Co-administration Of Estrogen Research Articles

Characteristics of systemic testosterone therapy for female hypoactive sexual desire disorder-a claims database analysis.

Testosterone therapy (TTh) is recommended for postmenopausal women with hypoactive sexual desire disorder (HSDD); however, there remain insufficient data to support use of TTh in premenopausal women with sexual dysfunction. In this study, we used a large national database to evaluate prescribing trends of TTh for women with HSDD. We conducted a cohort analysis of information from electronic health records acquired from the data network TriNetX Diamond. The study cohort consisted of women 18-70 years of age with a diagnosis of HSDD. We analyzed trends of testosterone prescriptions, routes of testosterone administration, and coadministration of testosterone with estrogen. Despite an increase in rates of testosterone prescriptions for HSDD, there remains a high degree of variability in the duration of treatment, route of administration, and coadministration of estrogen with significant underprescription of testosterone. Our query of the TriNetX database led to the identification of 33 418 women diagnosed with HSDD at a mean age of 44.2 ± 10.8years, among whom 850 (2.54%) women received a testosterone prescription. The testosterone prescriptions were highly variable with regard to duration and route of administration and coadministration with estrogen. For all patients until 2015, the prevalence of testosterone prescriptions for HSDD showed a positive quadratic relation was observed. Since 2015 a linear increase in prevalence was observed, with the highest rate of increase for patients aged 41-55years. The findings of this study reveal a significant need for further research investigating the optimal use of TTh to enhance the sexual health of women with HSDD, and further studies on the long-term effects of testosterone use must be undertaken to ensure that patients have access to safe and effective treatment. Limitations to this study include patient de-identification and lack of availability of testosterone dosage data. However, this study also has many strengths, including being the first, to our knowledge, to characterize the prescribing trends of testosterone for women with HSDD. Testosterone therapy should be considered as a potential therapy for premenopausal female patients with HSDD. Further studies on the long-term effects of testosterone use must be undertaken to address disparities in the management of HSDD and to ensure patients can access treatment.

Gender differences in non-cystic fibrosis bronchiectasis severity and bacterial load: the potential role of hormones.

Non cystic-fibrosis bronchiectasis (NCFB) is a complex chronic respiratory disease, characterised by excessive sputum production and abnormal permanent dilation of bronchi. Mucus accumulation leads to recurrent bacterial infections and increased bacterial load, causing vicious cycles of structural damage and decreased lung function. Respiratory physiotherapy management of NCFB includes airway clearance techniques and use of nebulised, hypertonic saline. Despite advances in treatment, a consistent relationship has been observed between gender and disease occurrence, with a higher prevalence amongst females. Furthermore, NCFB presents most aggressively amongst post-menopausal females, a group likely exposed to higher levels of progesterone (P4) over a longer period of time. The effects of gender-specific hormones on bacterial load and physiotherapy management of people living with NCFB remain unknown. The aim of this narrative review was to discuss the potential influence of gender specific hormones on NCFB disease progression and influence on physiotherapy, medical management and future research. SCOPUS and PUBMED electronic databases were used to conduct searches for relevant studies using specific inclusion and exclusion criteria. Secondary inclusion of relevant literature was obtained from primary paper references. Previous literature suggests that P4 may impair Cilia Beat Frequency (CBF) in airway epithelium. Reduction in CBF may further reduce ability to expectorate amongst individuals with NCFB, increasing bacterial load and likelihood of exacerbations, negatively impacting on disease progression. Furthermore, coadministration of Estrogen has been suggested to offer opposing effects to that of P4 only. These findings question whether hormonal levels may be monitored, controlled and optimised within management and treatment of females with NCFB to improve airway clearance, reduce exacerbations and improve quality of life. Larger scale, long-term trials are required to further explore the effects of gender specific hormones on NCFB and the viability of treatment with hormone replacement therapy.The reviews of this paper are available via the supplemental material section.

Ovarian Hormones Regulate SP-D Expression in the Mouse Uterus During Estrous Cycle and Early Pregnancy.

