Endometriose: aspectos clínicos do diagnóstico ao tratamento / Endometriosis: clinical aspects from diagnosis to treatment

A suspeita clínica de endometriose geralmente envolve a história clínica da paciente e exame físico, abordando sua sintomatologia e história pessoal e familiar. Entretanto, a apresentação clínica da doença varia consideravelmente, sem características clínicas patognomônicas, fato que dificulta o seu diagnóstico. Um diagnóstico presuntivo de endometriose pode ser fortemente sugerido pela ultrassonografia transvaginal e pela ressonância magnética em casos de endometrioma ou endometriose infiltrativa profunda. No entanto, esses exames de imagem não possuem a sensibilidade e a especificidade necessárias quando se trata de endometriose peritoneal superficial. O biomarcador sérico mais utilizado na investigação da endometriose foi o CA-125, que não apresenta sensibilidade (70%-75%) suficiente para sua indicação na prática clínica. Portanto, apesar de seu risco e alto custo, a videolaparoscopia e a análise anatomopatológica subsequente ainda se apresentam como o procedimento padrão-ouro para o diagnóstico definitivo de endometriose. Assim, com o objetivo de demonstrar quais exames seriam necessários para o diagnóstico dessa doença, realizamos uma revisão sistemática da literatura, cujos dados estão descritos a seguir.(AU)

Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis.

BACKGROUND: Endometriosis is known to have an impact on fertility and it is common for women affected by endometriosis to require fertility treatments, including in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), to improve the chance of pregnancy. It has been postulated that long-term gonadotrophin-releasing hormone (GnRH) agonist therapy prior to IVF or ICSI can improve pregnancy outcomes. This systematic review supersedes the previous Cochrane Review on this topic (Sallam 2006). OBJECTIVES: To determine the effectiveness and safety of long-term gonadotrophin-releasing hormone (GnRH) agonist therapy (minimum 3 months) versus no pretreatment or other pretreatment modalities, such as long-term continuous combined oral contraception (COC) or surgical therapy of endometrioma, before standard in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) in women with endometriosis. SEARCH METHODS: We searched the following electronic databases from their inception to 8 January 2019: Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL via the Cochrane CENTRAL Register of Studies ONLINE (CRSO), MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched trial registries to identify unpublished and ongoing trials. We also searched DARE (Database of Abstracts of Reviews of Effects), Web of Knowledge, OpenGrey, Latin American and Caribbean Health Science Information Database (LILACS), PubMed, Google and reference lists from relevant papers for any other relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving women with surgically diagnosed endometriosis that compared use of any type of GnRH agonist for at least three months before an IVF/ICSI protocol to no pretreatment or other pretreatment modalities, specifically use of long-term continuous COC (minimum of 6 weeks) or surgical excision of endometrioma within six months prior to standard IVF/ICSI. The primary outcomes were live birth rate and complication rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two independent review authors assessed studies against the inclusion criteria, extracted data and assessed risk of bias. A third review author was consulted, if required. We contacted the study authors, as required. We analysed dichotomous outcomes using Mantel-Haenszel risk ratios (RRs), 95% confidence intervals (CIs) and a fixed-effect model. For small numbers of events, we used a Peto odds ratio (OR) with 95% CI instead. We analysed continuous outcomes using the mean difference (MD) between groups and presented with 95% CIs. We studied heterogeneity of the studies via the I2 statistic. We assessed the quality of evidence using GRADE criteria. MAIN RESULTS: We included eight parallel-design RCTs, involving a total of 640 participants. We did not assess any of the studies as being at low risk of bias across all domains, with the main limitation being lack of blinding. Using GRADE methodology, the quality of the evidence ranged from very low to low quality. Long-term GnRH agonist therapy versus no pretreatment We are uncertain whether long-term GnRH agonist therapy affects the live birth rate (RR 0.48, 95% CI 0.26 to 0.87; 1 RCT, n = 147; I2 not calculable; very low-quality evidence) or the overall complication rate (Peto OR 1.23, 95% CI 0.37; to 4.14; 3 RCTs, n = 318; I2 = 73%; very low-quality evidence) compared to standard IVF/ICSI. Further, we are uncertain whether this intervention affects the clinical pregnancy rate (RR 1.13, 95% CI 0.91 to 1.41; 6 RCTs, n = 552, I2 = 66%; very low-quality evidence), multiple pregnancy rate (Peto OR 0.14, 95% CI 0.03 to 0.56; 2 RCTs, n = 208, I2 = 0%; very low-quality evidence), miscarriage rate (Peto OR 0.45, 95% CI 0.10 to 2.00; 2 RCTs, n = 208; I2 = 0%; very low-quality evidence), mean number of oocytes (MD 0.72, 95% CI 0.06 to 1.38; 4 RCTs, n = 385; I2 = 81%; very low-quality evidence) or mean number of embryos (MD -0.76, 95% CI -1.33 to -0.19; 2 RCTs, n = 267; I2 = 0%; very low-quality evidence). Long-term GnRH agonist therapy versus long-term continuous COC No studies reported on this comparison. Long-term GnRH agonist therapy versus surgical therapy of endometrioma No studies reported on this comparison. AUTHORS' CONCLUSIONS: This review raises important questions regarding the merit of long-term GnRH agonist therapy compared to no pretreatment prior to standard IVF/ICSI in women with endometriosis. Contrary to previous findings, we are uncertain as to whether long-term GnRH agonist therapy impacts on the live birth rate or indeed the complication rate compared to standard IVF/ICSI. Further, we are uncertain whether this intervention impacts on the clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, mean number of oocytes and mean number of embryos. In light of the paucity and very low quality of existing data, particularly for the primary outcomes examined, further high-quality trials are required to definitively determine the impact of long-term GnRH agonist therapy on IVF/ICSI outcomes, not only compared to no pretreatment, but also compared to other proposed alternatives to endometriosis management.

