Injection Of Estradiol Valerate Research Articles

Exploring the Therapeutic Potential of Sodium Hydrosulfide in Alleviating Oxidative Stress and Ovarian Dysfunction in a Rat Model of Polycystic Ovary Syndrome.

Oxidative stress is known to play a key role in the occurrence of polycystic ovary syndrome (PCOS) as the most common cause of anovulatory infertility. The purpose of the current study was to investigate whether diminished activity of ovarian enzymes responsible for hydrogen sulfide (H2S) production, cystathionine β-synthase (CBS), and cystathionine γ-lyase (CSE) contributes to oxidative stress in PCOS. The study also explored whether administration of sodium hydrosulfide (NaSH), an H2S donor, could ameliorate PCOS symptoms by reducing oxidative stress. The total eighteen rats were randomly assigned into three groups (n=6): control, PCOS, and PCOS+NaSH. PCOS was induced by intramuscular injection of estradiol valerate to induce PCOS in the PCOS and PCOS+NaSH groups. The PCOS+NaSH group received 30 μmol/L of NaSH in drinking water for 27 days after PCOS induction. Ovarian tissue samples were analyzed for oxidative stress indices including malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Additional analyses measured H2S levels, CBS, and CSE activity. PCOS induction led to a significant decrease in SOD activity, H2S levels, and CBS and CSE activity, accompanied by a significant increase in MDA levels (p<0.0001). Furthermore, PCOS caused severe histological alterations in the ovaries. However, administration of NaSH effectively restored all measured parameters to pre-PCOS induction levels (p<0.0001). This study showed that the decrease in the activity of H2S-producing enzymes and H2S levels may contribute to oxidative stress in PCOS. Therefore, administration of NaSH as a H2S donor can be considered as a potential therapeutic strategy for PCOS patients.

The significant improvement in ovarian PCOS syndrome using hydralazine and alendronate aromatase inhibitor FDA-approved drugs in Wistar rat models

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C, glutamine, mesalazine, hydralazine, and alendronate as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. PCOS was induced in rats by intramuscular injection of estradiol valerate (2 mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5 mg/kg), vitamin C (100 mg/kg), glutamine (1000 mg/kg), mesalazine (200 mg/kg), hydralazine (30 mg/kg), and alendronate (17.5 mg/kg). Serum testosterone, LH, FSH, estradiol and progesterone levels were determined by ELISA method. H&E staining was used for histological analysis in the ovarian tissues. The groups treated with hydralazine and alendronate, show a significant decrease in testosterone, LH hormone, cystic and atretic follicles, and a significant increase in the number of single layer, multilayer, antral, graafian follicles and the volume of corpus luteum as compared to the PCOS group. Hydrolazine and alendronate appear to be effective in restoring folliculogenesis and increasing ovulation in PCOS rat. So that the natural process of ovulation and the improvement of the histology of polycystic ovaries and its shift towards healthy and active ovaries were observed. This finding supports the potential beneficial effect of hydrolazine and alendronate on improving PCOS complication.

The effect of ellagic acid on sex hormones and miRNA-21 expression in rats with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. It is characterized by irregular menstrual cycles, hyperandrogenism, and polycystic ovaries. The syndrome's etiology is multifactorial, involving genetic, hormonal, metabolic, and environmental factors. Given its diverse effects, managing PCOS requires a comprehensive approach. This study employed a Sprague-Dawley rat model to investigate the effects of ellagic acid on polycystic ovary syndrome (PCOS). Forty adult female rats were randomly divided into four groups: a control group, a healthy group receiving ellagic acid (200mg/kg), a PCOS group, and an ellagic acid + PCOS group. PCOS was induced in the relevant groups through subcutaneous injection of estradiol valerate (2mg/kg), and ellagic acid was administered via subcutaneous injections for 14 days. Blood samples were collected for hormone analysis using the ELISA method, and ovarian tissues were processed for histological examination. Ellagic acid treatment showed reduced LH levels and restoration of follicular development, particularly primordial and graafian follicles, along with modulation of miRNA-21 expression. Moreover, ellagic acid exhibited positive effects on ovarian morphology, including decreased theca layer thickness, increased oocyte diameter, and improvements in antral and preovulatory follicles. This suggests ellagic acid's potential in addressing follicular development and oocyte quality in PCOS. These findings suggest ellagic acid as a potential complementary approach in PCOS management. While the study is promising, further research, including clinical trials, is required to elucidate ellagic acid's mechanisms and clinical efficacy in human PCOS subjects.