Differential expression of SP-D in the cycling human and mouse endometrium suggests its regulation by ovarian hormones. SP-D expression in the mouse uterus was analyzed across the estrous cycle and during early pregnancy. Effect of exogenous ovarian hormones on the uterine expression of SP-D was analyzed. SP-D expression varied across the estrous cycle and peaked in the estrous phase. SP-D transcript levels increased by fourfold in the uteri of estrogen-treated mice while co-administration of estrogen and progesterone enhanced SP-D levels by ninefold. However, treatment with progesterone alone significantly downregulated SP-D expression. Diethylstilbestrol enhanced SP-D transcript levels in the uteri of immature mice by 10-fold. During pregnancy, SP-D levels declined rapidly from 0.5 dpc to 6.5 dpc. In silico analysis predicted the presence of two potential ERE and 1 PRE in the mouse SP-D gene promoter region. Estrogen positively regulates expression of SP-D in the mouse uterus. Progesterone, along with estrogen synergizes SP-D expression, however, when administered alone results in negative regulation.

Subrenal xenograft model for human uterine leiomyoma in non obese diabetic severe combined immunodeficient mice

We established an in vivo xenograft model of human uterine leiomyoma (UL) in non-obese diabetic severe combined immunodeficient (NOD/SCID) interleukin (IL)-2Rγ-null mice1. In this model, a xenograft was grown beneath the kidney capsule by co-administration of estrogen (E) and progesterone (P); however, the low fecundity and high cost of the host together with the difficultly of the grafting procedure in the subrenal space have prohibited the use of this model as a research tool. Here, we modified the xenograft model using a severely immunocompromised host that is more suitable for UL research.

Estrogen and progesterone together expand murine endometrial epithelial progenitor cells.

Synchronous with massive shifts in reproductive hormones, the uterus and its lining the endometrium expand to accommodate a growing fetus during pregnancy. In the absence of an embryo the endometrium, composed of epithelium and stroma, undergoes numerous hormonally regulated cycles of breakdown and regeneration. The hormonally mediated regenerative capacity of the endometrium suggests that signals that govern the growth of endometrial progenitors must be regulated by estrogen and progesterone. Here, we report an antigenic profile for isolation of mouse endometrial epithelial progenitors. These cells are EpCAM(+) CD44(+) ITGA6(hi) Thy1(-) PECAM1(-) PTPRC(-) Ter119(-), comprise a minor subpopulation of total endometrial epithelia and possess a gene expression profile that is unique and different from other cells of the endometrium. The epithelial progenitors of the endometrium could regenerate in vivo, undergo multilineage differentiation and proliferate. We show that the number of endometrial epithelial progenitors is regulated by reproductive hormones. Coadministration of estrogen and progesterone dramatically expanded the endometrial epithelial progenitor cell pool. This effect was not observed when estrogen or progesterone was administered alone. Despite the remarkable sensitivity to hormonal signals, endometrial epithelial progenitors do not express estrogen or progesterone receptors. Therefore, their hormonal regulation must be mediated through paracrine signals resulting from binding of steroid hormones to the progenitor cell niche. Discovery of signaling defects in endometrial epithelial progenitors or their niche can lead to development of better therapies in diseases of the endometrium.

Regulation of expression of the retinoic acid metabolizing enzyme CYP26A1 in uteri of ovariectomized mice after treatment with ovarian steroid hormones

The retinoic acid (RA) synthesizing enzymes, retinaldehyde dehydrogenases (RALDH), are expressed in specific spatial and temporal patterns in uterine tissues during estrous cycle and early pregnancy in mice. Expression of RALDH1 and 2 has been shown to be induced by estrogen treatment within the uterus. In this study, we determined the influence of progesterone and 17-ss-estradiol on the uterine expression of the RA-metabolizing enzyme CYP26A1 after specific time intervals (1, 4, 24, and 48 hr after treatment of ovariectomized mice). In a following experiment, we investigated the influence of gestagen (promegestone 0.3 mg/kg body weight), estrogen (estradiol 3 microg/kg), their combination, as well as the antagonizing anti-progesterone hormone (RU 486 10 mg/kg) on the uterine expression of CYP26A1. Expression of CYP26A1 was localized using in situ hybridization and quantified using RT-PCR. CYP26A1 mRNA expression was strongly--although transiently--induced in uterine endometrial epithelial and glandular cells after administration of gestagen or the combination of gestagen + estrogen, but not by estrogen alone. These observations were confirmed by semi-quantitative RT-PCR experiments on whole uteri. Thus, we show that the expression of CYP26A1 in endometrial epithelial cells is regulated by progesterone and not significantly influenced by co-administration of estrogen. These data indicate an additional level of hormonal control of endogenous RA levels in the mouse uterus, where its synthesis would rely on estrogen-dependent expression of RALDH enzymes, whereas its active metabolism would be triggered by progesterone-induced CYP26A1 expression.