Effect of Punica granatum, Citrus limon and their combinations on the plasma Gonadotropins in female rabbits.

Fruits produce revitalizing effects, hence the impact of Punica granatum, Citrus limon and their combinations have been investigated on the plasma levels of gonadotropin, testosterone and sexual development capacity in female rabbits. Ninety female rabbits were randomly assigned into nine groups, each comprising of ten animals. One group was given saline and designated as control. Three groups were given P. granatum 2mL /kg, 5mL/kg, 8mL/kg, other three groups received C. limon 0.2mL/kg, 0.4mL/kg, 0.6mL/kg respectively, remaining groups received C. limon and P. granatum in combination i.e. 0.4mL/kg C. limon + 5mL/kg P. granatum and 0.2mL/kg C. limon + 8mL/kg P. granatum. Juices were administered once daily by mouth from day 0 of pups delivered to postnatal day15. Blood samples were gathered from ear vein at day11 and day15. There was significant increase in follicle stimulating hormone by P. granatum at 5 and 8mL/kg on day 11 and 15, by C. limon at 0.4 and 0.6mL/kg on day11, 0.4mL/kg at day15, by combination doses of C. limon and P. granatum 0.4 +5mL/kg at day 11, 0.4+5 mL/kg and 0.2 + 8mL/kg at day15. There was also significant increase in luteinizing hormone by P. granatum at 2, 5 and 8mL/kg and by C. limon 0.4mL/kg at day11. There was highly significant increase on day 11 in LH at combination doses of C. limon and P. granatum 0.4 + 5mL/kg. There was significant increase in testosterone level by P. granatum at 2, 5 and 8mL/kg on day 11 and 5mL/kg on day15 and highly significant increase at 2 and 8mL/kg. C. limon caused significant increase in testosterone at 0.4 mL/kg on day11, 0.2 and 0.6mL/kg on day 15 and highly significant increase at 0.4mL/kg on day15. Whereas combinations doses of C. limon and P. granatum at 0.4+5mL/kg caused highly significant increase in testosterone level as compare to control. Results of present study revealed increase in plasma gonadotropin and testosterone levels showing increase in sexual capacity of female rabbits which could be mainly accounted for high vitamin C and flavonoids contents of these juices.

On-label and off-label drug use in the treatment of female infertility.

Female infertility affects millions of couples worldwide and is estimated to account for one-third of all cases of infertility. The purpose of this article is to review the uses of both off-label treatments and those approved by the US Food and Drug Administration for female infertility, by examining the mechanism of action, the side-effect profile, fetal anomaly risks, and contraindications for the various drugs.

