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PubMed1964

CLINICAL AND LABORATORY ASSESSMENT OF A NEW PROGESTATIONAL AGENT.

Studies of the effects of megestrol (6-methyl, 6-dehydro, 17alpha-acetoxy progesterone) on human subjects indicated that this drug is a potent, orally effective progestational agent. The progestational effect was enhanced by estrogen. When combined with ethinyl estradiol satisfactory control of menstrual function and inhibition of ovulation were achieved. Increasing doses of this combination were effective in four patients with endometriosis. Side effects of the drug were minimal. No toxic effects on adrenal, hepatic or hematopoietic function were noted.

17-Ketosteroids↗
PubMed1977

Synthesis, antifertility activity, and protein binding affinity of 7(8 leads to 11 alpha)abeo steroids.

A series of 7(8 leads to 11 alpha)abeo steroids was synthesized by a modification of the previously described total synthesis of this class of compounds and evaluated for biological activity. In general, there was a marked reduction in the relative binding affinities of these compounds for the rabbit uterus estrogen and progestin receptor proteins. None of the compounds which were subjected to uterotropic, antiuterotropic, postcoital, progestational, antiprogestational, or antiandrogenic assays showed any significant activity.

Animals↗
PubMedDate not supplied

Vaginal cytologic evaluation as a practical link between hormone blood levels and tumor hormone dependency in exclusive medroxyprogesterone treatment of recurrent or metastatic endometrial adenocarcinoma.

In one hundred patients treated by means of one gram medroxyprogesterone a week for disseminated or recurrent endometrial adenocarcinoma, vaginal cytohormonal evaluation seemed to be an important predictive factor of hormone dependency and tumoral responsiveness to progestational therapy. Almost all 51 patients, representing the responsive group, revealed an evident drop of the Karyopyknotic Index and a complete shift to the left of the Maturation Index. Both cytohormonal and tumoral response to medroxyprogesterone seemed directly related to estrogen-progestogen interaction on a cellular level. The striking LH response in the responsive group has previously not been integrated in this mechanism of action.

Adenocarcinoma↗
PubMed1979

Plasma levels of adrenocorticotropin and cortisol in women receiving oral contraceptive steroid treatment.

The secretion rate and plasma concentration of the adrenocortical steroid cortisol is modified in subjects treated with estrogenic and/or progestational steroids. The effects of contraceptive steroids on the secretion of ACTH are poorly documented, however, In the current investigation, we found that concentrations of ACTH and cortisol in plasma obtained at 0800--0900 h from a group of women with normal cyclic menses (n = 4) ranged from 78--120 pg/ml and 77--137 ng/ml, respectively. Although significant cyclic changes in the plasma levels of LH, FSH, 17 beta-estradiol, and progesterone occurred during the ovarian cycle, no obvious cyclic fluctuations in plasma levels of ACTH or cortisol were observed. In women treated with Norinyl 1 + 80 (1.0 mg norethindrone plus 0.08 mg mestranol), plasma concentrations of LH, FSH, 17 beta-estradiol, and progesterone were significantly lower (P less than 0.001) than plasma levels of these hormones in normal women during the ovarian cycle. The mean daily plasma concentrations of ACTH were significantly lower (P less than 0.001), whereas plasma cortisol levels were significantly higher (P less than 0.001) in women treated with oral contraceptive steroids compared to the levels of these hormones in the untreated ovulatory women.

Adrenocorticotropic Hormone↗
PubMed1993

Reversal of activity profile in analogs of the antiprogestin RU 486: effect of a 16 alpha-substituent on progestational (agonist) activity.

16 alpha-Ethyl-17 beta-acetyl substitution in the D-ring of steroids having an 11 beta-aryl-4,9-dien-3-one structure resulted in compounds with strong progestational activity. These compounds caused endometrial proliferation in the uterus of estrogen-primed rabbits with a potency greater than that of progesterone and had no detectable antiprogestational activity in this model. This is in stark contrast with the marked antiprogestational activity in rabbits, rats and humans reported for most 11 beta-aryl-4,9-diene-3-keto steroids such as RU 486 and its 17 beta-acetyl-17 alpha-acetoxy analog, 17 alpha-acetoxy-11 beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene- 3,20-dione. Examination of structure activity relationships in combination with computer aided molecular modelling suggests that a binding interaction of the 16 alpha-ethyl group with the progesterone receptor (PR) or the PR-progestin response element complex may play the major role in this reversal of activity profile.

Animals↗
PubMed1978

Progestational potency of oral contraceptives: a polemic.

