several estratriene derivatives with fluorine-substitution in position 17 of the steroidal scaffold were synthesised and tested in vitro towards recombinant h17beta-HSD1, 2, 4, 5 and 7. Moderate, mostly unselective inhibitors of h17beta-HSD1 and h17beta-HSD2 and a selective inhibitor of h17beta-HSD5 were identified. The structure-activity relationship with respect to inhibitory strengths and selectivity of these compounds on five h17beta-HSDs is discussed.

Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11beta-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroids, asoprisnil suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner and reduced tumor volume in the absence of estrogen deprivation. In subjects with endometriosis, asoprisnil was effective in reducing nonmenstrual pain and dysmenorrhea. Asoprisnil may, therefore, provide a novel, tissue-selective approach to control endometriosis-related pain. SPRMs have the potential to become a novel treatment of uterine fibroids and endometriosis.

Discovery, chemistry, and reproductive pharmacology of asoprisnil and related 11beta-benzaldoxime substituted selective progesterone receptor modulators (SPRMs).

Asoprisnil (J 867; benzaldehyde, 4-[(11beta, 17beta)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4, 9-dien-11beta-yl]-, 1-oxime) is the prototype of a novel class 11beta-benzaldoxime-substituted selective progesterone receptor modulators (SPRMs) and the first-in-class SPRM to reach an advanced stage of clinical development for the treatment of uterine fibroids and endometriosis. This compound was selected in a drug discovery program aimed to identify progesterone receptor (PR) ligands with predominant agonist but also some antagonist activities. The screening program included a range of receptor binding studies and a hierarchy of in vivo tests. A series of 11beta-benzaldoxime-substituted steroidal compounds exhibiting mixed PR agonist/antagonist effects were synthesized and characterized. For inclusion in this class of compounds, two methods of synthesis were developed and optimized. The 11beta-benzaldoxime-substituted SPRMs showed high PR binding affinities, reduced glucocorticoid receptor affinities compared with the antiprogestin mifepristone, marginal androgen receptor binding affinities, and no binding to estrogen receptors. Animal tests in guinea pigs (luteolysis inhibition assay) and rabbits (McPhail test) constituted the secondary screening tests. A mosaic of progesterone agonist and antagonist effects were found in various models. The most agonistic compounds were selected for further evaluation in animal models with respect to labor induction and endometrial effects. Unlike progesterone antagonists, asoprisnil and related compounds showed marginal effects on labor and parturition in guinea pigs. Proof-of-concept studies in nonhuman primates revealed endometrial antiproliferative effects of selected compounds, including asoprisnil and J 1042, in the presence of amenorrhea and follicular phase estradiol concentrations. Asoprisnil was selected for further clinical development. It shows promising results in the treatment of uterine leiomyomata and endometriosis.

The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.

BACKGROUND: Asoprisnil (J867) is a novel selective progesterone receptor modulator (SPRM) that exhibits partial agonist and antagonist activities and tissue selective effects. This double-blind, dose-escalation study was conducted to evaluate the effects of asoprisnil in 60 regularly cycling premenopausal women. METHODS: Asoprisnil or placebo was administered orally for 28 days starting at the beginning of the menstrual cycle in doses of 5 mg once daily (QD), 5 mg twice daily (BID), 10 mg QD, 25 mg QD, 25 mg BID and 50 mg BID. Within each dose group, two women were randomized to placebo and eight to asoprisnil. Progesterone concentrations indicative of luteinization were defined as at least one progesterone measurement during the luteal phase exceeding 3.5 ng/ml. RESULTS: Asoprisnil consistently prolonged the menstrual cycle at doses > or = 10 mg QD. However, the effects on luteal phase progesterone indicative of luteinization were inconsistent and lacked dose dependency. Asoprisnil suppressed periovulatory estradiol but not below follicular phase levels. No significant changes were observed in cortisol and prolactin. Asoprisnil was well tolerated. CONCLUSIONS: Asoprisnil reversibly suppressed menstruation at doses > or = 10 mg QD irrespective of the effect on luteal phase progesterone concentrations indicative of luteinization. It induces amenorrhea primarily by targeting the endometrium in the absence of estrogen deprivation.

Estrone sulfate is a major source of local estrogen formation in human bone.

