Navigating a plethora of progesterone receptors: Comments on the safety/risk of progesterone supplementation in women with a history of breast cancer or at high-risk for developing breast cancer.

Progesterone and progestin agonists are potent steroid hormones. There are at least three major types of progesterone receptor (PR) families that interact with and respond to progesterone or progestin ligands. These receptors include ligand-activated transcription factor isoforms (PR-A and PR-B) encoded by the PGR gene, often termed classical or nuclear progesterone receptor (nPR), membrane-spanning progesterone receptor membrane component proteins known as PGRMC1/2, and a large family of progestin/adipoQreceptors or PAQRs (also called membrane PRs or mPRs). Cross-talk between mPRs and nPRs has also been reported. The complexity of progesterone actions via a plethora of diverse receptors warrants careful consideration of the clinical applications of progesterone, which primarily include birth control formulations in young women and hormone replacement therapy following menopause. Herein, we focus on the benefits and risk of progesterone/progestin supplementation. We conclude that progesterone-only supplementation is considered safe for most reproductive-age women. However, women who currently have ER + breast cancer or have had such cancer in the past should not take sex hormones, including progesterone. Women at high-risk for developing breast or ovarian cancer, either due to their family history or known genetic factors (such as BRCA1/2 mutation) or hormonal conditions, should avoid exogenous sex hormones and proceed with caution when considering using natural hormones to mitigate menopausal symptoms and/or improve quality of life after menopause. These individuals are urged to consult with a qualified OB-GYN physician to thoroughly assess the risks and benefits of sex hormone supplementation. As new insights into the homeostatic roles and specificity of highly integrated rapid signaling and nPR actions are revealed, we are hopeful that the benefits of using progesterone use may be fully realized without an increased risk of women's cancer.

The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study.

PURPOSE: The purpose of this study was to identify if switching from intramuscular (IM) to vaginal progesterone compared to staying on IM progesterone after a positive pregnancy test following embryo transfer (ET) is associated with miscarriage risk. METHODS: A retrospective cohort study was performed in a private university-affiliated fertility clinic and included women aged 18-50 years with a positive pregnancy test following ET. The two groups studied were: women who stayed on IM progesterone following a positive pregnancy test and those who switched to vaginal progesterone after a positive test. The main outcome measured was risk of miscarriage < 24 weeks gestation as a proportion of non-biochemical pregnancies. RESULTS: 1988 women were included in the analysis. Among the baseline characteristics, the presence of prior miscarriages as well as prior failed ETs, and frozen cycles (vs fresh) as type of transfer were associated with IM progesterone use (p values ≤ 0.01). As per miscarriage risk < 24 weeks, 22.4% (274/1221) of patients in the IM progesterone group experienced a miscarriage compared with 20.7% (159/767) in the vaginal progesterone group (OR 0.90; 95% CI 0.73-1.13). A multivariable logistic regression model revealed an adjusted OR (aOR) of 0.97 (95% CI 0.77-1.22). CONCLUSION: This study suggests that switching from IM to vaginal progesterone after a positive pregnancy test following an ET is not associated with miscarriage risk. Considering that IM progesterone imposes substantial discomfort, this study offers reassurance and some flexibility in treatment protocols. Further prospective studies are necessary to corroborate the results of this study.

In Defense of Progesterone: A Review of the Literature.