Dickey and Stone have attempted an evaluation of progestational potencies of oral contraceptives based upon such uterine criteria as subnuclear vacuolization and delay of menses. Their review, unfortunately, is marred by numerous errors which vitiate the potency estimates. The actions of progestagens in target organs depend upon the specific binding of the compounds to a protein receptor that is produced by estrogen treatment. Potency of hormones depends ultimately upon this binding. Since it seems unlikely that specific binding occurs in such nontarget sites as the blood vessels, direct potency relationships are highly improbable between diverse phenomena. Possible relationships between oral contraceptives and specific side effects must be studied in relationship to individual side effects and particular contraceptive products. Possible coincidental activities, no matter how analyzed, are unlikely to contribute meaningfully to our understanding of these drugs.

Castration↗
PubMed1988

Alternate delivery systems for contraceptive progestogens.

Research continues toward developing an universally acceptable, safe, and effective contraceptive to inhibit the female reproductive process. Progestational systems, either alone or in combination with small amounts of estrogen, approach such an ideal. The pregnane and 19-nortestosterone progestins were examined in this review with regard to contraceptive mechanisms of action and major side effects, such as menstrual abnormalities, metabolic changes, neoplasia, and teratogenicity. These steroids provide highly effective and long-acting contraception, and bypass the oral route of administration, resulting in fewer gastrointestinal and systemic side effects. Data regarding the lack of a deleterious effect of contraceptive progestogens on fetal malformation or cancer of the breast and genital tract reinforce their safety. Further study and refinement are needed, however, to lower the incidence of menstrual abnormalities, hypertension, and detrimental lipid alterations prior to approval for general use.

Abnormalities, Drug-Induced↗
PubMed1987

Contraceptive progestins and gonadotropin secretion in vitro.

In an in vitro bioassay using rat pituitary cell cultures the effect of contraceptive progestins was tested on basal and gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in vitro. Progestins diminished gonadotropin release in pituitary cells stimulated with GnRH, but did not alter basal values. This inhibitory effect was dose dependent in a range of 10(-10)-10(-5) M tested and the inhibitory action of most of the progestins examined was more potent than that of progesterone. The maximal reduction of LH and FSH values was by 60% of GnRH-induced control levels. Progestins also caused a shift in sensitivity of cells to GnRh (10(-12)-10(-6) M). When time dependence was investigated, some progestins potentiated GnRH effect on gonadotropins in pituitary cell cultures pre-incubated for a short time (4 h) with steroids. More prolonged pre-incubations from 23 to 71 h resulted in a progressive suppression of LH and FSH response to GnRH (10(-7) M). In order to examine intracellular effects, cells were pretreated with progestins and inositol phosphate metabolism was investigated. The data obtained in pituitary cells give evidence that polyphosphoinositide breakdown is potentially an early step in the action of GnRH on gonadotropin secretion by providing diacylglycerol and inositol phosphates. Addition of gonadotropin-releasing hormone to myo-2[3H]inositol-prelabeled rat pituitary cells in primary culture evoked a dose-dependent increase of the accumulation of [3H]inositol phosphates with a rise of inositol triphosphate, inositol diphosphate and inositol monophosphate within 1 min. Using one contraceptive progestin, gestoden, inositol phosphate production was inhibited by 80% compared to controls of GnRH-treated cells without the addition of steroids. The data obtained in this study suggest that this in vitro bioassay using rat pituitary cells is a useful tool in testing progestational compounds regarding their potency on gonadotropin release. In addition, these results show that one possible site of interference of progestins with GnRH-induced gonadotropin secretion may involve polyphosphoinositide breakdown.

Animals↗
PubMed1980

The mechanism of action of an antifertility vaccine in the rhesus monkey: reversal of the effects of antisera to the beta-subunit of ovine luteinizing hormone by medroxyprogesterone acetate.

Active immunization of female rhesus monkeys with the beta-subunit of ovine luteinizing hormone )oLH beta) significantly reduced their fertility. To determine whether the major action of the vaccine was interruption of pregnancy, by suppression of "corpus luteum rescue," or inhibition of ovulation, we administered the progestational agent medroxyprogesterone acetate (MPA) from day 4 through day 40 after mating. In the untreated immunized group, the pregnancy rate was significantly below that of control monkeys. MPA treatment restored the fertility rate of immunized animals to that of the control group. These results strongly support the assumption that the antifertility action of antibodies of oLH beta is due to prevention of corpus luteum rescue. Whether the lack of corpus luteum rescue resulted because of neutralization of rhesus monkey chorionic gonadotropin or from a defective corpus luteum, as is found in animals with short luteal phases, cannot be determined from these studies. The successful reversal of the antifertility effect, however, suggests that the circulating antibodies do not interfere with normal ovulation or with the normal development and implantation of the blastocyst.

Animals↗
PubMed1993

Antiandrogenic drugs.

