Síndrome dos ovários policísticos: particularidades no manejo da infertilidade / Polycystic ovary syndrome: particularities in the management of infertility

A síndrome dos ovários policísticos (SOP) é responsável por cerca de 80% dos casos de infertilidade anovulatória. Não há na literatura evidências suficientes para a definição do tratamento ideal da infertilidade na SOP, mas repete-se que deve ser iniciado por mudanças no estilo de vida, e frequentemente envolve a indução farmacológica da ovulação e, em casos selecionados, as técnicas de reprodução assistida e o drilling ovariano laparoscópico. Este texto pretende reunir informações atuais sobre o manejo da infertilidade em mulheres com SOP e, dessa forma, permitir ao ginecologista a escolha da melhor abordagem, de forma Individualizada e baseada nas melhores evidências disponíveis.(AU)

The impact of postnatal leuprolide acetate treatment on reproductive characteristics in a rodent model of polycystic ovary syndrome.

In this study, a GnRH agonist, leuprolide acetate (LA), was given as a single depot injection before 48 h of life to Wistar female rats allotted to prenatal (E16-18) and postnatal androgenization (day 5 of life) by the use of testosterone propionate, looking for reproductive endpoints. Remarkably, a single injection of LA increased the estrus cycles in the postnatal group (PostN) from 0% to 25% of the estrus cycles in the postnatal LA treated group (PostN L). LA also reduced the serum testosterone levels and cysts and atretic follicles in PostN L in contrast with rats (>100 days) from the PostN group (p = 0.04). Prenatally androgenized rats (PreN) exhibited significant modifications in the hypothalamic genes, such as Gnrh. To the best of our knowledge, this is the first study to show that blockage of the GnRH axis with leuprolide acetate depot prevented the development of typical features (anovulation, cysts, atretic follicles) in a postnatal testosterone propionate rat model of PCOS.

Hormone supplementation protocol using estradiol benzoate and long-acting progesterone is efficient in maintaining pregnancy of anovulatory recipient mares during autumn transitional phase.

The present research sought to determine whether the administration of estradiol benzoate and long-acting progesterone to anovulatory recipient mares could maintain the pregnancy after embryo transfer during the autumn transitional phase. Recipient mares (n = 40) received the hormonal supplementation (treated group) whereas the other 36 served as a control. The control group consisted of mares having typical estrous cycles with ovulations, development of a viable corpus luteum and received one transferred embryo 5 days after ovulation. Hormonal administrations in the treated group started 8 days before the embryo transfer. During the first 3 days, the mares received estradiol benzoate (5 mg the first day, 3 mg the second day and 2 mg the third day). At Day 5 subsequent to ovulation, the mares received one administration of 1500 mg long-acting progesterone, and the same treatments occurred at the day of embryo transfer. Afterwards, treated mares also received 1500 mg long-acting progesterone every 7 days until 120 days of gestation. For both control and treated groups, the recipient mares were classified as acceptable, marginally acceptable or unacceptable for embryo transfer, and the embryo quality was also determined. The pregnancy diagnosis in recipient mares was made at Days 13, 30 and 60 of pregnancy. While the pregnancy rate was greater (P < 0.05) in the treated than in the control group, the recipient classification did not influence pregnancy rates. In conclusion, pregnancy in anovulatory recipient mares during the autumn transitional phase can be achieved when estradiol benzoate and progesterone are administered.

Effects of tamoxifen and raloxifene on body and uterine weights of rats in persistent estrus.

PURPOSE: To evaluate the change in body and uterine weights of rats in persistent estrus, a model developed to mimic polycystic ovary syndrome treated with selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene. METHODS: Sixty Wistar-Hannover rats induced by a single subcutaneous dose of 1.25 mg testosterone propionate were divided into three groups of 20 animals: Group I (placebo); Group II (tamoxifen, 250 microg/day) and Group III (raloxifene, 750 microg/day). At 90 days of life, the treatment began for 30 consecutive days, in which the animals were weighed weekly. On the 31st day, the animals were sacrificed and the uterus removed. Data were analyzed statistically by analysis of variance and by the Tukey-Kramer multiple comparisons test (p<0.05). RESULTS: Means of body and uterine weights (g) after treatment were: 227.3+/-2.20 and 0.40+/-0.01; 185.3+/-2.45 and 0.25+/-0.01; 186.4+/-2.20 and 0.27+/-0.01 in Groups I, II and III, respectively (p<0.001). There was no statistical difference between groups II and III for body and uterine weight (p=0.727 and p=0.646, respectively). CONCLUSION: The present results indicate that, at the doses and during the time of treatment used, both tamoxifen and raloxifene reduce in a similar way the body and uterine weights of rats in persistent estrus showing a possible antiestrogenic effect of SERMs under high levels of estrogens.