Context • The medical literature on the use of progesterone in postmenopausal women is often confusing and contradictory. Some physicians implicate natural progesterone in an increase in the risk of breast cancer. The chemical structure of natural progesterone (P4) is quite different from chemically altered, synthetic chemicals called progestins, which results in different actions at the cell level. Objective • The research team intended to review the literature to examine the benefits and safety of natural progesterone and determine whether it can cause an increase or decrease in breast cancer risk. Design • A review of the medical literature to examine the benefits and safety of natural progesterone as compared with synthetic progestins. Intervention • Studies examined compared controls not receiving hormone therapy with women receiving estrogen alone and in combination with natural progesterone and with various synthetic progestins, such as medroxyprogesterone acetate-the most commonly used synthetic progestin. Outcome Measures • Outcome measures included factors such as progression and survival of breast and other cancers and other epidemiological and laboratory data. Results • A meta-analysis of 3 studies involving 86 881 postmenopausal women reported that the use of natural progesterone was associated with a significantly lower risk of breast cancer compared with synthetic progestins. Anovulation and low levels of serum progesterone have been associated with a significantly higher risk of breast cancer in premenopausal women. Use of progesterone has been linked to lower rates of uterine and colon cancers and may also be useful in treating other cancers such as ovarian, melanoma, mesothelioma, and prostate. Progesterone may also be helpful in preventing cardiovascular disease and preventing and treating neurodegenerative conditions such a stroke and traumatic brain injury. Conclusions • Physicians should have no hesitation prescribing natural progesterone. The evidence is clear that progesterone does not cause breast cancer. Indeed, progesterone is protective and preventative of breast cancer.

A MOUSE MODEL OF MAMMARY HYPERPLASIA INDUCED BY ORAL HORMONE ADMINISTRATION.

BACKGROUND: Mammary hyperplasia is one of the most common benign breast disorders. Although traditional Chinese medicine has a vast experience in the treatment of mammary hyperplasia, it is not accepted widely due to its unclear mechanism. METHODS AND MATERIALS: To address the mechanism, we developed a mouse model of mammary hyperplasia. We gave mice estradiol valerate tablets and progesterone capsules sequentially for one month by intragastric administration. RESULTS: Mice treated by this method had a series of pathological changes which are similar to those detected in women with mammary hyperplasia, including ectopic level of estradiol and progesterone in serum, hyperplasia of mammary glands and increased expression of ERα and PR. CONCLUSION: This model will facilitate the mechanical study of traditional medicine on mammary hyperplasia.

Nephroprotective and antioxidant properties of Artemisia arborescens hydroalcoholic extract against oestroprogestative-induced kidney damages in rats.

OBJECTIVE: Currently, medicinal plants are found to have biological and pharmacological activities and are used in various domains. This study, carried out on Wistar rats, evaluates the beneficial effects of Artemisia arborscens extract on oestroprogestative-induced damages in kidney. MATERIALS AND METHODS: Thirty-six 3-month-old Wistar rats were divided into 4 batches of nine each: a control group, a group of rats receiving oestroprogestative treatment, a group undergoing oestroprogestative treatment after receiving Artemisia arborescens extract in drinking water, and a group that received only Artemisia arborescens. RESULTS: Artemisia arborescens extract was found to optimize many parameters which were shifted to pathological values as a consequence of oestroprogestative toxicity: plasma creatinine and urea levels were decreased, uric acid and proteins were restored to normal values. The alteration of renal architecture was also suppressed. In addition, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities that had been reduced in kidney of the treated group were restored by Aretmisia arborscens-based treatments and, therefore, the lipid peroxidation level was reduced in the renal tissue compared to the control group. CONCLUSION: The obtained results confirmed that the Artemisia-based treatment allowed efficient protection against oestroprogestative-induced nephrotoxicity by restoring the activities of kidney. The protective effect of Artemisia arborescens was mainly attributed to antioxidant properties as well as the presence of phenolic acids and flavonoids detected by means of HPLC.

Pharmacologic Management of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.

Effect of ovariectomy, 17-beta estradiol, and progesterone on histology and estrogen receptors of bladder in female partial bladder outlet obstruction rat model.

