Use Of Progestational Agents Research Articles

Selecting optimal progestational agents either alone or in combination in common pediatric endocrine settings: challenges of unmet needs.

Progesterone is a natural hormone, mainly produced by the corpus luteum, with the foremost endocrine function on the secretory glands of the endometrium. Since being isolated, both natural and synthetic forms have been produced and are utilized for several purposes, including regulating the menstrual cycle and preventing endometrial hyperplasia. Specifically, the use of progestational agents is essential in the treatment of many common endocrine conditions, including polycystic ovary syndrome, congenital adrenal hyperplasia Turner syndrome and functional hypothalamic amenorrhea. Although these agents are essential for disease management, literature that focuses on the benefits of specific progestins as well as the effects on glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and androgenic receptors (AR) is limited. In this review, we provide a disease specific summary of the available literature and highlight where more information is needed.

A systematic review and meta-analysis of progestogen use for maintenance tocolysis after preterm labor in women with intact membranes.

The use of progestogens for maintenance tocolysis remains controversial, with randomized controlled trials having conflicting results on their efficacy. To evaluate the use of progestational agents for maintenance tocolysis after preterm labor in a systematic review of randomized controlled trials. Electronic databases were searched for reports published before December 2014. Keywords included "tocolysis," "progesterone," "preterm labor," "17-alpha-hydroxyprogesterone," and "vaginal progesterone." Only randomized controlled trials involving progestational agents for maintenance tocolysis were included. Outcomes were analyzed on an intent-to-treat basis and meta-analysis was performed where appropriate. Relative risks and mean differences with 95% confidence intervals were calculated. Four studies (362 women) were included. There were no significant differences between progestational agents and placebo/no treatment in terms of delivery before 34weeks or before 37weeks of pregnancy, time from randomization to delivery, and respiratory distress syndrome. Progestogens were associated with an increase in the neonatal birth weight (mean difference 203.32g, 95% confidence interval 110.85-295.80; P=0.032). The current evidence does not support the routine use of progestational agents for maintenance tocolysis after an episode of preterm labor.

The rationale for use of progesterone in the prevention of preterm birth?

Pineda-Torres and co-investigators explored the anti-inflammatory properties of progesterone (P4) using an in vitro model of choriodecidual infection. These experiments were performed to determine if progesterone can suppress an induced immune response in fetal membranes. As expected from prior work, the authors demonstrate a potent cytokine response from lipopolysaccharide (LPS) administration. The lowest dose of P4 had really no or minimal effect on the LPS-induced cytokine production. The higher doses of P4 did suppress the immune response in the choriodecidual and amniotic compartments. Notably, administering RU486 (a progesterone antagonist) abrogated the immunoprotective effect of P4, suggesting a progesterone-receptor-specific action in the ability of P4 to provide immunosuppression. Progesterone has long been believed to have immunosuppressive properties. The ability of steroids to modify the immune response through binding the glucocorticoid receptor (GR) is well described. However, the mechanisms by which progesterone exerts immunomodulatory effects are more convoluted. Progesterone typically binds the progesterone receptor (PR) to induce downstream effects; yet, progesterone can also bind GR with varying affinity (Simoncini et al. Endocrinology 2004;145:5745). Additionally, progesterone may have other non-PR or non-genomic mechanisms of action. As progesterone levels are elevated during pregnancy, it is theorised that these high levels of progesterone maintain a relative immunosuppressed state in gestational tissues. If this is indeed correct, the question remains how administering progesterone (either through an injection of 17-alpha hydroxyprogesterone caproate or via vaginal application of progesterone) further modifies the immune response in the normal gestational state and/or in one in which there is active infection or inflammation (such as may be the case in preterm birth). In fact, in vivo work in mice failed to demonstrate any key mechanisms by which progestational agents alter in the normal gestational state (Nold et al. Am J Obstet Gynecol 2013;208:223 e1). Other in vivo studies utilising mouse models of preterm birth demonstrate immunomodulatory properties of progestational agents supporting the in vitro findings presented in this paper (Elovitz et al. Am J Obstet Gynecol 2004;190:693; Elovitz et al. Am J Obstet Gynecol 2005;193:1149; Elovitz et al. J Maternal-fetal Neonatal Med 2008;21;223; Yellon et al. Reprod. Sci. 2009;16:257). However, these in vivo studies noted the most profound immunosuppressive effects from medroxyprogesterone acetate, which is known to exert downstream effects via GR and PR. The studies presented here, while adding further evidence that P4 can induce immunomodulatory properties and that those effects are mitigated by P4 via a receptor-mediated mechanism (PR or GR), cannot provide sufficient evidence to explain possible findings from use of progestational agents in the prevention of preterm birth in the clinical setting. Understanding the need to elucidate mechanisms and that such trials in humans are difficult, we remain unclear about the role of progesterone in preventing preterm birth. Although this study, and other studies, suggest that P4 can provide immunosuppression, whether the clinically used progestational agents prevent preterm birth by suppressing an immune response in the cervix, uterus, placenta or fetal membranes, remains unknown. The more that we reveal about the pathogenesis of preterm birth, the more likely we are to discover specific therapeutics that target this precise pathway and lead to greater prevention of preterm birth. None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Progestational agents for treating threatened or established preterm labour.