Estrone sulfate (E1S) is the most abundant estrogen in the circulation of adults. The present study was undertaken to assess estrone (E1) and estradiol formation from E1S in freshly resected bone [bone fragments (BFs)] and osteoblast-like cells (hOB) cultured from BFs. Furthermore, we compared estrogen formation from E1S in rat and human osteosarcoma (OS) cell lines and that of estrogen formation from E1S with that of aromatization of androstenedione and testosterone in BFs and those from E1S and androstenedione in hOB cells. The bone used was from the head of the femur from a total of 15 women and 12 men. Steroid sulfatase activity (STA) was found, and the formation of estrone and estradiol from E1S was demonstrated. STA was similar in cells derived from BFs of men and women. STA was significantly lower in OS cell lines, compared with hOB cells. Estrogen formation from E1S in BFs was at least 20 times higher than that from androstenedione and about 50 times higher than that from testosterone. Similarly, estrogen formation from E1S in hOB cells exceeded the values derived from aromatization of androstenedione by two orders of magnitude. Based on these results, we conclude that hOB cells express the same pattern of E1S metabolism as resected bone and thus may accurately mirror the in vivo situation in man. In comparison with hOB cells, STA is fundamentally lower in widely used OS cell lines that express an osteoblastic phenotype. This shortcoming precludes their use as model cell lines to unravel STA metabolic pathways and its regulation in nontumorous bone. E1S is a major source of local bioactive estrogen formation in human bone. Because bone is highly susceptible to estrogen action, local estrogen formation from E1S may play an important role in bone maturation and homeostasis, particularly in elderly adults.

Dissecting physiological roles of estrogen receptor alpha and beta with potent selective ligands from structure-based design.

The distinct roles of the two estrogen receptor (ER) isotypes, ERalpha and ERbeta, in mediating the physiological responses to estrogens are not completely understood. Although knockout animal experiments have been aiding to gain insight into estrogen signaling, additional information on the function of ERalpha and ERbeta will be provided by the application of isotype-selective ER agonists. Based on the crystal structure of the ERalpha ligand binding domain and a homology model of the ERbeta-ligand binding domain, we have designed steroidal ligands that exploit the differences in size and flexibility of the two ligand binding cavities. Compounds predicted to bind preferentially to either ERalpha or ERbeta were synthesized and tested in vitro using radio-ligand competition and transactivation assays. This approach directly led to highly ER isotype-selective (approximately 200-fold) and potent ligands. To unravel physiological roles of the two receptors, in vivo experiments with rats were conducted using the ERalpha- and ERbeta-selective agonists in comparison to 17beta-estradiol. The ERalpha agonist induced uterine growth, caused bone-protective effects, reduced LH and FSH plasma levels, and increased angiotensin I, whereas the ERbeta agonist did not at all or only at high doses lead to such effects, despite high plasma levels. It can thus be concluded that estrogen effects on the uterus, pituitary, bone, and liver are primarily mediated via ERalpha. Simultaneous administration of the ERalpha and ERbeta ligand did not lead to an attenuation of ERalpha-mediated effects on the uterus, pituitary, and liver parameters.

The significance of the 20-carbonyl group of progesterone in steroid receptor binding: a molecular dynamics and structure-based ligand design study.

Polar functional groups in the A- and D-ring (positions 3 and 17beta or 20) are common to all natural and synthetic steroid hormones. It was assumed that these pharmacophoric groups are involved in strong hydrogen bonding interactions with the respective steroid receptors. High resolution X-ray structures of the estrogen and androgen receptors have confirmed these assumptions. Also site-directed mutagenesis studies of the human progesterone receptor (hPR) suggest an important role for Cys891 in the recognition of the progesterone 20-carbonyl group. Surprisingly, the crystal structure of the hPR ligand binding domain (LBD) in complex with progesterone suggests that the carbonyl oxygen in position 20 (O20) is not involved in hydrogen bond contacts. To investigate these surprising and contradicting results further, we performed a molecular dynamics simulation of the hPR-progesterone complex in an aqueous environment. The simulation revealed hPR-Cys891 as the sole but weak hydrogen bonding partner of progesterone in the D-ring. In contrast to the site-directed mutagenesis data a major role of hPR-Cys891 in progesterone recognition could not be confirmed. Isolated hydrogen bond acceptors, such as the prosterone O20 group, in a relatively lipophilic environment of the receptor led to a decrease in affinity of the ligand. Based on this consideration and the structure of the PR, we designed compounds lacking such an acceptor function. If the X-ray structure and the calculations were right, these compounds should bind with comparable or higher affinity versus that of progesterone. E-17-Halomethylene steroids were synthesized and pharmacologically characterized in vitro and in vivo. Although the compounds are unable to form hydrogen bonds with the hPR in the D-ring region, they bind with superior affinity and exert stronger in vivo progestational effects than progesterone itself. Our investigations have confirmed the results of the X-ray structure and disproved the old pharmacophore model for progestogenic activity, comprising two essential polar functional groups on both ends of the steroid core. The 20-carbonyl group of progesterone is likely to play a role beyond PR-binding, e.g. in the context of other functions via the androgen and mineralocorticoid receptors and as a site of metabolic inactivation.