AIM: The aim of this study was to investigate the effect of bilateral ovariectomy (OVX), 17-beta estradiol (E2), and progesterone (P4) on the histology and estrogen receptor (ER) expression of the bladder using a female partial bladder outlet obstruction (pBOO) rat model. MATERIAL AND METHODS: A total of 60 female Sprague-Dawley rats were evenly assigned into six groups of 10 each. Group A served as the control. Groups B-F underwent induced pBOO. Groups C-F underwent OVX. Groups D-F were given E2 (0.1 mg/kg/day), Group E was given P4 (1 mg/kg/day), and Group F was given P4 and dehydroepiandrosterone (DHEA) (300 µg/kg/day) by an Alzet pump. Four weeks later, serum E2 and P4 levels were evaluated. Each rat was anesthetized and the urinary bladder was removed for weighing and histological study. RESULTS: Expression of ER-ß was not significantly different between the control group and the other study groups. pBOO was shown to increase both bladder weight and detrusor muscle thickness. OVX had an additive effect to BOO on increased blood vessel density in the bladder. E2 was shown to increase blood vessel density, while P4 supplementation decreased blood vessel density. DHEA did not cause any significant effects on blood vessel density. CONCLUSION: Hormone therapy did not change the expression of ER in bladder outlet obstruction. Estradiol stimulated the increased angiogenesis of the bladder detrusor but P4 decreased the angiogenesis of the bladder detrusor. DHEA had no effect on the bladder detrusor.

Steroid hormone hypersensitivity: clinical presentation and management.

Hypersensitivity to estrogens and progestogens is often undiagnosed. The condition has many manifestations, including premenstrual syndrome, dysmenorrhea, and impaired fertility. Diagnosis is confirmed by skin testing for inflammatory responses to small doses of the hormone, and desensitization with small doses of the hormone is the most appropriate form of management.

The effects of high dose progesterone on neural tube development in early chick embryos.

BACKGROUND: Although folic acid deficiency is known to be one of the factors in the development of spina bifida and other neural tube defects (NTD) the exact pathophysiology still remains unclear. Progesterone is an endogenous hormone which increases significantly during pregnancy. AIMS: We aimed to study the possible negative effects of high dose progesterone on neural tube development in early chick embryos. In order to test our hypothesis, early chick embryos were exposed to physiological saline, normal and high doses of progesterone. SETTINGS AND DESIGN: 160 fertile, specific pathogen free white leghorn eggs (Gallus gallus), all at stage eight of development were divided into four equal groups. MATERIALS AND METHODS: The first group was incubated without any operation. The second group was injected with physiological saline. The third and fourth groups were injected with two and twenty times more than physiologic doses of progesterone respectively. After 48 hours of incubation, all embryos were analyzed for the presence of NTDs under light microscopy. STATISTICAL ANALYSIS USED: None. RESULTS: At 48 hours of incubation, 84% (135/160) of the embryos passed characteristics of Stage 12 development and were included to the study. None of the eggs in the first three groups showed NTDs, whereas 81.8% (27/33) of the eggs in the fourth group showed NTDs. CONCLUSIONS: Our study showed that progesterone at levels twenty times more than its physiologic level might cause NTDs. Further studies are needed to explain the mechanisms of this teratogenic effect.

Acute eosinophilic pneumonia associated with intramuscular administration of progesterone as luteal phase support after IVF: case report.

We report two cases of acute eosinophilic pneumonia induced by i.m. administration of progesterone used as luteal phase support after IVF. For both patients, the symptoms began 3 weeks after the first injection of progesterone. Both patients were in respiratory distress, and one of them required ventilatory assistance for a week, with 5 days in the intensive care unit. Symptoms improved as the i.m. form was shifted to a vaginal form of progesterone together with the administration of corticosteroids. Sesame oil (used as excipient) and benzyl alcohol (used as preservative) could both be incriminated in the development of the hypersensitivity reaction. The need for luteal phase support is clearly established in IVF cycles with GnRH agonist protocols, and progesterone is the generally recommended compound. However, there is no definitive consensus regarding the optimal route of administration of progesterone. These two cases of acute drug-induced disease show that the use of i.m. progesterone can be associated with a severe morbidity in otherwise healthy young patients. This is an additional argument to advocate the use of vaginal progesterone as luteal support in IVF.