(017) Systemic Estradiol Menopause Management: Return to the Old-Fashioned Way

Abstract Introduction The mean systemic estradiol value in menopausal women is &amp;lt; 10 pg/ml, consistent with ovarian failure. Such low values are associated with multiple symptoms including hot flashes, night sweats, insomnia, mood changes and irritability, cognitive changes, weight gain and slowed metabolism. Contemporary management with systemic estradiol, maximizing safety and efficacy, emphasizes non-oral, non-injection estradiol replacement therapies including systemic daily gels, twice weekly or weekly patches or three-month vaginal rings. Most women (&amp;gt;60%) who try these systemic therapies in our sexual medicine clinic have been successful at reducing bothersome symptoms. We have identified a subset of women who cannot achieve sufficient symptom relief despite using contemporary estradiol strategies due to lack of efficacy, negative side effects, (rings cannot stay in the vagina or values are too high initially and then too low, patches cause rashes or fall off, gels are too messy) or financial concerns. For these patients, we have advised a return to the “old-fashioned way” using weekly intramuscular (IM) injection of either estradiol valerate or cypionate. Estradiol cypionate was first described as well as introduced for medical use in 1952. Objectives This study examines the experiences of this subset of women in one practice using weekly injections of estradiol valerate or cypionate for either efficacy or financial reasons. Methods This chart review identified a subset of 16 patients (mean age 59 +/− 8 years) at a single site who had been prescribed estradiol valerate or cypionate when symptoms of genitourinary syndrome of menopause (GSM) persisted despite use of estradiol replacement gels, patches or rings, or cost was prohibitive. We have advised weekly IM injection of either estradiol valerate (20 mg/ml; starting dose 0.05 ml or 1 mg) or estradiol cypionate (5 mg/ml; starting dose 0.2 ml or 1 mg). We compared relief of bothersome symptoms from earlier estradiol treatments to current IM injection and compared monthly costs of each treatment based on GoodRx prices, assuming medications were not covered by insurance. Results All patients using weekly injections of estradiol valerate or cypionate had their estradiol-based GSM symptoms ameliorated without complaint of inconvenience or discomfort using injections. The risks of IM injections of estradiol are similar to those of topical administration, requiring concomitant progesterone use in women with a uterus. Concerning finances, using a GoodRx coupon, a 5 ml bottle of estradiol valerate costs approximately $50 and should last at least one year, reducing monthly cost to approximately $5/month. A 5 ml bottle of estradiol cypionate costs approximately $150 and should last at least 6 months, thus about $25/month. In contrast, generic patches are approximately $40/month, gels $150/month and the ring $170/month. While there remains an abhorrence for injections, the motivation for systemic estradiol replacement superseded any inconvenience of using an injectable medication and the 27-gauge ½ inch needle is associated with minimal pain. No significant side effects were noted with IM injection. Conclusions For certain individuals, sometimes the “old-fashioned way” works better both in terms of efficacy and cost, providing relief of bothersome menopausal symptoms. Disclosure No.

The Effects of Clove Oil on The Biochemical and Histological Parameters, and Autophagy Markers in Polycystic Ovary Syndrome-Model Rats.

This study aimed to determine whether syzygium aromaticum (clove) could help polycystic ovary syndrome (PCOS) rats. In this experimental study, forty adult female Wistar rats (weighing 250 ± 10 g) were divided randomly into five groups; G1: control, G2: PCOS group, G3: PCOS+clove (30 mg/kg/ orally/daily) group, G4: PCOS+clove (60 mg/kg/orally/daily) group, and G5: PCOS+gonadectomy group. The PCOS was induced by a single dose injection of estradiol valerate (16 mg/kg/IM). Following PCOS induction, the rats were treated for 14 days. Histological parameters, follicle apoptosis, mRNA expression of autophagy markers (Lc3, Beclin1), oxidative stress markers, insulin and blood glucose levels, as well as serum levels of aromatase and testosterone were evaluated in these rats. Finally, the ratio of serum luteinizing hormone (LH) to follicle-stimulating hormone (FSH) levels was also calculated. The autophagy markers (Lc3, Beclin1), histological parameters, oxidative stress, insulin, and hormone levels changed significantly in the PCOS rats (G2). In G3 and G5 groups, it was observed that the levels of LH/FSH and testosterone decreased significantly in comparison to the PCOS group, and inhibition of autophagy was also observed in these groups. Treatment with cloves in the G3 group significantly improved oxidative stress, histological parameters, and insulin levels. These findings demonstrated that oxidative stress, apoptosis, and excessive autophagy could be improved by treatment with low doses of clove and gonadectomy. Cloves may help to improve these parameters by regulating and inhibiting excessive autophagy. However, discovering the direct role of this extract in regulating the parameters such as oxidative stress, insulin, and androgens requires further investigation. In the present study, P<0.05 was considered statistically significant.