Conception and pharmacodynamic profile of drospirenone.

Progesterone is more than a progestin. Beyond functions in cycle and pregnancy, progesterone binds with high affinity to the mineralocorticoid receptor (MR) acting as an antagonist, with obvious significance for electrolyte homeostasis, an array of MR-related functions in the circulation as well as in the CNS. Progesterone induces natriuresis at physiological concentrations. Lack of antimineralocorticoid activity with conventional progestins may account for sodium and water retention, minor elevation of blood pressure and "pill hypertension" in susceptible women on oral contraceptives. Ethinylestradiol (EE) contributes to this problem by distinct activation of the renin-angiotensin-aldosterone (RAAS) system. Drospirenone (DRSP: 6beta,7beta,15beta,16beta-dimethylene-3-oxo 17alpha-pregn-4-ene-21,17 carbolactone) is the first synthetic progestin with antialdosterone activity. DRSP and progesterone bind to PR in uterine (affinity of both is about 30% of R5020) and MR in kidney cytosol (affinity about 230 and 100% of aldosterone, respectively). Intrauterine administration of DRSP in silastic tubes induced maximum local progestational effects in rabbits. At systemic subcutaneous (s.c.) administration (McPhail-assay) full endometrial transformation was obtained at 1mg per animal per day. At 1-3mg DRSP per animal per day subcutaneously, pregnancy maintenance after ovariectomy, antiovulatory activity, and antimineralocorticoid activity were seen in the respective assays in rats. The latter activity indicates about eight-fold higher potency than spironolactone. DRSP decreased blood pressure in male hypertensive rats, whereas an increase was noted under conventional progestins. DRSP also prevented hypertension and fetal growth retardation in pregnant rats after L-NAME, an inhibitor of nitric oxide synthase. DRSP has antiandrogenic activity. Feminizing effects were recorded during sexual differentiation in male fetuses at high doses. Powerful antiandrogenic effects were also seen in gonad intact and testosterone substituted castrated male rats. The antiandrogenic potency of DRSP is superior to that of spironolactone but below that of cyproterone acetate. Endometrial transformation, inhibition of ovulation, and antimineralocorticoid, i.e. natriuretic effects and mild antiandrogenic effects were recorded at the same range of oral doses (0.5-4 mg per day) in humans. Combined with EE (3 mg DRSP+30 microg EE), DRSP provides effective inhibition of ovulation and cycle control. Body weight compared to conventional oral contraceptives was reduced. DRSP (3 mg per day+15, 20, or 30 microg ethinyl estradiol per day) prevented the mild increase of blood pressure seen under a conventional levonorgestrel-containing contraceptive and even tended to reduce pretreatment blood pressure. Studies on modulation (i.e. inhibition) of glucocorticoid effects at the MR in the CNS remain an unexplored and interesting area for research.

Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy.

Asoprisnil is a novel selective steroid receptor modulator that shows unique pharmacodynamic effects in animal models and humans. Asoprisnil, its major metabolite J912, and structurally related compounds represent a new class of progesterone receptor (PR) ligands that exhibit partial agonist and antagonist activities in vivo. Asoprisnil demonstrates a high degree of receptor and tissue selectivity, with high-binding affinity for PR, moderate affinity for glucocorticoid receptor (GR), low affinity for androgen receptor (AR), and no binding affinity for estrogen or mineralocorticoid receptors. In the rabbit endometrium, both asoprisnil and J912 induce partial agonist and antagonist effects. Asoprisnil induces mucification of the guinea pig vagina and has pronounced anti-uterotrophic effects in normal and ovariectomized guinea pigs. Unlike antiprogestins, asoprisnil shows only marginal labor-inducing activity during mid-pregnancy and is completely ineffective in inducing preterm parturition in the guinea pig. Asoprisnil exhibits only marginal antiglucocorticoid activity in transactivation in vitro assays and animal models. In male rats, asoprisnil showed weak androgenic and anti-androgenic properties. In toxicological studies in female cynomolgus monkeys, asoprisnil treatment abolished menstrual cyclicity and endometrial atrophy. Early clinical studies of asoprisnil in normal volunteers demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no antiglucocorticoid effects. Unlike progestins, asoprisnil does not induce breakthrough bleeding. With favorable safety and tolerability profiles thus far, asoprisnil appears promising as a novel treatment of gynecological disorders, such as uterine fibroids and endometriosis.