Prematurity is not only the leading cause of perinatal morbidity and mortality but is associated with long-term impairment. Studies of various tocolytic agents have shown mixed results with little effect in improving pregnancy duration and insufficient data to confirm a definite beneficial effect on neonatal morbidity or mortality. Progesterone is known to have an inhibitory effect on uterine contractility and is thought to play a key role in the maintenance of pregnancy until term. To determine if the use of progestational agents is effective as a form of treatment or co-treatment for women with threatened or established preterm labour with intact membranes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2013), CENTRAL (The Cochrane Library 2013, Issue 10), MEDLINE (1966 to August 31 2013) and Embase (1974 to 31 August 2013). We checked the reference lists of all included studies to identify any additional studies and communicated with authors and the pharmaceutical industry. Randomised controlled trials that compared progestational agents, given either alone or in combination with other tocolytics, with a control group receiving another tocolytic, placebo or no treatment, for the treatment of preterm labour. Two review authors independently extracted data and assessed trial quality. Eight studies were included in this review, involving 563 women, but only seven studies, involving 538 women, contributed data for analyses. There are some data suggesting that the use of progestational agents results in a reduction of preterm deliveries at less than 37 weeks of gestation and an increase in birthweight. The use of a progestational agent may also reduce the frequency of uterine contractions, prolong pregnancy and attenuate the shortening of cervical length. However, the analysis was limited by the relatively small number of available studies. The power of the meta-analysis was also limited by the varying types, dosages and routes of administration of progesterone. There is insufficient evidence to advocate progestational agents as a tocolytic for women presenting with preterm labour.

Luteal insufficiency in first trimester

Luteal phase insufficiency is one of the reasons for implantation failure and has been responsible for miscarriages and unsuccessful assisted reproduction. Luteal phase defect is seen in women with polycystic ovaries, thyroid and prolactin disorder. Low progesterone environment is created iatrogenically due to interventions in assisted reproduction. Use of gonadotrophin-releasing hormone analogs to prevent the LH surge and aspiration of granulosa cells during the oocyte retrieval may impair the ability of corpus luteum to produce progesterone. Treatment of the underlying disorder and use of progestational agents like progesterone/human chorionic gonadotrophin have been found to be effective in women with a history of recurrent miscarriage. There has been no proved beneficial effect of using additional agents like ascorbic acid, estrogen, prednisolone along with progesterone. Despite their widespread use, further studies are required to establish the optimal treatment. Literature review and analysis of published studies on luteal phase support.