BACKGROUND: Prostate cancer is the most frequent cancer diagnosed in American men today. Currently, about half of all patients with newly diagnosed prostate cancer present with metastatic diseases. METHODS: Antiandrogenic drugs, or more appropriately androgen-receptor antagonists, represent a group of compounds that currently have played a limited role in the treatment of metastatic prostate cancer. Their method of action is primarily one of blocking androgens at their receptor sites in target tissues. They generally are classified as steroidal or nonsteroidal compounds. Cyproterone acetate and megestrol acetate are synthetic steroidal antiandrogenic drugs that, not only compete with testosterone and dihydrotestosterone for androgen receptors, but also have progestational activity and reduce pituitary luteinizing hormone and subsequently plasma testosterone. Nonsteroidal antiandrogenic agents (flutamide, Casodex [ICI Pharmaceuticals, England], and nilutamide) block cellular binding of androgens only, and there is no reduction of testosterone levels. RESULTS: Antiandrogenics have been used in numerous trials both in Europe and the United States. This group of compounds have been used as monotherapy and in combination therapy, ie, with orchiectomy or with LHRH agonists. CONCLUSIONS: Currently, antiandrogens are used primarily in conjunction with conventional medical or surgical castration to achieve maximal androgen deprivation; however, ongoing clinical studies are comparing these compounds alone against standard hormonal therapy. It seems probable that antiandrogens will play an expanding role in the treatment of metastatic prostate cancer as well as having a role in the treatment of prostate cancer.

Androgen Receptor Antagonists↗
PubMed2000

The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites.

Gestodene (17 alpha-ethynyl-13 beta-ethyl-17 beta-hydroxy-4, 15-gonadien-3-one) is the most potent synthetic progestin currently available and it is widely used as a fertility regulating agent in a number of contraceptive formulations because of its high effectiveness, safety and acceptability. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether gestodene (GSD) administration may induce oestrogenic effects, even though the GSD molecule does not interact with intracellular oestrogen receptors (ER). To assess whether GSD may exert oestrogenic effects through some of its neutral metabolites, a series of experimental studies were undertaken using GSD and three of its A-ring reduced metabolites. Receptor binding studies by displacement analysis confirmed that indeed GSD does not bind to the ER, whereas its 3 beta,5 alpha-tetrahydro reduced derivative (3 beta GSD) interacts with a relative high affinity with the ER. The 3 alpha,5 alpha GSD isomer (3 alpha GSD) also binds to the ER, though to a lesser extent. The ability of the A-ring reduced GSD derivatives to induce oestrogenic actions was evaluated by the use of two different molecular bioassays: (a) transactivation of a yeast system co-transfected with the human ER alpha (hER alpha) gene and oestrogen responsive elements fused to the beta-galactosidase reporter vector and (b) transactivation of the hER alpha-mediated transcription of the chloramphenicol acetyl transferase (CAT) reporter gene in a HeLa cells expression system. The oestrogenic potency of 3 beta GSD was also assessed by its capability to induce oestrogen-dependent progestin receptors (PR) in the anterior pituitary of castrated female rats. The results demonstrated that 3 beta GSD and 3 alpha GSD were able to activate, in a dose-dependent manner, the hER alpha-mediated transcription of both the beta-galactosidase and the CAT reporter genes in the yeast and HeLa cells expression systems respectively. In both assays the 3 beta derivative of GSD exhibited a significantly greater oestrogenic effect than its 3 alpha isomer, while unchanged GSD and 5 alpha GSD were completely ineffective. Neither 3 beta GSD nor 3 alpha GSD exhibited oestrogen synergistic actions. Interestingly, the pure steroidal anti-oestrogen ICI-182,780 diminished the transactivation induced by 3 beta GSD and 3 alpha GSD in the yeast expression system. Furthermore, administration of 3 beta GSD resulted in a significant increase of oestrogen-dependent PR in the anterior pituitaries of castrated rats in comparison with vehicle-treated animals. The characteristics of the 3 beta GSD-induced PR were identical to those induced by oestradio benzoate. The overall results demonstrate that 3 beta GSD and its 3 alpha isomeric alcohol specifically bind to the ER and possess a weak intrinsic oestrogenic activity, whereas unmodified GSD does not. The data contribute to a better understanding of the GSD mechanism of action and allow the hypothesis to be advanced that the slight oestrogenlike effects attributable to GSD are mediated by its non-phenolic, tetrahydro reduced metabolites.

Animals↗
PubMed1976

Abnormal uterine bleeding.

The management of patients with abnormal uterine bleeding requires a logical, rational approach, and an awareness of etiologic factors. A careful history and examination should attempt to answer these questions: (1) Is the bleeding truly from the uterus? (2) Is the bleeding superimposed upon ovulatory cycles or (3) is the bleeding anovulatory? The endometrial biopsy obtained during the bleeding episode, and the basal temperature chart are diagnostically useful. Massive uterine bleeding not due to a complication of pregnancy, neoplasis, or blood dyscrasia, usually responds immediately to curettage, done in operating room or office; follow-up hormonal therapy with progesterone and a progestational agent should control the episode. More chronic forms of abnormal uterine bleeding are approached by identifying and treating the etiologic cause. If the cause is not correctable (e.g., obesity), most patients will respond satisfactorily to the cyclic administration of a progestational agent, or, if indicated, to induction of ovulation.