Progesterone receptor antagonist is effective in relieving neuropathic pain

Injury to the spinal nerves of mice induces allodynia and hyperalgesia. Intrathecal injection of the progesterone/estrogen receptor antagonist ICI 182,780 produced antinociceptive effects. Co-administration of estrogen did not reduce but tended to enhance the antinociceptive effect of ICI 182,780. On the other hand, co-administration of progesterone dose-dependently reduced the antinociceptive effect of ICI 182,780, indicating that the antinociceptive effect is through antiprogesterone receptor activity of ICI 182,780. These results suggest that spinal progesterone receptors play an important role in neuropathic pain, and that controlling the activity of progesterone receptors may be of great importance in the treatment of neuropathic pain.

Severely Suppressed Bone Turnover: A Potential Complication of Alendronate Therapy

Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.

Alteration of dopamine transport in the striatum and nucleus accumbens of ovariectomized and estrogen-primed rats following N-(p-isothiocyanatophenethyl) spiperone (NIPS) treatment

The ability of N-(p-isothiocyanatophenethyl) spiperone (NIPS, 10 mg/kg, 24 h), a selective, irreversible alkylating agent of the dopamine D 2 receptor, to alter properties of dopamine uptake and clearance in the striatum and nucleus accumbens of ovariectomized and estrogen-primed (estradiol benzoate, 10 μg, 48 h, 24 h) rats was examined using voltammetry. The effectiveness of NIPS was evaluated independently by measuring agonist mediated potentiation of [ 35S]-guanosine 5′-(γ-thiotriphosphate) ([ 35S]-GTPγS) binding and [ 3H]-dopamine uptake. A decrease in E max for ligand potentiated [ 35S]-GTPγS binding and a loss of quinpirole potentiated [ 3H]-dopamine uptake was observed consistent with a NIPS mediated alkylation and functional down-regulation of the dopamine D 2 receptor. This down-regulation was associated with an attenuation of the dose dependent uptake of dopamine in both the striatum and the accumbens. Co-administration of estrogen and NIPS resulted in a further attenuation of dopamine potentiated [ 35S]-GTPγS binding measured in vitro and dopamine uptake measured in vivo. Analysis of the voltammetric profile revealed that clearance and T 50 times were significantly prolonged in animals treated with estrogen and NIPS compared with those treated with NIPS alone. These data are consistent with both a steroid mediated impairment in dopamine autoreceptor/dopamine transporter coupling and an independent action of estrogen at the level of the dopamine transporter.

Estrogen blocks neurotoxic effects of β-amyloid (1–42) and induces neurite extension on B103 cells

Clinical studies have shown that estrogen replacement therapy is associated with reduced risk of Alzheimer's disease (AD). We tested whether or not estrogen blocks neurotoxic effects of β-amyloid (1–42) (A β 1–42) on cultured B103 cells. A β 1–42 (1 μM) induced typical necrotic cell death, as revealed by light and electron microscopic examinations. Co-administration of estrogen not only blocked A β 1–42 toxicity to a large degree, but also enhanced neurite extension. Pretreatment with estrogen was even more effective in blocking A β 1–42 toxicity. When added 18 h after the beginning of A β 1–42 treatment, estrogen was still effective in halting the progress of cell death and enhancing neurite extension. The protection against A β 1–42-induced neuronal death by estrogen was unlikely due to a blockade of lipid peroxidation injury, since estrogen completely failed to attenuate ferrous chloride-induced cell death. These results demonstrate that estrogen blocks A β 1–42-induced neurotoxicity and enhances neurite extension on B103 cells, both of which may well be underlying mechanisms of beneficial effects of estrogen in AD.