The clinical ramifications of polycystic ovarian morphology in oocyte donors.

OBJECTIVE: To determine the relationship between Polycystic Ovary (PCO) morphology and In Vitro Fertilization (IVF) outcome in oocyte donation cycles. DESIGN: Cross sectional study SETTING: Private IVF clinic PATIENTS: 164 consecutive ovum donors and their recipients were reviewed, 149 were included in the study where 113 patients had normal ovarian morphology and 36 patients had PCO morphology. INTERVENTIONS: All donors underwent ovarian stimulation in conjunction with GnRH agonist or antagonist in standard fashion. MAIN OUTCOME MEASURES: Baseline donor characteristics were recorded, as well as details of IVF stimulation and embryo data. Recipient data on pregnancy and miscarriage were also collected. RESULTS: Patients with PCO ovaries had significantly higher peak estradiol levels and required less gonadotropins during IVF stimulation. In addition, the baseline characteristics between donor groups did not differ except for ovarian morphology. The number of oocytes retrieved and indicators of embryo quality did not differ between the two groups, and there was no significant difference between pregnancy and miscarriage rates in the recipients. CONCLUSIONS: Oocyte donors with PCO morphology have equivalent pregnancy rates and do not need to be excluded as potential donors.

Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial.

OBJECTIVE: To estimate the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy. METHODS: One hundred hormone-insensitive breast cancer participants (aged 18-40 years) were recruited from two university-affiliated oncology centers in Egypt. Opting for type of cotreatment was based on available timeframe until start of chemotherapy. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes. RESULTS: Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71). There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months. CONCLUSION: GnRH analogue cotreatment does not offer a significant protective effect on ovarian function in patients treated by cyclophosphamide-based chemotherapy. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. www.anzctr.org.au, ACTRN12609001059257. LEVEL OF EVIDENCE: I.

Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization.

OBJECTIVE: To investigate associations between serum bisphenol A (BPA) concentrations and follicular response to exogenous ovary stimulation. DESIGN: Fasting serum was prospectively collected on the day of oocyte retrieval and assessed for unconjugated BPA using high-performance liquid chromatography with Coularray detection. Multivariable linear regression and negative binomial regression were used to assess associations between concentrations of BPA and outcome measures. Models were adjusted for race/ethnicity, antral follicle count at baseline, and cigarette smoking. SETTING: A reproductive health center. PATIENT(S): Forty-four women undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Peak E(2) level and the number of oocytes retrieved during IVF. RESULT(S): The median unconjugated serum BPA concentration is 2.53 ng/mL (range = 0.3-67.36 ng/mL). Bisphenol A is inversely associated with E(2) (ß = -0.16; 95% confidence interval = -0.32, 0.01), as well as with E(2) normalized to the number of mature-sized follicles at the hCG trigger (ß = -0.14; 95% confidence interval = -0.24, -0.03). No association is observed for BPA and the number of oocytes retrieved (adjusted risk ratio = 0.95; 95% confidence interval = 0.82, 1.10). CONCLUSION(S): Bisphenol A is associated with a reduced E(2) response during IVF. Although limited by the preliminary nature of this study, these results merit confirmation in a future comprehensive investigation.

Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications.

The gonadotropins, luteinizing hormone, human chorionic gonadotropin and follicle-stimulating hormone, are key regulators of reproduction. As a result of this function, they have been the focus of research for many years. Isolated or recombinant proteins have been successfully used therapeutically for the treatment of infertility; and, in the case of compounds that block gonadotropin activity, for their potential utility in contraception. Until recently, selective small molecules modulating gonadotropin receptor activity have proven difficult to identify. The gonadotropins are glycoproteins that are released into the plasma as differently glycosylated isoforms and bind to specific G protein-coupled receptors. The degree of glycosylation on the gonadotropins has been shown to be important for the biological activities of these hormones and is differentially regulated depending on the steroidal status. Recent data from the study of glycosylated variants of LH, hCG and FSH have revealed that these isoforms have distinct signaling properties that allow for gonadotropin pleiotropic signals to be transduced effectively at the level of the receptor. Thus, glycosylated variants of the gonadotropins behave as biased agonists. Recently, newly developed, small molecule, synthetic allosteric compounds have been identified that are capable of mimicking this biased signaling. This opens the door to development of orally available, drug-like therapies for reproductive disorders that offer similar pleiotropic richness as that offered by the complex, endogenous hormones.