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The use of progestational agents for preterm birth: Lessons from a mouse model

On the basis of the recent Maternal Fetal Medicine Unit Networks clinical trial, the American College of Obstetricians and Gynecologists supports the administration of 17-alpha hydroxyprogesterone caproate to high-risk patients. Because inflammation/infection is believed to be a contributing factor in many cases of preterm birth, it is imperative to understand the effect of 17-alpha hydroxyprogesterone caproate treatment in this clinical situation. Using a mouse model of localized intrauterine inflammation, we investigated the ability of progestational agents to prevent preterm birth. On gestational day 15 (E15), dams were assigned randomly to treatment with 17-alpha hydroxyprogesterone caproate, medroxyprogesterone acetate, or vehicle before intrauterine infusion of lipopolysaccharide. All dams were monitored for morbidity and preterm birth. Three separate sets of experiments were performed to assess different outcomes at 6, 24, and 96 hours. At 6 and 24 hours, C-reactive protein, interleukin-6, and interleukin-10 levels were measured in maternal serum by enzyme-linked immunosorbent assay. Pretreatment with 17-alpha hydroxyprogesterone caproate or medroxyprogesterone acetate before intrauterine lipopolysaccharide treatment significantly decreased the preterm birth rate, compared with lipopolysaccharide treatment alone. Medroxyprogesterone acetate treatment was more effective than 17-alpha hydroxyprogesterone caproate treatment in the prevention of preterm birth and resulted in live pups at term. Treatment with 17-alpha hydroxyprogesterone caproate was associated with significant maternal morbidity. In the setting of intrauterine inflammation, progestational agents decrease the preterm birth rate but can result in maternal morbidity. 17-Alpha hydroxyprogesterone caproate should not be used in patients who are suspected of having subclinical infection and/or acute preterm labor. The mechanisms by which progestational agents inhibit preterm birth warrants further investigations so that the use of this drug to appropriate populations could be pursued without undue fetal or maternal harm.

Pregnancy, progesterone and progestins in relation to breast cancer risk

In the last two decades the prevailing opinion, supported by the “estrogen augmented by progesterone” hypothesis, has been that progesterone contributes to the development of breast cancer (BC). Support for this opinion was provided by the finding that some synthetic progestins, when added to estrogen in hormone replacement therapy (HRT) for menopausal complaints, increase the BC risk more than estrogen alone. However, recent findings suggest that both the production of progesterone during pregnancy and the progesterone endogenously produced or exogenously administered outside pregnancy, does not increase BC risk, and could even be protective. The increased BC risk found with the addition of synthetic progestins to estrogen in HRT seems in all likehood due to the fact that these progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) are endowed with some non-progesterone-like effects which can potentiate the proliferative action of estrogens. The use of progestational agents in pregnancy, for example to prevent preterm birth, does not cause concern in relation to BC risk.

Progestational Agents to Prevent Preterm Birth: A Meta-Analysis of Randomized Controlled Trials

To perform an updated systematic review with meta-analysis to further elucidate the efficacy of progestational agents for the prevention of preterm births in patients at elevated risk. Computerized databases, references in published studies, and textbook chapters in all languages were used to identify randomized controlled trials (RCTs) evaluating the use of progestational agents for the prevention of preterm births in women at elevated risk. We identified RCTs that compared progestational agents with placebo for patients at risk for preterm birth and evaluated at least one of the following: delivery before 37 weeks of gestation, birth weight less than 2,500 g, threatened preterm labor, respiratory distress syndrome, and perinatal mortality. The primary outcomes assessed were preterm delivery and perinatal mortality. Ten studies met inclusion criteria for this review. For each study with binary outcomes, an odds ratio (OR) with 95% confidence intervals (CIs) was calculated for selected outcomes. Homogeneity was tested across the studies. Compared with women allocated to receive placebo, those who received progestational agents had lower rates of preterm delivery (26.2% versus 35.9%; OR 0.45, 95% CI 0.25-0.80). Similar results were noted when comparing patients who were specifically treated with 17alpha-hydroxyprogesterone caproate (29.3% versus 40.9%; OR 0.45, 95% CI 0.22-0.93). Additionally, subjects allocated to receive 17alpha-hydroxyprogesterone caproate had lower rates of birth weights less than 2,500 g (OR 0.50, 95% CI 0.36-0.71). No differences in rates of hospital admissions for threatened preterm labor or perinatal mortality were noted for subjects receiving progestational agents in general or for those receiving only 17alpha-hydroxyprogesterone caproate specifically. The use of progestational agents and 17alpha-hydroxyprogesterone caproate reduced the incidence of preterm birth and low birth weight newborns.