Effect of estradiol sulfamate (ES-J995) on affinity of hemoglobin for oxygen, cardiovascular function and acid-base balance in ovariectomized rats.

Oral administration of estradiol sulfamate (ES, prodrug of estradiol) leads to increased systemic and reduced hepatic effects than estradiol because ES is accumulated in erythrocytes. However, possible alterations of erythrocytic oxygen transport by intraerythrocytic ES accumulation has not been studied. Therefore, ovariectomized adult female rats (n = 58; body wt.) were randomly treated orally either with single doses (day 1) or multiple dose (days 1-4) with vehicle, with estradiol sulfamate (ES-J995, 1 mg x kg(-1) b.w.) or with estradiol (30 mg x kg(-1) b.w.). Under general anesthesia arterial blood pressure, heart rate, blood gases, and acid-base balance were measured. Hypoxia was performed by lowering the inspired fraction of oxygen from 0.35 to 0.12. In addition, individual oxygen dissociation curves and ES-J995 distribution in blood and plasma were estimated. ES-J995 was accumulated in erythrocytes by approximately 98% (P < 0.01), but oxygen transport capacity was not altered (P50: 35.6 +/- 1.0 mm Hg to 37.1 +/- 1.1 mm Hg). Blood gases and acid-base balance parameters were not altered after ES-J995 treatment under normoxic and hypoxic conditions. In conclusion, ES-J995 accumulation in erythrocytes does not alter the affinity of hemoglobin for oxygen nor any function which would indicate an impaired oxygen delivery to the body.

Effects of estradiol and estradiol sulfamate on the liver of ovariectomized or ovariectomized and hypophysectomized rats.

This study was performed to evaluate and compare the effects of estradiol sulfamate (J995) and estradiol (E2) on the hepatic levels of the estrogen receptor (ER) and its mRNA, in ovariectomized (OVX) and OVX+hypophysectomized (OVXHX) female rats and to study the effects on the liver-derived serum compounds angiotensin I, triglycerides, high-density lipoprotein (HDL) and cholesterol. ER concentrations were determined using ligand-binding assay (LBA) and enzyme immuno assay (EIA), and the mRNA levels using solution hybridization. The rats were treated orally (p.o.) or subcutaneously (s.c.) for 7 days, with treatments initiated 14 days after surgery. No differences were found in ER mRNA levels between J995 and E2 treated rats. The s.c. administered estrogens increased ER levels in OVX rats. Addition of GH+DEX to OVXHX rats restored the ER to levels above those seen in intact rats, whereas simultaneous oral treatment with E2 significantly decreased ER levels again. The s.c. treatment with either J995 or E2 limited the increase caused by addition of GH+DEX. After oral treatment angiotensin I levels were increased by E2, but not by J995, while triglycerides, HDL and cholesterol levels were decreased by oral E2, J995 showing a similar pattern but was less effective. In summary, these results on hepatic ER levels and estrogen dependent compounds produced by the liver showed that J995 has a lower impact on the normal liver functions after oral treatment than E2. Thus, J995 is a very promising substance for development of oral estrogen treatment with reduced hepatic side effects.

Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis.

Endometriosis, the presence of endometrial tissue outside the uterus, is a progressive, estrogen-dependent disease and occurs nearly exclusively in menstruating women of reproductive age. Pain syndrome, however, represents the major clinical problem of this disease, manifested as dysmenorrhea, pelvic pain, lower abdominal pain, and dyspareunia. The manifestation of the disease, that is, the pain syndrome, rather than the disease itself currently represents the major indication for both the medical and surgical therapies of endometriosis. The major drawbacks of current medical therapies of endometriosis are sometimes severe side effects. In this review, selective progesterone receptor modulators (SPRMs, mesoprogestins) as a potential therapeutic concept in endometriosis are discussed. Due to endometrial selectivity and favorable pharmacological profile, SPRMs may have advantages over the current medical treatments of this disease. Other emerging therapeutic approaches for this disease are also mentioned.