Novel pathways in gonadotropin receptor signaling and biased agonism.

Gonadotropins play a central role in the control of male and female reproduction. Selective agonists and antagonists of gonadotropin receptors would be of great interest for the treatment of infertility or as non steroidal contraceptive. However, to date, only native hormones are being used in assisted reproduction technologies as there is no pharmacological agent available to manipulate gonadotropin receptors. Over the last decade, there has been a growing perception of the complexity associated with gonadotropin receptors' cellular signaling. It is now clear that the Gs/cAMP/PKA pathway is not the sole mechanism that must be taken into account in order to understand these hormones' biological actions. In parallel, consistent with the emerging paradigm of biased agonism, several examples of ligand-mediated selective signaling pathway activation by gonadotropin receptors have been reported. Small molecule ligands, modulating antibodies interacting with the hormones and glycosylation variants of the native glycoproteins have all demonstrated their potential to trigger such selective signaling. Altogether, the available data and emerging concepts give rise to intriguing opportunities towards a more efficient control of reproductive function and associated disorders.

[Ovarian gonadotropic inhibition and endometriosis. About fighting false dogmas...]. / Inhibition gonadotrope et endométriose. Comment lutter contre les dogmes s'ils sont erronés ?

Ovarian gonadotropic inhibition is today an efficacious tool in the treatment of endometriosis mainly when associated with surgery and sometimes by itself. However, to be useful, this inhibition must be stable - without any cyclical looseness - of long duration, sometimes during years and sufficiently powerful. Depending on the severity of symptoms and that of the disease, the choice will be among GnRH agonists, gestagens and combined OCs. The recent development of continuous oral contraception with protracted amenorrhoea makes treatment by continuous hormonal administration easier for the patients with endometriosis.

Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone.

BACKGROUND: Recently we found that testosterone levels are higher in older men than young men receiving exogenous testosterone. We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels. OBJECTIVE: The objective of the study was to compare aMCR-T in older and young men and identify predictors of aMCR-T. METHODS: Sixty-one younger (19-35 yr) and 60 older (59-75 yr) men were given a monthly GnRH agonist and weekly testosterone enanthate (TE) (25, 50, 125, 300, or 600 mg) for 5 months. Estimated aMCR-T was calculated from the amount of TE delivered weekly and trough serum testosterone concentrations, corrected for real-time absorption kinetics from the im testosterone depot. RESULTS: Older men had lower total (316 +/- 13 vs. 585 +/- 26 ng/dl, P < 0.00001) and free testosterone (4 +/- 0.1 vs. 6 +/- 0.3 ng/dl, P < 0.00001) and higher SHBG (52 +/- 3 vs. 33 +/- 2 nmol/liter, P < 0.00001) than younger men at baseline. Total and free testosterones increased with TE dose and were higher in older men than young men in the 125-, 300-, and 600-mg dose groups. aMCR-T was lower in older men than young men (1390 +/- 69 vs. 1821 +/- 102 liter/d, P = 0.006). aMCR-T correlated negatively with age (P = 0.0007), SHBG (P = 0.046), and total testosterone during treatment (P = 0.02) and percent body fat at baseline (P = 0.01) and during treatment (P = 0.004). aMCR-T correlated positively with lean body mass at baseline (P = 0.03) and during treatment (P = 0.01). In multiple regression models, significant predictors of aMCR-T included lean body mass (P = 0.008), percent fat mass (P = 0.009), and SHBG (P = 0.001). CONCLUSIONS: Higher testosterone levels in older men receiving TE were associated with an age-related decrease in apparent testosterone metabolic clearance rates. Body composition and SHBG were significant predictors of aMCR-T.

The role of O-linked and N-linked oligosaccharides on the structure-function of glycoprotein hormones: development of agonists and antagonists.