The Effect of Sitagliptin on Inflammatory Mediators in the Ovary of Rat with Polycystic Ovary Syndrome

Background and Aims: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disease in females of reproductive age and is a significant infertility cause. Inflammation plays a crucial role in the pathogenesis of PCOS. The present study evaluated whether sitagliptin, dipeptidyl peptidase-4 inhibitor, attenuates inflammatory markers C-reactive protein (CRP), interleukin(IL)-6, tumor necrosis factor-α (TNF-α), IL-1β, and transforming growth factor-β (TGF-β) in a rat model of PCOS.&#x0D; Materials and Methods: Twenty-two female adult Wistar rats were randomly divided into four groups: control, PCOS model, PCOS+sitagliptin (25 mg/kg), and PCOS+sitagliptin (50 mg/kg). PCOS was induced by injection of estradiol valerate, intraperitoneally. Sitagliptin was gavaged daily for 30 days to both groups of animals. After the treatment period, blood and ovaries tissue were collected to analyze inflammatory parameters.&#x0D; Results: The mRNA levels of IL-6, IL-1β, TGF-β, and TNF-α in the PCOS model group were markedly elevated compared with the control group (p&lt;0.01). These parameters' mRNA levels were reduced in the sitagliptin treatment groups compared with the PCOS group (p&lt;0.01). Also, the serum concentration of CRP in the PCOS group was more than the control. This increase significantly decreased in groups treated with sitagliptin compared with the PCOS group.&#x0D; Conclusion: The presented study suggested that the protective effects of sitagliptin on PCOS may be due to its inhibitory effect on expression and inflammatory markers' levels.

Systemic Estradiol Menopause Management: Return to the Old-Fashioned Way

ABSTRACT Introduction Low systemic estradiol values (&amp;lt;10 pg/ml) experienced by menopausal women are associated with multiple symptoms including hot flashes, night sweats, insomnia, mood changes/irritability, vaginal dryness, dyspareunia, dysuria, low libido, reduced arousal/orgasm, cognitive changes, weight gain and slowed metabolism. Intramuscular estradiol cypionate was first described for medical use in 1952 to treat symptoms of menopausal ovarian failure. Systemic management has evolved, including daily gels, weekly/twice weekly patches and three-month vaginal rings. These therapies have successfully reduced bothersome symptoms in &amp;gt;60% women presenting to our clinic. A subset of women cannot achieve sufficient symptom relief using these strategies due to lack of efficacy, negative side effects, (rings cannot stay in the vagina; values are too high initially and then too low; patches cause rashes or fall off; gels are too messy) or financial concerns. For these patients, we have advised returning to the “old-fashioned way” using weekly or twice weekly intramuscular (IM) injection of either estradiol valerate or cypionate. Objective This study examines experiences of this subset of women in our practice using injections of estradiol valerate or cypionate for either enhancing efficacy or financial reasons. Methods This chart review identified 22 patients (mean age 61 +/- 8 years) who had been prescribed estradiol valerate or cypionate when symptoms of genitourinary syndrome of menopause (GSM) persisted despite use of estradiol replacement gels/patches/rings, or cost was prohibitive. We have advised weekly/twice weekly IM injection of either estradiol valerate (20 mg/ml; starting dose 0.05 ml (1 mg) weekly or 0.025 ml (0.5 mg) twice weekly) or estradiol cypionate (5 mg/ml; starting dose 0.2 ml weekly (1 mg) or 0.1 ml (0.5 mg twice weekly), utlizing 1 ml syringes with 27-gauge ½ inch needle. Injections were administered into the vastus lateralis on the antero-lateral surface at mid-thigh. Alcohol was used to prepare the skin, and compression was applied for 2 minutes after the injection. We compared relief of bothersome symptoms from earlier estradiol treatments to current IM injection and monthly costs of each treatment based on GoodRx prices, assuming medications were not covered by insurance. Results All patients using injections of estradiol valerate or cypionate had their estradiol-based GSM symptoms ameliorated without complaint of inconvenience or discomfort using injections. All described injection pain as minimal. No significant side effects were noted with IM injection. The risks of IM injections of estradiol are similar to those of topical administration, requiring concomitant progesterone use in women with a uterus. Concerning finances, using a GoodRx coupon, a 5 ml bottle of estradiol valerate lasting at least a year costs approximately $50, reducing monthly cost to approximately $5/month. A 5 ml bottle of estradiol cypionate lasting at least 6 months costs approximately $150, thus about $25/month. In contrast, generic patches can cost approximately $40/month, gels $150/month and the ring $170/month. Conclusions While there remains an aversion to injections in some patients, the motivation for IM systemic estradiol replacement superseded any inconvenience. For certain individuals, the “old-fashioned way” works better both in terms of efficacy and cost, providing relief of bothersome GSM symptoms. Disclosure No

Molecular docking and mouse modeling suggest CMKLR1 and INSR as targets for improving PCOS phenotypes by minocycline.