Aromatase gene polymorphism does not influence clinical phenotype and response to oral contraceptive pills in polycystic ovary syndrome women.

AIMS: To assess whether a single nucleotide polymorphism (SNP50) of the aromatase gene (CYP19) is associated with polycystic ovary syndrome (PCOS) phenotypes and to investigate the influence of this polymorphism on the response of PCOS to treatment with oral contraceptive pills (OCP). METHODS: 162 hirsute women were stratified into a classic PCOS group (hyperandrogenism, ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS). 51 women completed a 6-month OCP trial (20 µg ethinyl estradiol + 75 µg gestodene, 21/28 days per cycle, plus 100 mg spironolactone in 32 women with moderate to severe hirsutism). We considered the presence of the polymorphic allele A (AG+AA) in comparison to the absence of the polymorphism (GG) to express results and to perform the comparisons regarding clinical variables. RESULTS: Mean age was 23.3 ± 6.9 years. Hirsutism score was similar in c-PCOS and ov-PCOS (15 (11-20) vs. 13 (11-20)). The differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A. In the OCP trial subsample, no differences were observed between genotypes after 6 months' treatment. CONCLUSION: The differences between c-PCOS and ov-PCOS cannot be explained by the genetic variation at SNP50 in the CYP19 gene.

[Insulin sensitivity in patients not responding to ovulation induction using clomiphene citrate]. / Sensibilidad a la insulina en pacientes con falta de respuesta a la inducción de ovulación con citrato de clomifeno.

BACKGROUND: The role of insulin resistance (IR) of infertile patients with chronic anovulation in their therapeutic failure to clomiphene citrate (CC) is not quite clear. OBJECTIVE: Determine the sensitivity to insulin in patients with chronic anovulation and failure to the treatment with clomiphene citrate. MATERIAL AND METHODS: A cross-sectional clinical study in infertile patients with clomiphene citrate resistance and in patients with adequate response to clomiphene citrate was carried out. In all patients insulin resistance was determined by the rate of glucose/insulin, HOMA (Homestatic Model Assessment) and the insulin sensitivity test. For the inferential statistical analysis, a Student's t test for independent samples was used. RESULTS: The average total basal insulin was 19.6 +/- 8.1 microU/mL. We observed higher concentrations in the clomiphene citrate resistance group (22.1 +/- 8.9 vs. 15.8 +/- 5.1 mU/mL p = 0.07). The glucose/insulin rate was statistically minor in patients with resistance to clomiphene citrate (4.2 +/- 1.9 versus 6.9 +/- 2.1 p = 0.02), but HOMA was not significantly different in both groups (4.3 +/- 1.4 vs. 3.9 +/- 1.3 p = 0.6). The total rate of glucose disappearance (KIIT) was 4.1 +/- 1.2. However, the statistical analysis did not show significant statistical differences between the two groups. CONCLUSIONS: Our preliminary results suggest that insulin resistance can be a mechanism involved in the pharmacologic response to ovulation induction in infertile patients, but coexisting pathophysiological mechanisms such as hyperandrogenism might also account for the lack of response to clomiphene citrate.

Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study.

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

Metformina en el tratamiento de la anovulación asociada a insulino-resistencia / Use of metformin on anovulation associated insulin-resistance

Se presentan 18 casos de pacientes infértiles anovulatorias en que se efectuó el diagnóstico de insulino resistencia y fueron tratadas con metformina. Once pacientes se embarazaron, 7 con metformina y 4 al asociar citrato de clomifeno. Seis pacientes tuvieron parto de término, 2 presentaron aborto de primer trimestre y 3 embarazos están en curso. De los 6 embarazos de término, 2 presentaron diabetes gestacional. Se revisa la literatura y se discute la conveniencia de mantener el tratamiento con metformina durante el embarazo para prevenir diabetes gestacional.

[Favorable reproductive and menstrual evolution in adult women, who presented in the adolescence, menstrual disturbances by hypothalamic dysfunction and lack of response to clomiphene]. / Evolución menstrual y reproductiva favorable en mujeres adultas, que presentaron en la adolescencia trastornos menstruales por disfunción hipotalámica con respuesta alterada al clomifeno.