Thyrotropin (TSH) and the gonadotropins; follitropin (FSH), lutropin (LH) and human chorionic gonadotropin (hCG) are a family of heterodimeric glycoprotein hormones. These hormones composed of two noncovalently linked subunits; a common alpha and a hormone specific beta subunits. Assembly of the subunits is vital to the function of these hormones. However, genetic fusion of the alpha and beta subunits of hFSH, hCG and hTSH resulted in active polypeptides. The glycoprotein hormone subunits contain one (TSH and LH) or two (alpha, FSHbeta and hCGbeta) asparagine-linked (N-linked) oligosaccharides. CGbeta subunit is distinguished among the beta subunits because of the presence of a carboxyl-terminal peptide (CTP) bearing four O-linked oligosaccharide chains. To examine the role of the oligosaccharide chains on the structure-function of glycoprotein hormones, chemical, enzymatic and site-directed mutagenesis were used. The results indicated that O-linked oligosaccharides play a minor role in receptor binding and signal transduction of the glycoprotein hormones. In contrast, the O-linked oligosaccharides are critical for in vivo half-life and bioactivity. Ligation of the CTP bearing four O-linked oligosaccharide sites to different proteins, resulted in enhancing the in vivo bioactivity and half-life of the proteins. The N-linked oligosaccharide chains have a minor role in receptor binding of glycoprotein hormones, but they are critical for bioactivity. Moreover, glycoprotein hormones lacking N-linked oligosaccharides behave as antagonists. In conclusion, the O-linked oligosaccharides are not important for in vitro bioactivity or receptor binding, but they play an important role in the in vivo bioactivity and half-life of the glycoprotein hormones. Addition of the O-linked oligosaccharide chains to the backbone of glycoprotein hormones could be an interesting strategy for designing long acting agonists of glycoprotein hormones. On the other hand, the N-linked oligosaccharides are not important for receptor binding, but they are critical for bioactivity of glycoprotein hormones. Deletion of the N-linked oligosaccharides resulted in the development of glycoprotein hormone antagonists. In the case of hTSH, development of an antagonist may offer a novel therapeutic strategy in the treatment of thyrotoxicosis caused by Graves' disease and TSH secreting pituitary adenoma.

GnRH antagonist improved blastocyst quality and pregnancy outcome after multiple failures of IVF/ICSI-ET with a GnRH agonist protocol.

BACKGROUND: To determine the efficacy of a gonadotrophin-releasing hormone (GnRH) antagonist, cetrorelix, in improving the quality of embryos and pregnancy outcome, we performed a study in patients with a history of multiple failures of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles with a GnRH agonist (GnRHa) long protocol. METHODS: Forty women with no live births after conventional IVF or ICSI embryo transfer (ET) and subsequent blastocyst transfer (BT) with a GnRHa long protocol entered this study. The treatment protocol consisted of a daily dose of clomiphene citrate 100 mg for 5 days and gonadotrophin injections daily from cycle day 4 onward. Cetrorelix, 0.25 mg/day, was started when the leading follicle reached 14 mm. Induction of ovulation was triggered with human chorionic gonadotrophin (HCG) (N = 36) or GnRHa (N = 4). It was possible to perform BT in 38 patients. RESULTS: Comparison of the results with the results for BT with the previous GnRHa protocol showed no significant differences in number of oocytes retrieved or the zygote- and blastocyst-development rate. With the cetrorelix protocol, however, number of patients whose embryos had developed to at least one expanded blastocyst on day 5 was significantly higher than with the GnRHa protocol (25 vs. 9) (p < 0.001), and 16 of the women became pregnant (42.1%), with 7 delivering 9 infants, 4 ending in abortion (25%), and 5 in progressing. CONCLUSIONS: The use of a GnRH antagonist in controlled ovarian hyperstimulation improves the outcome of pregnancy of patients with a history of multiple failure of IVF/ICSI-ET in a GnRHa protocol, most likely due to improvement of the quality of the blastocysts generated.

Reproductive biology and IVF: ovarian stimulation and endometrial receptivity.

The influence of ovarian stimulation on endometrium receptivity has been inadequately addressed in medical literature. Hormonal effects of ovarian stimulation on endometrial changes as compared with the natural cycle should be elucidated and correlated with the potential of the embryo to implant. It is important to distinguish between the endometrial effect of induction of ovulation in anovulatory women and those of ovarian (super)ovulation in ovulatory women. Induction of ovulation leads to in vivo conception whereas ovarian stimulation results in in vitro fertilization. The available data in the field indicate that endometrial changes have an impressive negative influence on the potential of embryonic implantation. The aim of this review is to analyse the effects of gonadotropin, GnRH-agonist and GnRH-antagonist administration on endometrial behaviour, to highlight the gaps in current knowledge and to propose areas in which research is needed.