A Meta-Analysis of Randomized Control Trials of Progestational Agents in Pregnancy

GOLDSTEIN, PETER; BERRIER, JAYNE; ROSEN, SCOTT; SACKS, HENRY S.; CHALMERS, THOMAS C. Author Information

The central role of progesterone receptors and progestational agents in the management and treatment of breast cancer.

This article summarizes the role of progesterone receptors (PgRs) as markers of hormone-dependent breast cancers and the use of progestational agents in breast cancer treatment. We discuss the structure of PgRs, their purification, the production of anti-PgR monoclonal antibodies, and the use of these antibodies for clinical assays.

Spontaneous Abortion and Ectopic Pregnancy

The incidence, clinical presentation, diagnosis, and treatment of 2 problems of early pregnancy--spontaneous abortion and ectopic pregnancy--are reviewed. The incidence of spontaneous abortion is reported to be 10-20% of all pregnancies and may be decreasing. Abnormal development of the pregnancy, unsuccessful implantation, maternal disease, noxious agents, previous surgery, abnormalities of the genital tract, and psychological stress have all been implicated in the etiology of spontaneous abortion. The clinical presentations include threatened, inevitable, incomplete, complete, missed, septic, and habitual abortion. The management of threatened abortion has changed from strict limitations of activity and the use of progestational agents to more liberal recommendations regarding activity and the avoidance of progestins. Combined use of radioimmunoassay for the beta subunit of human chorionic gonadotropin and ultrasound examination of the pelvis can lead to accurate prediction of the pregnancy outcome in patients with 1st trimester bleeding. Evacuation of the uterus is the treatment of choice in inevitable or incomplete abortion. Clinicians should be aware of the guilt feelings, grief reactions, and fears about future pregnancies that often follow spontaneous abortion. Reports of the incidence of ectopic pregnancy have ranged from 1 in 250 to 1 in 70 pregnancies, and the rate has been increasing. The significant morbidity and mortality associated with this condition make early diagnosis essential. The 3 most common symtoms are abdominal pain, amenorrhea, and abnormal vaginal bleeding. Ultrasonography and new methods of measuring human chorionic gonadotropin facilitate early diagnosis. Culdocentesis remains the definitive method of diagnosis. Earlier diagnosis has led some physicians to advocate salpingostomy via laparoscopy rather than salpingectomy for treatment in selected cases.

Amenorrhea After Medroxyprogesterone

To the Editor:— The article, Irregular Menses, Amenorrhea, and Infertility Following Synthetic Progestational Agents, by Whitelaw, Nola, and Kalman (195:780, 1966) was of particular interest because of the report of seven patients with amenorrhea given medroxyprogesterone acetate (Depo-Provera) intramuscularly. Of 15 patients with amenorrhea following the use of progestational agents, seven had received this drug. Since it is prescribed much less frequently than the oral progestational agents which the other patients in the report had received, the incidence of amenorrhea following the use of medroxyprogesterone would appear to be higher than that following the use of other progestational agents. Amenorrhea following the intramuscular administration of medroxyprogesterone acetate accounts for a considerable fraction of the patients with amenorrhea seen recently in our infertility clinic. Of 145 patients with amenorrhea or oligomenorrhea seen at the Stanford Clinic between January 1963 and August 1965, amenorrhea had developed in six following injections of

Use of progestational agents in the management of endometrial cancer.

Use of progestational agents in the management of endometrial cancer.

Treatment of carcinoma in situ of the endometrium.

A review of the pathology development and treatment of endometrial hyperplasia (carcinoma in situ) its relation to estrogen administration and its subsequent development into carcinoma is given. 3 clinical case reports illustrate the usual endometrial changes which occurred with continuous and prolonged use of progestational agents or n onsteroidal hormonal antagonists. Cystic and adenomatous hyperplasia gl ands regress and stroma can convert into decidua with treatment with progestational agents. Atypical endometria in menopausal or postmenopausal women may be converted into progestational endometria wit h these drugs but it is not considered a cure of carcinoma in situ.