Sex differences in anxiety, sensorimotor gating and expression of the alpha4 subunit of the GABAA receptor in the amygdala after progesterone withdrawal.

In a progesterone withdrawal (PWD) model of premenstrual anxiety, we have previously demonstrated that increased hippocampal expression of the alpha4 subunit of the GABAA receptor (GABAA-R) is closely associated with higher anxiety levels in the elevated plus maze. However, several studies indicate that sex differences in regulation of the GABAA-R in specific brain regions may be an important factor in the observed gender differences in mood disorders. Thus, we investigated possible sex differences in GABAA-R subunit expression and anxiety during PWD. To this end, we utilized the acoustic startle response (ASR) to assess anxiety levels in male and female rats undergoing PWD as the ASR is also applicable to the assessment of human anxiety responses. We also investigated GABAA-R alpha4 subunit expression in the amygdala, as the amygdala directly regulates the primary startle circuit. Female rats exhibited a greater ASR during PWD than controls, indicating higher levels of anxiety and arousal. In contrast, male rats undergoing PWD did not demonstrate an increased ASR. The sex differences in the ASR were paralleled by sex differences in the expression of the GABAA-R alpha4 subunit in the amygdala such that alpha4 subunit expression was up-regulated in females during PWD whereas alpha4 levels in males undergoing PWD were not altered relative to controls. These findings might have implications regarding gender differences in human mood disorders and the aetiology of premenstrual anxiety.

Exposición ocupacional al cadmio y cáncer / Occupational environmental exposition at cadmium and cancer

La exposición ocupacional a metales pesados ha dado lugar a un nuevo tipo de patología en los últimos tiempos, ya que entre otras, estos metales pueden ser causa de cáncer en el hombre. En el mecanismo de daño celular resulta importante el aumento en los procesos redox celulares. El cadmio es una toxina metálica que, aparte de tener múltiples usos industriales, es uno de los componentes de¡ tabaco. La exposición al cadmio tanto por inhalación como por ingestión resulta peligrosa para el hombre, pero los efectos carcínogenéticos sólo se producen por vía inhalatoria. Su larga vida media incrementa sus efectos tóxicos y recientemente ha sido incluido en el grupo 1 (sustancias carcinógenas probadas en el hombre) por la IARC. Así, la exposición ocupacional al cadmio se ha relacionado con un incremento en el riesgo de cáncer de pulmón y puede dañar riñones, huesos y próstata. El mecanismo de la inducción tumoral es desconocido, pero se sabe que el cadmio produce cambios oxidativos por estrés en las células, así como interacciones DNA/metal. Sin embargo, en algunas circunstancias el cadmio puede comportarse como antícarcinógeno por su capacidad de aumentar la actividad de varios proto-oneogenes. Los efectos carcinogénicos de¡ cadmio de modifican cuando interacciona con otras sustancias como zinc, proteínas de la dieta, ácido L-ascórbico, selenio y progesterona. (AU)

Clinical challenges in menopausal management: a case study approach.

Selecting an appropriate hormone replacement regimen can pose many challenges to the clinician and the patient. This report offers 4 case studies and clinical considerations illustrating both scientific and clinical considerations when collaborating with women to find an acceptable method to manage menopausal symptoms. Both traditional and complementary therapies are considered.

Unapproved use of high-dose combined pills in Japan: a community study on prevalence and health characteristics of the users.

BACKGROUND: Because of the ban on oral contraceptive use in Japan, only high-dose combined pills (HDCP), permitted as treatment for menstrual disorders, can be used as a contraceptive. We determined the prevalence of the use of such preparations in a community in Japan and assessed the health characteristics of the users. METHODS: A total of 18,435 female residents age 35 years and over in a city of Gifu Prefecture, Japan, responded in 1992 to a health questionnaire that included questions on the use of HDCP, lifestyle, and dietary habits. The response rate was 92%. RESULTS: The rates of current and past HDCP use were 1.3 and 7.1%, respectively, among women ages 35-49 years, and 2.2% of the women had used HDCP for longer than any other method of contraception. Current HDCP users were more likely to be smokers. They had lower intakes of carotene, fiber, and vitamins C and E and a lower polyunsaturated/saturated fat ratio than never-users. CONCLUSIONS: The prevalence of HDCP use was 1.3% among Japanese women ages 35-49 years. Potential risk factors for cardiovascular diseases, such as smoking and a diet with lower intakes of antioxidants, were prevalent among current HDCP users.