BACKGROUND: Hypothalamic dysfunction is a cause of menstrual disturbances in women, in whom other diseases have been discarded. This condition is characterized by a failure of the GNRH pulse generation system and is associated to psychological and environmental factors. A lack of ovulatory response to the administration of clomiphene can be a sign of bad prognosis in hypothalamic dysfunction. AIM: To report the natural history of patients with hypothalamic dysfunction and a bad or deficient response to the administration of clomiphene. PATIENTS AND METHODS: Fifty patients with hypothalamic dysfunction, that consulted for menstrual disturbances at the age of 15 to 20 years old, were studied. All received clomiphene and 31 had an ovulatory response, 12 had menses without ovulation and 7 did not menstruate. Of these 19 women eleven were interviewed again about their menstrual and reproductive history, after a lapse of 9 to 17 years of loss from follow up. RESULTS: Eight of the eleven women had stressful events during adolescence (going away from family house in 3, starting university studies in 3, migration out of the natal country in one and non competitive physical activity in one). All restarted their menses and eight with active sexual life had spontaneous pregnancies, giving birth from two to five children. Ovulatory cycles were documented in women without active sexual life. CONCLUSIONS: In teenagers with hypothalamic dysfunction and menstrual disturbances, a deficient or bad response to clomiphene does not necessarily indicate a bad prognosis in terms of menses or fertility.

[Clomiphene acetate and prednisone: alternative approach for the management of patients with chronic anovulation and clomiphene treatment failure]. / Citrato de clomifeno y prednisona: un esquema alternativo de manejo en pacientes con anovulación crónica y falla terapéutica al clomifeno.

Chronic anovulation is a common neuroendocrine cause of infertility. Pharmacological management of such condition includes the use of clomiphen citrate (CC), which is the most utilized of the ovulation inductors. Clinical efficacy of CC provides ovulation rates of around 70%. Those patients who did not respond are candidates to receive gonadothrophin treatment, which will increase costs and the risk of ovarian hyperstimulation and multiple pregnancies. Because of that, new alternative treatments have been assayed, such as the concomitant use of dexametasone. This alternative has improved the response, but its use has been limited because the side effects of this treatment overcome their benefits. Another alternative is the use of prednisone throughout the menstrual cycle together with CC administered in pre-established days. This treatment is expected to improve the response without adding side effects. However, its clinical efficacy and clínical tolerance have not been studied. In this study we used CC and prednisone in a sample of patients diagnosed with infertility and chronic anovulation, and with previous failure to the treatment with CC. Patients were compared to a group of women with similar characteristics but who received additional cycles of CC. The group that received prednisone and CC increased their ovulation rates in 38%, compared to 8% in women that received only CC. Similarly, pregnancy rates increased 20% in the CC plus prednisone group while the group that received CC alone remained in 0 pregnancies. In the total sample, tolerance to treatment was adequate. There were no side effects associated to the use of prednisone. We conclude that the treatment with CC plus prednisone is an alternative treatment for patients in which the classical treatment with CC has failed.

Citrato de clomifeno y prednisona: un esquema alternativo de manejo en pacientes con anovulación crónica y falla terapéutica al clomifeno / Clomiphen citrate and prednisone: an alternative treatment in chronic anovulatory and clomiphen failure patients

La anovulación crónica es una alteración neuroendocrina frecuente en esterilidad. El manejo farmacológico de esta alteración incluye el uso de inductores de la ovulación. Hasta la fecha el citrato de clomifeno (CC) es uno de los fármacos más utilizados. Su eficacia clínica brinda tasas de ovulación de alrededor de 70 por ciento y el porcentaje de pacientes que no responden serán candidatas de manejo con gonadotropinas con lo que se incrementan los costos y el riesgo de hiperestimulación ovárica así como de embarazo múltiple, lo que limita su generalización terapéutica. Por ello se han ensayado esquemas alternativos de manejo como lo es adicionar dexametasona, con lo que han mejorado las tasas de respuesta, pero su uso ha sido limitado ya que sus efectos colaterales sobrepasan sus beneficios. Se ha propuesto que la administración conjunta de prednisona a lo largo del ciclo y CC en días fijos, mejoran las tasas de respuesta con pocos efectos colaterales. Con el fin de probar su eficacia clínica en nuestra población utilizamos CC + prednisona en una muestra de pacientes con esterilidad y anovulación crónica y falla previa al CC comparándolas con un grupo de pacientes con las mismas características que recibieron sólo CC en ciclos adicionales. Encontramos que en el grupo en el que se adicionó prednisona las tasas de ovulación se incrementaron hasta en 38 por ciento y las de embarazo en 20 por ciento, en contraste con el grupo control en el que la tasa de ovulación fue de 8 por ciento y la de embarazo de 0 por ciento. En todas las pacientes estudiadas la tolerancia medicamentosa fue adecuada y no hubo efectos colaterales asociados al uso de la prednisona. Con estos resultados concluimos que el esquema CC + prednisona es una buena alternativa terapéutica en pacientes con falla previa a inducción de ovulación con el esquema clásico con CC, previamente al uso de gonadotrofinas. Ya que el esquema CC + prednisona mejora las tasas de ovulación y embarazo con buena tolerancia medicamentosa.