Effect of Chronic Exposure of Pregnant Rats to Malathion and/or Estrogen and/or Progesterone on Xenobiotic Metabolizing Enzymes

Pregnancy as well as exogenous administration of steroid hormones alters drug metabolizing enzymes, which could result in a change in the toxicity of malathion. The present study investigated the effect of exogenous estrogen and/or progesterone on malathion toxicity in pregnant rats and their 21-day-old pups. The activity of acetylcholinesterase in brain was taken as an index of malathion toxicity. Coadministration of estrogen plus malathion potentiated the malathion-induced toxicity while progesterone plus malathion at low dose decreased the toxicity, as evidenced by the changes in acetylcholinesterase activity in brain. The higher level of cytochrome P450 observed in estrogen plus malathion-administered rats might have stimulated the increased conversion of malathion to more potent malaoxon and also by blocking the glutathione S-transferase- and carboxylesterase-related detoxication process, resulting in increased malathion toxicity. However, coadministration of progesterone and malathion offered some degree of protection by stimulating the hepatic glutathione S-transferase- and carboxylesterase-mediated detoxication of malathion.

Sex Steroids and Growth Factors Differentially Regulate the Growth and Differentiation of Cultured Human Endometrial Stromal Cells*

We have studied the interaction between growth factors and sex steroids in regulating human endometrial stromal cell growth and differentiation using an in vitro serum-free cell culture model system. None of the growth factors [epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin, insulin-like growth factor-I (IGF-I), IGF-II, or platelet-derived growth factor] stimulated the growth of human endometrial stromal cells grown in progestin-free medium. However, the growth of progestin-treated cultures was dramatically increased by EGF, bFGF, or platelet-derived growth factor, but not by insulin, IGF-I, or IGF-II. Estrogen could not substitute for progesterone in this protocol, and coadministration of estrogen with progestin did not enhance the response over that to progesterone alone. In contrast to their positive effects on growth, only EGF, not bFGF, stimulated stromal cell differentiation, as measured by an increase in PRL, laminin, and fibronectin production; moreover, stimulation of differentiation was dependent upon the presence of progestin in the culture medium. Thus, human endometrial stromal cell growth is 1) regulated by a discrete set of growth factors, only a subset of which regulates stromal cell differentiation; and 2) regulation of stromal cell growth and stromal cell differentiation by growth factors is progestin dependent. Our results provide direct evidence for interaction between growth factors and sex steroids in the regulation of stromal cell growth and differentiation in vitro and suggest that growth factors may be absolutely required in conjunction with progesterone for the decidual response in vivo.

DNA adduct formation in liver and kidney of male Syrian hamsters treated with estrogen and/or α-maphthoflavone

Chronic administration of estrogens to male Syrian hamsters induces kidney tumors. Co-administration of estrogen plus alpha-naphthoflavone (ANF) suppresses this kidney carcinogenesis but induces liver tumors instead. In an attempt to elucidate the mechanism of the switch from estrogen-induced kidney to liver carcinogenesis in response to ANF treatment, patterns of kidney and liver DNA adducts were investigated by 32P-postlabeling analysis and compared to controls. Chronic treatment of hamsters with ANF alone or in combination with estradiol resulted in a flavone-specific DNA adduct pattern in livers of these animals. These spots, adducts 1 and 2, on 32P-postlabeling maps were taken as evidence of covalent ANF-DNA modifications. The kidney-specific estrogen-induced indirect DNA adducts, observed previously in hamsters treated chronically with estrogen, occurred in renal but not hepatic DNA of animals treated with estradiol alone or in combination with ANF. Pretreatment of hamsters with ANF for 3 days decreased by 75-80% the hepatic and renal diethylstilbestrol (DES)-DNA adducts, which are formed after injection of a single large dose of DES. It is concluded from these changes in DNA adduct patterns and levels that estrogen quinone-DNA adduction may play an etiological role in estrogen-induced kidney cancer. The prevention of estrogen-induced kidney tumors by ANF co-treatment may be a consequence of the decrease in renal concentrations of these adducts in response to ANF. Hepatic concentrations of estrogen quinone-DNA adducts also decrease, but ANF-DNA adducts, observed only in liver, may assume an etiological role in the induction of hepatomas.