Polycystic ovary syndrome (PCOS) is the most common cause of women's infertility. Some inflammatory pathways play a pivotal role in the pathogenesis of PCOS. This study aimed to investigate the possible beneficial effects of minocycline on chemokine-like receptor 1 (CMKLR1) and Insulin Receptor (INSR) in a PCOS model. A molecular docking study was implemented using Molecular Operating Environment (MOE) software. The PCOS was induced in NMRI mice (mean body weight 14.47±0.23) by 28 days estradiol valerate injection (2 mg/kg/day). The mice were then divided into six groups (n=8 per group, mean body weight 17.77± 0.26): control (received normal saline), PCOS model, control for minocycline, minocycline treated PCOS (50 mg/kg), letrozole treated PCOS (0.5 mg/kg), and metformin-treated PCOS (300 mg/kg). Serum FSH, LH, estradiol (E2), and testosterone were detected by ELISA. The ovarian tissues were stained by hematoxylin and eosin. The CMKLR1 and INSR expression levels were determined by Real-time-PCR. The molecular docking studies showed scores of -10.92 and -9.30 kcal/mol, respectively, for minocycline with CMKLR1 and INSR. Estradiol valerate treatment led to a significant increase in E2, graffian follicle, and decrease in corpus luteum (CL) numbers (P<0.05), while minocycline treatment improved these PCOS features. The minocycline treatment significantly decreased the CMKLR1 expression and increased the INSR expression (P<0.05) while the CMKLR1 expression was increased in PCOS model. Minocycline may improve ovulation in PCOS model by returning E2 to a normal level and increasing CL number (ovulation signs). These beneficial outcomes may be related to the changes in CMKLR1 and INSR gene expression involved in glucose metabolism and inflammation.

Modulatory effects of R10 fraction of garlic (Allium sativum L.) on hormonal levels, T cell polarization, and fertility-related genes in mice model of polycystic ovarian syndrome

Polycystic ovary syndrome (PCOS) is an inflammatory endocrine-metabolic disorder related to reproductive system characterized by polycystic ovarian morphology, androgen excess, and chronic anovulation. Current treatments haven’t been very successful in PCOS treatment and the problem still remains as a challenge. Therefore, new approaches should be applied to overcome the disease. Previous studies demonstrated immunomodulatory effects of R10 fraction of garlic in the treatment of inflammatory conditions such as cancer. Considering previous studies suggesting immunomodulatory therapy for PCOS, therapeutic effects of R10 fraction was evaluated in a mouse model of PCOS. To do so, PCOS was developed by intramuscular injection of estradiol valerate. Treatment with R10 fraction, isolated from garlic, was performed and the alterations in hormonal levels (estradiol, progesterone, and testosterone), T cell polarization markers (IFN-γ, IL-4, and IL-17), and expression of fertility-related genes (Gpx3 and Ptx3) were evaluated. The results showed that hormonal levels were elevated in PCOS model comparing to normal animals but were markedly modulated after treatment with R10 fraction. Moreover, a severe disturbance in T cell polarization with a significant reduction of fertility-related genes expression were detected in PCOS-induced ovaries. Treatment with R10 fraction also represented modulatory effects on T cell polarization by increasing IL-4 and decreasing IL-17 and IFN-γ levels. Accordingly, fertility-related genes were also modulated following treatment with R10 fraction in PCOS. Our study elucidated that R10 fraction of garlic possess immunomodulatory effects alleviating PCOS symptoms. This approach could be adjusted to give rise the optimum therapeutic results and considered as a candidate therapeutic approach for PCOS.

Therapeutic potential of hydrolysable tannin on weight management oxidative stress and reproductive health in polycystic rats

Phytonutrients get attention now days due to their wide application and their tendency to improve the productive and reproductive performance in humans. Hydrolysable tannin (HT) is one of these bionutrients. The present study was aimed to investigate the therapeutic effect of HT on the induced polycystic ovarian syndrome (PCOS) in rats. Forty-five adult female rats with 4 to 5 days regular estrous cycle were selected. The PCOS was induced by a single intramuscular injection of Estradiol Valerate 4 mg/rat/kg. The rats were offered 0.5, 1, 1.5 and 2% of HT/kg body weight through oral gavage for two months. The results had shown a reduction (p<0.05) in average feed intake, body weight and weight gain, total oxidative stress and nutrient digestibility in PCOS rats. Similar reduction trend (p<0.05) in serum luteinizing hormone and insulin was observed; while serum follicular stimulating hormone, serum prolactin and total antioxidant capacity were improved (p<0.05). The ovarian histopathology showed no signs of reduction in cystic follicles while no improvement was observed in healthy follicles. The study concluded that the treatment with 1.5% level of HT had shown the best therapeutic potential for weight management, reduction of oxidative stress and improvement in reproductive health of PCOS rats.