Dilatation and Curettage↗
PubMed1977

Further studies on a new bioassay of progestational activity (traumatic deciduoma formation in immature rats).

Six synthetic steroids were tested subcutaneously in a new bio-assay for short- and long-lasting progestational activity, using traumatic deciduoma production in immature female rats. As reference standard, a daily subcutaneous dose of 0.25 mg progesterone regularly induced a distinct deciduomagenic effect. A single dose of 12.5 mg of progesterone showed a prolonged activity. Medroxyprogesterone acetate showed a distinct deciduomagenic effect at the 0.05 mg daily s.c. dose level; a distinct prolonged effect was induced with a single s.c. injection of 0.5 mg. 16alpha-Aethylprogesterone induced regularly decidual reaction at the 0.1 mg s.c. dose level, it showed prolonged activity at the 0.25 mg dose level. The daily threshold dose for chlormadinone acetate was 0.25 mg; prolonged activity was shown with 2.5 mg. The daily threshold dose for duphaston is between 0.5 mg and 1.0 mg. A single s.c. dose of as much as 20.0 mg of 17alpha- hydroxyprogesterone caproate did not have a deciduomagenic effect.

Animals↗
PubMed1988

An overview of megestrol acetate for the treatment of advanced breast cancer.

Megestrol acetate was one of the first progestational agents to be evaluated for use in the hormonal therapy of advanced breast cancer. Since that time, megestrol acetate has become a standard for progestin antitumor research because of its progestational potency and excellent safety profile. As single-agent therapy, the average overall response rate to megestrol acetate therapy is 30%. This response rate is equivalent to that reported for tamoxifen, another hormonal agent widely used in treatment of breast cancer. Furthermore, although the side-effect profiles of these two agents are similar, the weight gain associated with megestrol acetate use may be beneficial in breast cancer patients who also have cancer cachexia. Because megestrol acetate and tamoxifen have been shown to be somewhat non-cross-resistant, megestrol acetate may prove useful as first-line treatment for disease that progresses during adjuvant tamoxifen therapy. Other focuses of research, including treatment of estrogen- and progestogen-receptor negative disease and moderation of weight loss for cancer cachexia, may offer hope to many cancer patients, even those with a currently unfavorable prognosis.

Breast Neoplasms↗
PubMed2000

Hormonal pathology of the endometrium.

The endometrial tissue is a sensitive target for steroid sex hormones and is able to modify its structural characteristics with promptness and versatility. This article discusses briefly endogenous hormonal effects (cyclic changes, luteal phase defect, unopposed estrogen effect) and describes the histologic patterns encountered in the most commonly used hormone therapies: oral contraceptives, ovulation stimulation, hormone replacement therapy, and antitumoral hormone therapy. Oral contraceptives exert a predominant progestational effect on the endometrium, inducing an arrest of glandular proliferation, pseudosecretion, and stromal edema followed by decidualized stroma with granulocytes and thin sinusoidal blood vessels. Prolonged use results in progressive endometrial atrophy. Ovulation induction therapy accelerates the maturation of the stroma and is often associated with a discrepancy between early secretory glands and an edematous or decidualized stroma with spiral arterioles. Hormone replacement therapy with estrogen alone may result in continuous endometrial proliferation, hyperplasia, and neoplasia. The use of both estrogen and progesterone elicits a wide range of histologic patterns, seen in various combinations: proliferative and secretory changes, often mixed in the same tissue sample; glandular hyperplasia (in polyps or diffuse) ranging from simple to complex atypical; stromal hyperplasia and/or decidual transformation; epithelial metaplasia (eosinophilic, ciliated, mucinous); and inactive and atrophic endometrium. Progesterone therapy for endometrial hyperplasia and neoplasia induces glandular secretory changes, decidual reaction, and spiral arterioles. Glandular proliferation is usually arrested, but neoplastic changes may persist and coexist with secretory changes. Lupron therapy produces a shrinking of uterine leiomyomas by accelerating their hyaline degeneration, similar to that in postmenopausal involution. It generally produces endometrial atrophy. Tamoxifen for breast carcinoma has an estrogen agonist effect on the uterus in approximately 20% of patients, who develop endometrial polyps, glandular hyperplasia, adenomyosis, and/or leiomyomata. Both endometrioid and nonendometrioid carcinomas are seen, often in polyps. Their causal relationship to tamoxifen therapy is debatable.

Antineoplastic Agents, Hormonal↗

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