Administration of long-term estradiol and progesterone followed by progesterone withdrawal does not alter the plasma oxytocin secretory response to cholecystokinin or the pituitary oxytocin content in ovariectomized rats.

The hormone oxytocin (OT) is important for several pre- and postpartum events, including uterine contractions at parturition, the induction of maternal behavior, and milk ejection during nursing. During late pregnancy, OT mRNA is increased in the paraventricular nucleus (PVN) due to high estrogen and declining progesterone levels. Administration of sequential estrogen and progesterone to, followed by withdrawal of progesterone from, an ovariectomized rat also increases OT mRNA. However, pituitary OT peptide is not affected. In the present experiment, we determined if this steroid exposure alters peripheral OT secretion during a provocative stimulus to OT release, such as cholecystokinin (CCK). Adult ovariectomized Sprague-Dawley rats were implanted on day 1 with either estrogen or empty silastic capsules, on day 3 with progesterone or empty capsules, and on day 14 progesterone or empty capsules were removed. Forty-eight hrs after removal of the progesterone capsules, plasma OT was measured before and after i.v. injection of 10 micrograms/kg of CCK. At the completion of the study, pituitary glands were removed and OT peptide was measured. No significant differences were found between the sham and hormone-treated animals either in their basal or CCK-stimulated plasma OT levels or their pituitary content of OT peptide. Although sequential exposure to estradiol and progesterone followed by withdrawal of progesterone has been shown previously to increase PVN OT mRNA, neither pituitary OT immunoreactivity nor basal and CCK-stimulated release of plasma OT is affected by this treatment. Although the mechanism of this steroid effect is not yet understood, our observations suggest a unique action of gonadal steroids upon PVN OT neurons.

Short notes on intrauterine devices.

The DATTA panelists emphasized the critical importance of patient selection when considering IUDs for contraception The IUD is an acceptable method of contraceptives, in a stable monogamous relationship, and not at risk for sexually transmittel diseases. Within these constraints, the panelists gave overwhelming support to the IUD as a safe and effective method of contraception. The minority opinion (two panelists) that these devices were not established for safety or effectiveness was based on concerns over possible infectious complications.

PIP: This is an informative review on patient selection, history and distribution of IUDs, with a more detailed description of the Copper T 380A and the Progestasert IUDs currently available in the U.S. The DATTA panelists (of India) have recommended that copper and progesterone containing IUDs are safe and effective as long as they are not given to women with multiple sex partners, pelvic infections, undiagnosed bleeding disorders or previous ectopic pregnancy.. Nulliparity is a relative contraindication. While IUDs with multifilamented strings such as the Dalkon shield are now considered unsafe, there is no evidence proving that other IUDs put women at risk for infection. The Copper T 380 A (ParaGard, Gynopharma, Sommerville, NJ) is described in detail. It has a Pearl Index of 0.83. Copper IUDs work by causing a general inflammatory response, reducing implantation, and by liquefying endometrial mucopolysaccharides thereby decreasing sperm transport and metabolism. The Progestasert IUD is also described. It has a Pearl index of 2.9 and must be replaced yearly. Progesterone atrophies endometrial glands and inhibits sperm capacitation. IUD side effects of bleeding and pain do occur with these models, but bleeding is relatively less with the progestasert, while copper IUDs cause a lighter flow that may last longer. Women should be supplemented with iron and be given prostaglandin inhibitors during IUD use. Management of perforation, pregnancy and pelvic infection during IUD use is outlined briefly.