Participation of the Cholinergic System in the Development of Polycystic Ovary Syndrome.

In rats with polycystic ovary syndrome (PCOS) induced by injection of estradiol valerate (EV), unilateral or bilateral section of the vagus nerve restores ovulatory function in 75% of animals, suggesting that the vagus nerve participates in the development of PCOS. Since the vagus nerve is a mixed nerve through which mainly cholinergic-type information passes, the objective of the present study was to analyze whether acetylcholine (ACh) is involved in the development of PCOS. Ten-day-old rats were injected with 2.0 mg EV, and at 60 days of age, they were microinjected on the day of diestrus in the bursa of the left or right ovary with 100 or 700 mg/kg of ovarian weight atropine, a blocker of muscarinic receptors, and sacrificed for histopathological examination after the surgery. Animals with PCOS microinjected with 100 mg of atropine showed a lack of ovulation, lower serum concentrations of progesterone and testosterone, and cysts. Histology of the ovaries of animals microinjected with 700 mg of atropine showed corpus luteum and follicles at different stages of development, which was accompanied by a lower concentration of progesterone and testosterone. These results allow us to suggest that in animals with PCOS, ACh, which passes through parasympathetic innervation, is an important component in the persistence and development of the pathophysiology.

A role for GABA agonist in controlling the reproduction of female rats via hypothalamic ghrelin, kisspeptin, and RFRP-3 gene expression

Kisspeptin stimulates gonadotropin releasing hormone (GnRH). The GnRH neurons receive inhibitory inputs from ghrelin, RFamide related peptide-3 (RFRP-3), and gamma-aminobutyric acid (GABA) neurons. Polycystic ovary syndrome (PCOS) is associated with increased levels of GnRH/LH and kisspeptin, and decreased release of GABA, ghrelin, and RFRP-3. In the present study, the effects of GABAB receptor agonist, baclofen, were investigated on GnRH, KiSS1, RFRP-3, and ghrelin gene expression in the hypothalamus of PCOS model rats. For induction of PCOS, female Wistar rats weighing 180-200g received intra-muscular injection of estradiol valerate. Fifteen PCOS rats in three groups received intraperitoneal injections of saline, 5, or 10 mg/kg baclofen for two weeks. The hypothalamic samples were dissected. Gene expression levels of GnRH, KiSS1, RFRP-3, and ghrelin were determined by real time qPCR method. Results revealed that baclofen significantly decreased the mean relative KiSS1 gene expression compared to PCOS group. Also, the mean relative RFRP-3 gene expression significantly increased in the baclofen-receiving rats in comparison to PCOS group. Furthermore, baclofen did not change GnRH or ghrelin mRNA levels in comparison to PCOS group. According to these results it can be concluded that in PCOS condition the GABAergic signaling pathway may suppress GnRH neural activity via down or up regulation of the intra-hypothalamic neuropeptides upstream of GnRH neurons.

Beneficial effects of minocycline on the ovary of polycystic ovary syndrome mouse model: Molecular docking analysis and evaluation of TNF-α, TNFR2, TLR-4 gene expression

Polycystic ovary syndrome (PCOS) is the most common cause of ovulatory infertility. Inflammation may be involved in the pathogenesis and development of PCOS. We investigated the anti-inflammatory effect of minocycline on TNF-α, TNFR2, and TLR4 expression levels and the key features of PCOS in a mouse model. Molecular docking was performed by Molecular Operating Environment software. PCOS was induced by estradiol valerate injection (EV) (2 mg/kg/day) in 40 mice. After 28 days, the mice were divided into five groups, including control, PCOS, minocycline control, minocycline PCOS model (50 mg/kg), and letrozole PCOS (0.5 mg/kg). The Levels of FSH, LH, E2, and testosterone were determined by ELISA. H&E staining was used for histological analysis in the ovarian tissues. Docking scores were −10.35, −10.57, and −12.45 kcal/mol for TNFα, TLR-4, and TNFR2, respectively. The expression levels of TNF-α, TNFR2, and TLR4 were detected by Real-Time PCR. PCOS models exhibited acyclicity, a significant increase in E2 levels (P < 0.01), and no difference in FSH, LH, and testosterone. The expression levels of TNF-α, TNFR2, and TLR-4 significantly increased in PCOS (2.70, 7.90, and 14.83-fold, respectively). EV treatment significantly increased graafian follicles (P < 0.001) and decreased corpus luteum (CL) (P < 0.01). Minocycline treatment in PCOS led to a significant decrease in E2 (P < 0.01) and graafian follicles (P < 0.001) and a significant increase in the CL numbers (P < 0.05). Our findings showed the positive effects of minocycline on estradiol level, CL and graafian follicles counts, suggesting that minocycline might inhibit these proteins and improve ovulation in our mouse model of PCOS.