Gonadotropin release in periovulatory heifers after GnRH analogs measured by two types of immunoassays.

This study on heifers (n = 27) compared the effects of a GnRH antagonist (Antarelix) and those of an agonist (Triptorelin) on gonadotropin release during the periovulatory period of the oestrous cycle. In three experiments (EXP I-III), an initial injection of GnRH analogs was given 48 h after a single PGF 2alpha pretreatment during the luteal phase, with a further five at 12 h intervals. A challenge by a GnRH agonist (Gonavet) was performed six hours after the last application of analogs. In EXP I (n = 9), heifers received six times 1.5 mg of Antarelix, 0.5 mg of Triptorelin, and mannitol (5%; control), respectively. In EXP II (n = 12), identical Antarelix and Triptorelin treatments were followed by a single injection of estradiol-17beta valerate (6 h after Gonavet). The dosage of Antarelix was increased to 5 mg for each injection in EXP III (n = 6). Measurement of LH in blood plasma frequently sampled was performed parallely by a competitive RIA method (EXP I + II) and by a sandwich-type electro-chemiluminescence-immunoassay (ECLIA) in EXP III. This non-isotopic technique was also used to additionally analyse FSH levels. Results of EXP I showed that the GnRH antagonist equally suppressed LH surges and ovulation. On the contrary, prior to suppression of LH levels due to down-regulation of pituitary GnRH receptors the agonist Triptorelin induced an initial increase in LH concentration which was followed by ovulation. In the control animals we observed endogenous LH surges as well as smaller elevations after the agonist (Gonavet) challenge. An increase was also observed in antagonist, but not in Triptorelin treated heifers. Pituitary GnRH receptors were not detectable in animals previously treated by the analogs, whereas concentrations between 2.2-21.0 fmol/mg protein were measured in controls. Results of EXP II confirmed the described effects of GnRH analogs. Additionally, it was shown that exogenous estradiol is able to release LH from the pituitary, although a previous treatment by a GnRH agonist had dropped the pulsatile gonadotropin secretion. Contrary to the LH pattern and despite elevated amounts of the antagonist, the mean concentration and pulse number of FSH were not influenced by the antagonist treatment (EXP III). These data confirmed that (a) the reversibly blocked pituitary function induced by a potent GnRH antagonist may be a useful tool to study gonadotropin-dependent final follicular growth as well as ovulation in cyclic heifers and (b) the novel non-isotopic ECLIA methods for the determination of FSH and LH provided practical alternatives to other immunoassay types.

Managing anemia and blood loss in elective gynecologic surgery patients.

Hysterectomy is the second-most-common surgical procedure among premenopausal women. The conditions that lead to the need for a hysterectomy often are accompanied by chronic blood loss that can lead to anemia. Moreover, hysterectomy and myomectomy may result in significant blood loss, which exacerbates the anemia. The presence of fatigue associated with anemia has a substantially negative impact on quality of life and the ability to perform activities of daily living. Options for alleviating perioperative anemia include minimizing surgical blood loss, blood transfusion, supplementation with hematinics, such as iron and folic acid, and treatment with recombinant human erythropoietin. Treating preoperative anemia is expected to help correct anemia prior to surgery and may have a positive impact on anemia-related symptoms and surgical outcomes.

Management of hirsutism.