Effect of clomiphene citrate on ovulation after treatment withdrawal.

The effect of clomiphene citrate (CC) on ovarian function in cycles subsequent to treatment withdrawal was studied. Thirty two out of 45 patients with anovulation due to polycystic ovarian syndrome (PCOS) and with no other factor affecting fertility who got pregnant were included. All patients received CC to induce ovulation. Pregnancies in CC treated cycles and after treatment were recorded. Twenty pregnancies were achieved during CC treated cycles and 12 in the cycles after it was withdrawn. In the latter group, eight pregnancies were achieved in the cycle following CC therapy, and four in the second subsequent cycle. In relation to pregnancy complications no significant statistical differences were found between the group of patients who became pregnant during the stimulation cycles and in the cycles after CC.

Amenorrea hipotalámica, concepto, clasificación y alternativas terapeúticas / Hipothalamic amenorrhea, concept, clasification and therapeutical alternatives

El desarrollo de amenorrea hipotalámica refleja generalmente una respuesta individual al stress ambiental y al propio estilo de vida. En la mayoría de los casos, no hay una anormalidad anatómica detestable del eje hipotálamo-hipófisis-ovario-endometrio. Numerosas evidencias sugieren que el defecto de base es una reducción de la actividad del generador hipotalámico de pulsos de GNRH. Los factores neuroendocrinos que regulan la función de este centro son parcialmente conocidos. El sistema opioidérgico y dopaminérgico han sido implicados como posibles factores en la reducción de la secreción pulsátil de GNRH. Debido a la naturaleza por lo general funcional del trastorno, se espera una reactivación de la actividad pulsátil de GNRH una vez superado los factores que lo desencadenaron. La persistencia de la anovulación obliga a una terapia de reemplazo hormonal fundamentalmente por el riesgo de terapia de reemplazo hormonal fundamentalmente por el riesgo de osteoporosis. En las pacientes que desean fertilidad, la inducción de ovulación con GNRH pulsátil es la alternativa terapéutica más efectiva

[Ovulation induction with pure FSH in anovulatory patients resistant to clomifene citrate]. / Inducción de la ovulación con FSH pura en pacientes anovulatorias resistentes a citrato de clomifeno.

The objective was to evaluate the utility of the pure FSH as treatment of women clomiphene-resistant. Seventy two patients clomiphene-resistant were treated with pure FSH. Ovulation induction was started with 75 IU of pure FSH on day 3 of the menstrual cycle, monitoring the follicular growth with transvaginal ultrasonography, additional doses of pure FSH were administered accordingly. Human chorionic gonadotropin (10,000 IU) was administered when the dominant follicle reached a diameter > or = 16 mm. The pregnancy rate per cycle was 18.0%, on the other hand, the cumulate rate of pregnancy was 72.2%. There was not significant difference in the pregnancy rate between patients with primary or secondary infertility. The rate of spontaneous abortions was similar to the general population. As conclusion, it therefore appropriate to offer the treatment with pure FSH to patients clomiphene-resistance. The cases with gonadotropin-resistance, will be candidates to surgical procedures.

Inductores de la ovulación, su estado actual y experiencia institucional / Ovulation inductors, present state and instutional experience

Antecedentes. La anovulación o esterilidad por factor endócrino ovárico representa del 20 al 30 por ciento de todas las parejas estériles y aunque en la actualidad existen diversos fármacos capaces de inducir ovulación , siguen siendo el citrato de clomifeno y las gonadotropinas menopáusicas humanas los medicamentos de primera línea para el tratamiento de la esterilidad por factor anovulatorio, como hace 30 años que se inició su uso. Objetivo. En el presente trabajo se analiza el marco teórico para la selección de las pacientes candidatas a uno u otro medicamento, así como los esquemas terapéuticos utilizados, efectos secundarios y resultados tanto de ovulación como de embarazos. Método. Se compararon los resultados promedio de la literatura, con la experiencia institucional de los autores. Resultados. Con el citrato de clomifeno en casos bien seleccionados se obtiene ovulación en aproximadamente 80 por ciento de los casos y embarazo en el 40-50 por ciento; en el INPer se obtuvo en un análisis de 200 casos ovulación en el 72 por ciento y embarazo en el 58 por ciento. Con las gonadotropinas menopáusicas humanas los resultados son mas variables encontrando un promedio en la literatura de ovulación del 70 al 90 por ciento y de embarazo del 25 al 55 por ciento. En el INPer de 128 ciclos de tratamiento se obtuvo ovulación el 75.7 por ciento y embarazo en el 36 por ciento de un grupo de 100 mujeres anovulatorias tratadas