SUN-LB8 Cross Sex Hormone Therapy and Breast Cancer in Transgender Male to Female

Case Presentation: We are presenting a 53-year-old Male to Female transgender patient who has been receiving estradiol valerate injections every 14 days for 13 years and had no gender surgical reassignment procedures or breast implants. Her past medical history was significant for HIV on Highly Active Anti-retroviral therapy (HAART). No family history of breast cancer. She presented with severe bilateral left elbow, lower back and bilateral chest pain for 3 days. Chest CT done to exclude pulmonary embolism showed an incidental 4 cm right breast mass. Enlarged lymph nodes in the right axilla, scattered lytic lesions in the axial skeleton and the left humeral head were also noted. Breast exam was not performed until the significant findings were seen in CT chest and it showed a palpable hard-circumscribed subareolar right breast mass without skin changes. Ultrasound guided biopsy of the breast mass confirmed invasive ductal carcinoma of the breast. The patient had no previous mammogram testing. Oncology work-up was positive for estrogen and progesterone receptors but negative for human epidermal growth factor-2 receptor. The patient opted to return home in another state to seek treatment and further oncological workup but subsequently lost follow up. Discussion: Male to female breast cancer was first recognized in 1968. However, risk factors for this condition remain unclear. In our patient, long-term use of Cross-sex Hormone Therapy (CHT) represented a major risk factor for breast cancer. In a Dutch study, the risk of breast cancer increased during a relatively short duration of CHT and the cancer characteristics reassembled female pattern. As theoretically implicated, increased estrogen exposure in males may have a role in the proliferation of neoplastic breast epithelium. There are growing evidence to support increasing rates of breast cancer in HIV-positive population, making it a potential risk factor as well. Loss of CXCR-4 protective effect promoted by HIV virus may explain the increase in the breast cancer incidence after the introduction of HAART. In general, routine screening for breast cancer in MTF transgender population remains controversial. The Endocrine Society Clinical Practice guidelines suggest that MTF transsexual individuals who have no known increased risk of breast cancer should follow screening guidelines for biological women. While the Canadian Cancer Society recommends screening mammography every two years for MTF individuals taking CHT for more than 5 years and those between the ages of 50 and 69 years. Conclusion:Breast cancer in MTF transgender patients is associated with receiving CHT and represents diagnostic and treatment challenge. More research is need to comment on routine breast cancer screening in this population. However, physicians should remember performing a regular breast exam in MTF individuals looking for a possible mass.

A combination of spearmint and flaxseed extract improved endocrine and histomorphology of ovary in experimental PCOS

BackgroundPolycystic ovary syndrome (PCOS) is a complex reproduction and endocrine disorder of women in the reproductive age. Spearmint (Mentha spicata L.) has anti-androgenic activity and flaxseed (Linum usitatissimum L.) contains phytoestrogen and was reported to improve PCOS conditions. This study aimed to evaluate PCOS conditions following administration of a mixture of these two plants.MethodsTwenty-four rats with regular cycles were randomly divided into four groups as control (C) and treatment-control (TC) received a combination of spearmint extract (SE) + flaxseed extract (FE). PCOS was induced in PCOS and treatment (T) groups by a single intramuscular injection of estradiol valerate. The treatment group received a combination of SE and FE for 30 days, 7 weeks after injection of estradiol valerate. Estrous cycles were monitored for 10 days and in the last day animals were sacrificed, ovaries were collected for the histomorphometric study and the serum levels of progesterone, testosterone, estradiol, and dehydroepiandrosterone (DHEA) were measured.ResultSignificant rise in progesterone and a decrease in testosterone and estradiol with no significant change of DHEA in the T group, was observed in comparison with the PCOS group (P < 0.05). No significant difference noticed between T and control groups (C &CT) regarding evaluated hormones. A significant increase in primary, pre-antral and antral follicles noticed in the T group compared to the PCOS group. The number of cystic follicles decreased in the T group compared with the PCOS group. Granulosa layer thickness increased while the thickness of theca decreased significantly in the T group compared to the PCOS group (P < 0.05). No significant endocrine or histological differences noticed between C and TC groups.ConclusionA combination of flaxseed and spearmint extract improved the endocrine profile and the histomorphometric features of the ovary in the T group compared to the PCOS group.

Comparison the Effect of Metformin and Clomiphene Citrate on Sirtuin3 gene Expression in the Oocytes of Mice with Polycystic Ovary Syndrome.