This review reports our own experience with, and literature studies of, the pharmacological management of hirsutism in women with hyperandrogenism (polycystic ovary syndrome) or with normal serum androgen levels and regular ovulatory menstrual cycles (idiopathic hirsutism). Treatment consists of suppressing ovarian or adrenal androgen secretion, or blocking androgen actions in the skin. The major drugs used are gonadotropin-releasing hormone (GnRH) agonists, combined oral contraceptives (COCs), and steroidal (cyproterone acetate and spironolactone) or nonsteroidal (flutamide and finasteride) antiandrogens. GnRH agonists, suppressing the pituitary, decrease androgen and estradiol secretion and improve severe hirsutism. To avoid estrogen deficiency problems, 'add back' therapy with estrogen-progestogen or COCs is advisable. This method of treatment is complicated and expensive, limiting its use to severe forms of ovarian hyperandrogenism with hyperinsulinemia. The third-generation COCs, containing new progestogens or cyproterone, have very restricted effectiveness in the short term (6 cycles), but their long term use (> 12 cycles) cures mild-to-moderate hirsutism and improves severe hirsutism. As well as suppressing gonadotropins and ovarian androgen steroidogenesis, these formulations decrease free testosterone levels and may also decrease adrenal androgen production. In women being treated with antiandrogens, COCs are important to provide control of the menstrual cycle and contraception. Cyproterone, a progestational agent, inhibits gonadotropin secretion and blocks androgen action. It is used in COCs or in a reverse sequential regimen. In the latter, it is very effective in the short term treatment of hirsutism. Spironolactone blocks androgen receptors. Its effectiveness in hirsutism is dosage-dependent: low dosages are less active than other antiandrogens, whereas high dosages (200 mg/day) are very effective at the cost of several adverse effects (particularly dysfunctional uterine bleeding), but the concomitant use of a COC may prevent these. Flutamide is a pure antiandrogen that blocks androgen receptors and inhibits hair growth. It is very effective in treating hirsutism within 6 to 12 months. Dry skin is very frequent during treatment with flutamide, and hepatotoxicity is possible at high dosages. Finasteride, a 5 alpha-reductase type 2 inhibitor, is the least effective antiandrogen, but a dosage of 5 mg/day decreases hirsutism without adverse effects. Pregnancy must be avoided during therapy with antiandrogens because of the possible risk of abnormal development of a male fetus. Antiandrogens, especially flutamide (250 to 500 mg/day) and cyproterone (12.5 to 50 mg/day in a reverse sequential regimen), alone or in association with COCs, seem to be the most effective agents for the treatment of hirsutism.

Cistos ovarianos funcionais na reproduçäo assistida / Functional ovarian cysts in assisted reproduction

Os procedimentos envolvidos na reproduçäo assistida têm apresentado uma rápida evoluçäo, pois o insucesso destas açöes ocasiona frustraçäo aos casais que apresentam alta expectativa quanto a este tipo de tratamento. Na década passada, a introduçäo dos agonistas de GnRH nos protocolos de estimulaçäo da ovulaçäo para a realizaçäo de FIV constituiu um grande avanço, o que se refletiu em melhores taxas de gravidez. Apesar deste benefício, os agonistas de GnRH podem apresentar alguns efeitos adversos, como a formaçäo de cistos ovarianos funcionais. Isto se deve basicamente ao efeito flare-up que acontece no momento da administraçäo dos agonistas. Tem-se verificado que estes cistos influenciam negativamente a reproduçäo assistida, por isso, nos últimos anos muito trabalho tem sido empreendido na tentavia de prevenir o seu surgimento. A utilizaçäo de progestogênios, por aspiraçäo transvaginal destas estruturas, tem surgido num esforço para contornar este efeito. Desta forma, uma adequada compreensäo de como estes cistos se formam e dos aspectos relativos a prevençäo e tratamento deste problema é útil na utilizaçäo destes medicamentos na reproduçäo assistida.

Effects of a gonadotropin releasing hormone agonist on oocyte maturation, fertilization, and embryonal development of mice.

PURPOSE: The effects of a GnRH agonist (GnRHa) on oocyte quality were investigated by assessing the influence of GnRHa on oocytes, and fertilized oocytes were examined in vivo and in vitro. Administration of gonadotropin in conjunction with GnRHa induced a significantly greater degree of germinal vesicle breakdown, significantly higher rates of in vitro fertilization, and significantly faster development of the oocytes than the pregnant mare serum gonadotropin alone RESULTS: The hatching-success rate in the GnRHa treated hypophysectomized mice was higher than in control mice. The rate of in vitro fertilization was also higher in oocytes cultured in the presence of low loses of GnRHa and these effects were reversed by a GnRH antagonist. CONCLUSION: Oocytes obtained following ovarian stimulation with GnRHa were of higher quality than control oocytes, and the efficacy of GnRHa may be due in part to its direct action on the ovary.