Anovulaçäo: terapêutica / Anovulation: treatment

Estudamos 209 pacientes. Selecionamos algumas drogas indutoras de ovulaçäo que nos pareceram apropriadas a cada paciente e avaliamos os resultados obtidos. Em 80 pacientes, empregamos estrogênios isolados ou mais comumente associados a progestogênios. Obtivemos 94,02 por cento de regularizaçäo do ciclo menstrual e 61,66 por cento de gestaçöes. Em 33 pacientes, foi utilizado o clomifeme. Obtivemos 85 por cento de regularizaçäo do ciclo e 70 por cento de gestaçöes. Em 31 pacientes, ao clomifene associamos outras drogas. O índice de regularizaçäo do ciclo foi de 73,6 por cento e em 52,63 por cento obtivemos gestaçöes. Em 39 pacientes, usou-se bromocriptina. Houve regularizaçäo do ciclo em 78,78 por cento dos casos e gestaçöes em 50 por cento. Em 18 pacientes com a ressecçäo cuneiforme dos ovários obtivemos 71,42 por cento de regularizaçäo do ciclo e 57,19 por cento de gestaçöes. Em cinco outras pacientes, obtivemos bons resultados de gestaçöes em três: com uso de corticóides em uma e em duas outras, obesas, com dieta de emagrecimento.

[Ovulation induction with gonadotropins aided by cervix mucus analysis and echography]. / Inducción de la ovulación con gonadotropinas mediante evaluación del moco cervical y ecografía.

Induction of ovulation was performed in 148 cycles using human menopausal gonadotropins (HMG) in 52 patients, seven with hypothalamic-pituitary failure and 45 suffering dysfunction at this level. Several induction schemes were used beginning on the second day of the cycle, until one or more follicles larger than 14 mm were found, to administrate 10,000 UI of human chorionic gonadotropin (HCG). Clinical valuation of cervical mucus and ultrasound of the ovaries to assess follicular development were done, from day eight of the cycle. Twenty five pregnancies resulted in 23 patients (44%), three in patients with failure and 22 in the dysfunction group. A total of 19 healthy babies were taken home, however three neonatal deaths, four miscarriages and one ectopic pregnancy occurred. Multiple gestation was present in three patients (12%), one was quadruplet, one triplet and one twin. The ovarian hyperstimulation syndrome (OHS) was detected in seven patients (13.4%), three were mild, two moderate and two severe; two cases of OHS had multiple pregnancies. Although induction of ovulation with HMG in patients with anovulation is a complex procedure requiring strict clinical vigilance and advanced technological resources, in this clinical study it was possible to obtain similar results to other series, using high resolution ultrasound only, without daily measurements of hormones.

Inducción de la ovulación con citrato de clomifeno en pacientes infértiles / Ovulation induccion with citrate of clomifeno in infecundity patients

Se presenta un estudio retrospectivo, abarcando la casuística del Servicio de Infertilidad del Hospital Loayza correspondiente al periodo 1980-1991, en el que se revisa la experiencia en el tratamiento de las alteraciones de la función ovulatoria, con citrato de clomifeno. Son incluidas 56 pacientes, quienes recibieron tratamiento para un total de 297 ciclos. Fueron divididas en dos categorias diagnósticas principales: anovulación crónica oligoanovulación (30 pacientes) y defecto de fase lútea (26 pacientes). Se encontró uno o mas factores de infértilidad asociados en el 75 por ciento de los pacientes, siendo el factor tubo-peritoneal el mas prevalente (p menor 0.0001). En la presente revisión, un 84 por ciento de las pacientes consiguen ovulación, y se encuentra una tasa de gestación del 29 por ciento. Se obtiene una diferencia significativa entre tener uno o mas factores de infértilidad asociados y, lograr o no la gestación (p menor 0.0001), siendo el factor tubo-peritonial el que ejerce el efecto mas importante (p menor 0.0001). Como efecto secundario importante, se confirma que el citrato de clomifeno ejerce un efecto negativo sobre la producción del moco cervical (p<0.0001). Cinco pacientes (9 por ciento), presentaron hiperestimulación ovárica, de grado leve en todos los casos. Se compara nuestra experiencia con la referida en la literatura extranjera