Oxidative stress (OS) is a common biological event in polycystic ovarian syndrome (PCOS), causing oocytes to undergo OS-induced changes. Sirtuin3 (Sirt3) has a critical role in oocyte maturation through the modulation of OS. In the current study, we compared the effects of metformin and clomiphene citrate on the expression of the Sirt3 gene in oocytes obtained from the mice, induced by PCOS. The induction of PCOS was performed by the single injection of estradiol valerate. The animals were divided into control, PCOS, metformin (500 mg/Kg), and clomiphene (18 mg/kg) groups. At the end of the experiment, the levels of LH and FSH were determined using the ELISA method. The ovarian tissues were evaluated histologically, and the expression of the Sirt3 gene was analyzed by the Real-time PCR. The induction of PCOS led to an increase in the ratio of LH/FSH elevation, the number of follicle atresia, as well as the presence of hydrated cysts. The results showed that both treatment regimens returned the altered parameters to the baseline values. The gene of Sirt3 was significantly (P < 0.001) reduced in the PCOS group compared to the control. Also, no significant difference was found in the expression of Sirt3 between clomiphene and PCOS group, whereas, in the metformin group, Sirt3 expression had the higher rate of expression in comparison with the PCOS group (P < 0.05). The administration of metformin and clomiphene showed that metformin is capable of preventing the downregulation of the Sirt3 gene in oocytes, collected from PCOS mice.

Alteration of ACTH and Cortisol Levels After Estradiol Valerate Treatment in a Male Subject With Gender Dysphoria: A Case Report

Background: The number of subjects with gender dysphoria has been increasing. In general, male-to-female transsexual subjects are treated with estradiol valerate therapy. In this report, we showed the time course of ACTH and cortisol levels after estradiol valerate injection in a male subject with gender dysphoria. It seemed that alteration of estradiol levels influenced ACTH and cortisol levels via some pathway.Case presentation: A 31-year-old man with estradiol valerate therapy for gender dysphoria was referred due to an elevation of serum cortisol levels. She started hormone therapy at 26 years old. Her laboratory analyses showed an elevation of plasma ACTH and cortisol levels. There were no remarkable changes in the adrenal gland and pituitary gland. Her estradiol levels were elevated 7 days after estradiol valerate injection, but they were not detected 18 days after such treatment. Interestingly, plasma ACTH and serum cortisol levels were moderately decreased 7 days after estradiol valerate injection, but both were markedly elevated 18 days after such treatment.Conclusions: We should bear in mind the possibility of elevation in plasma ACTH and serum cortisol levels when we start estradiol valerate injection in subjects with gender dysphoria. In addition, we may need to check ACTH and cortisol levels when we use estrogen replacement therapy for a long period of time in subjects with gender dysphoria.

In Adult Rats With Polycystic Ovarian Syndrome, Unilateral or Bilateral Vagotomy Modifies the Noradrenergic Concentration in the Ovaries and the Celiac Superior Mesenteric Ganglia in Different Ways.

In rats with polycystic ovarian syndrome (PCOS) induced by estradiol valerate (EV) injection, sectioning of the vagus nerve in the juvenile stage restores ovulatory function, suggesting that the vagus nerve stimulates the onset and development of PCOS. We analyzed whether in adult rats, the role played by the vagus nerve in PCOS development is associated with the nerve’s regulation of noradrenergic activity in the celiac superior mesenteric ganglion (CSMG). Ten-day-old rats were injected with corn oil [vehicle (Vh)] or EV (2 mg). At 76 days of age, rats injected with Vh or EV were subjected to sham surgery or the sectioning of one or both vagus nerves (vagotomy). The animals were sacrificed at 80–82 days of age at vaginal estrus smear. Compared to Vh-treated animals, EV-induced PCOS rats showed a lack of ovulation, the presence of follicular cysts, and a high concentration of testosterone, without changes in noradrenaline concentrations in the CSMG or ovaries. In PCOS rats, sham surgery lowered serum testosterone and noradrenaline concentrations in the CSMG but did not restore ovulation. In animals with PCOS, vagotomy lowered testosterone concentrations to a larger degree than in sham-surgery animals. The ovaries of rats with PCOS and vagotomy showed fresh corpora lutea, indicating ovulation. In EV-treated rats with unilateral vagotomy, the concentration of noradrenaline in the CSMG was similar to that in rats with PCOS and sham surgery, which did not ovulate, while in the ovaries of PCOS rats with left or bilateral vagotomy, the noradrenaline concentration was lower than that in sham-surgery-treated animals. Our results suggest that the vagus nerve regulates PCOS development through a different mechanism than the increase in the noradrenergic activity in the CSMG; however, in ovaries, the restoration of ovulation is associated with a decrease in ovarian noradrenaline.

Use of Photobiomodulation and Mesenchymal Stem Cells in Polycystic Ovary Syndrome‐Induced Rats

Evaluation was made of glycemia and gonadosomatic index (GSI) variations in rats with induced polycystic ovary syndrome (PCOS), following application of photobiomodulation (PBM) and injection of mesenchymal stem cells (MSCs). Eighty adult Wistar rats (n = 10 per group) were divided into control (C), PCOS, PBM, MSC, PCOS/PBM, PCOS/MSC, PBM/MSC, and PCOS/PBM/MSC groups. PCOS was induced by single injection of estradiol valerate (EV) (2 mg/kg/bw/i.m.). The animals were evaluated 30 and 60 days after induction. MSCs were injected directly into the ovaries (5×105cells/0.2 mL physiological solution in each ovary), on the same day as PCOS induction. The animals were irradiated with a laser (wavelength 808 nm, power 60 mW), using a dose of 3 Joules(J)/point on each ovary, 3 times weekly, totaling 6 J of energy for each irradiated animal per day of application. After sacrifice, plasma glucose was determined and the ovaries were removed and weighed for GSI determination (ovary weight/body weight × 100). Statistical analysis of the data was performed using ANOVA and Fisher's test. The results were reported as means ± SEM. This study was approved by the local Animal Care and Use Committee (CEUA–UNIARA, protocol nº 019/16). Glycemia: There were reductions in glycemia for all exposed groups, compared to the 30‐day C group (260.2 ±37 mg/dL), with the lowest values for the PCOS/PBM/MSC group (103.6 ±12.58 mg/dL). Compared to the 30‐day PCOS group (186.2 ±79.7 mg/dL), glycemia was lower for groups PBM/MSC (115.6 ±15.32 mg/dL) and PCOS/PBM/MSC (103. 6 ±12.58 mg/dL). After 60 days of treatment, the PCOS/MSC group presented lower glycemia (101.8 ±20.03 mg/dL), compared to the C group (160.6 ±42.3 mg/dL). 30‐days GSI: The PCOS/PBM(0.019 ±0.006%), PCOS/MSC (0.018 ±0.0061%), PBM/MSC (0.029 ±0.02%), and PCOS/PBM/MSC (0.027 ±0.008%) groups showed increased GSI, compared to the C group (0.012 ±0.0013%). 60‐daysGSI: There were increases of GSI for the PCOS/MSC (0.013 ±0.0048%), PBM/MSC (0.02 ±0.0035%), and PCOS/PBM/MSC (0.017 ±0.0036%) groups, compared to the C group (0.008 ±0.0039%). The results indicated that the PBM/MSC combination reduced glycemia 30 days after PCOS induction by EV. In addition, the combined use of PBMand MSC resulted in higher GSI, 30 days after PCOS induction, compared to the PCOS group, which was indicative of ovarian modulations induced by this treatment. Morphological, immunohistochemical, and hormonal studies are underway in our laboratory to complement the present study.Support or Funding InformationFunding: FAPESP (Grant 2016/02811‐4)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Antioxidant effect of genistein on ovarian tissue morphology, oxidant and antioxidant activity in rats with induced polycystic ovary syndrome.

Background Oxidative stress is the most frequent cause of female infertility disorders including polycystic ovary syndrome (PCOS). Genistein as a major component of soybean isoflavone scavenges free radicals by antioxidant activities.ObjectiveThe present study examines the antioxidant effects of genistein on ovarian tissue following experimental PCOS in rats.Materials and MethodsTwenty female Wistar rat were randomly divided into the following groups (n=5 each group): (I) control group (no treatment); (II) induced PCOS (injection of estradiol valerate); (III) genistein-treated non-PCOS (received genistein); and (IV) genistein-treated PCOS groups. The weight of rats were measured and the blood samples collected and centrifuged. The oxidant and antioxidant activity of plasma and ovaries were measured. All rats were sacrificed under anesthesia, and ovaries were collected and weighted. Histological examination and follicular quality were assessed by staining.ResultsIn histological observation, the induced PCOS rats displayed more number of atretic follicles and the follicular quality in genistein-treated rats was similar to the control groups. The plasma and ovaries malondialdehyde levels significantly increased in PCOS rats (p 0.001), while the total antioxidant capacity levels, glutathione peroxidase, and superoxide dismutase activities significantly decreased (p 0.001). The plasma and ovary malondialdehyde levels significantly decreased in PCOS rats that were treated with genistein (p 0.001) and the total antioxidant capacity (p 0.05), glutathione peroxidase, and superoxide dismutase activities significantly increased (p 0.001).ConclusionTreatment with genistein preserved follicular quality by increasing antioxidant activities and scavenging oxidant levels in PCOS rats.