Atualizações na terapêutica farmacológica para infertilidade na mulher diagnosticada com síndrome de ovários policísticos: revisão de literatura / Updates on pharmacological treatments for infertility in women diagnosed with polycystic ovary syndrome: a literature review

Objetivo: Abordar atualizações referentes à terapia medicamentosa para indução da ovulação nas mulheres diagnosticadas com síndrome dos ovários policísticos (SOP). Métodos: Revisão de literatura por meio de levantamento bibliográfico do período de 1975 a 2021, nas bases eletrônicas PubMed, SciELO e MedLine, complementado pela Diretriz Internacional Baseada em Evidências para a Avaliação e Manejo da SOP de 2018 e pelo manual da Febrasgo para SOP. Sete descritores que atendessem à finalidade da pesquisa foram utilizados. Resultados: A literatura aponta atualmente algumas drogas como opção na terapêutica para a indução de ovulação, como metformina, letrozol e citrato de clomifeno, evidenciando que o uso de letrozol isolado e em associação com a metformina apresentaram melhores taxas de ovulação, 71,5% e 75,4%, respectivamente. Conclusão: O uso do letrozol isolado ou combinado com a metformina apresentou os melhores resultados nas taxas de gravidez e ovulação, todavia o tratamento para indução ovulatória deve ser individualizado.(AU)

Objective: To address updates of medicinal therapy for ovulation induction in women diagnosed with polycystic ovary syndrome (PCOS). Methods: Reviewing Literature through a bibliographic survey from 1975 to 2021, on the electronic databases PubMed, SciELO and MedLine, complemented by the International Evidence-Based Guideline for the Evaluation and Management of PCOS 2018 and the Febrasgo guide for PCOS. Seven descriptors that matched to the purpose of the research were applied. Results: Some drugs are currently indicated in the literature as an option for ovulation induction therapy, such as: metformin, letrozole and clomiphene citrate, showing that the use of letrozole alone and in association with metformin had better ovulation rates, 71.5% and 75.4%, respectively. Conclusion: The use of letrozole alone or combined with metformin showed the best results in pregnancy and ovulation rates, however, treatment for ovulatory induction must be individualized.(AU)

Therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of polycystic ovary syndrome

SUMMARY OBJECTIVE In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.

RESUMO OBJETIVO Tendo em vista a alta incidência de síndrome dos ovários policísticos (SOP) e os efeitos terapêuticos insatisfatórios da dimetildiguanida ou do citrato de clomifeno isoladamente, nosso estudo teve como objetivo investigar os efeitos terapêuticos da dimetildiguanida associada ao citrato de clomifeno no tratamento da SOP. MÉTODOS Um total de 79 pacientes com POCS e 35 mulheres saudáveis foram incluídos, e biópsias endometriais foram obtidas. A expressão da proteína de ligação do elemento regulador de esterol-1 (SREBP1) nos tecidos endometriais foi detectada por qRT-PCR. Pacientes POC foram divididos aleatoriamente em grupo A (n=40) e grupo B (n=39). Os pacientes do grupo A foram tratados com dimetildiguanida combinada com citrato de clomifeno, enquanto os pacientes do grupo B foram tratados apenas com citrato de clomifeno. O número de folículos maduros e muco cervical, taxa de desenvolvimento folicular e taxa de ovulação, taxa de gravidez, abortamento precoce, taxa de ovulação, espessura endometrial, taxa positiva de três linhas, nível de hormônio folículo estimulante e nível de hormônio luteinizante foram comparados entre os dois grupos. RESULTADOS O nível de expressão do SREBP1 foi maior nos pacientes com SOP do que no controle normal. A expressão de SREBP1 foi inibida após o tratamento, enquanto os efeitos inibidores do tratamento combinado foram mais fortes do que os do citrato de clomifeno isoladamente. Comparado com o citrato de clomifeno sozinho, o tratamento combinado melhorou significativamente a pontuação do muco cervical, a taxa de desenvolvimento folicular, a taxa de ovulação do folículo único, a espessura endometrial, a taxa positiva de três linhas de sinal e o nível de hormônio folículo estimulante. CONCLUSÃO O efeito terapêutico do tratamento combinado é melhor do que o citrato de clomifeno isolado no tratamento da SOP.

Clomiphene treatment may be effective in refractory episodic and chronic cluster headache / Tratamento de 15 casos episódicos e crônicos de cefaleia em salvas de difícil controle com clomifeno

ABSTRACT Objective To describe the evolution of 15 patients who were treated for difficult-to-control episodic and chronic cluster headaches with clomiphene. Methods Clomiphene treatment was used for seven chronic and eight episodic cluster headache patients. The chronic patients were refractory to the medication being used, and the episodic patients, in addition to being resistant to conventional medication, had longer cluster headache periods, exceeding the average time of previous cluster cycles. Our main analysis was of the time to pain-free, complete remission, and the length of pain-free time and complete remission. Results Clomiphene was used for 45-180 days. The average time to being pain-free was 15 days and cluster remission was up to 60 days. The average time between being pain-free until cluster remission was 26 days. Conclusions Clomiphene treatment was significantly efficient. It interrupted chronicity in all patients, suggesting the capability of changing the pattern of attacks. It proved to be safe and well tolerated.

RESUMO Objetivo Descrever a evolução de 15 casos de cefaleia em salvas de difícil controle, episódicos e crônicos, tratados com clomifeno. Métodos Foram tratados 7 casos crônicos e 8 episódicos. Os crônicos, refratários aos medicamentos preventivos em uso e os episódicos, além de refratários, apresentaram salva mais longa que as anteriores. Foram analisados o tempo para a ausência das crises, fim da salva e o tempo entre os dois parâmetros. Resultados O clomifeno foi usado por 45 a 180 dias. A média de tempo para a remissão das crises foi de 15 dias e da salva foi de 60 dias. A média entre o fim das crises e da salva foi de 26 dias. Conclusão O clomifeno foi eficaz em ambos os padrões. Foi capaz de interromper a cronicidade em todos os casos, o que sugere uma ação neuromodulatória capaz de mudar o padrão das crises. Mostrou-se seguro e bem tolerado.

Metformina e citrato de clomifeno no tratamento de fertilidade na síndrome dos ovários policísticos / Metformin and clomiphene citrate in polycystic ovary syndrome's treatment

A síndrome dos ovários policísticos (SOP) é uma complexa desordem endócrina caracterizada por distúrbios reprodutivos e metabólicos, sendo a causa mais comum de infertilidade ovariana. A prevalência é entre 5 e 10% em mulheres na idade reprodutiva. Sua etiologia permanece obscura e a variabilidade de expressão fenotípica continua a desafiar os cuidados clínicos e pesquisas sobre a heterogeneidade desta condição. Embora mudanças no estilo de vida bem como o uso de citrato de clomifeno (CC) serem o padrão para o tratamento da infertilidade nestas pacientes, o uso da metformina tem se destacado como tratamento para esse fim ante sua eficácia. Partindo deste princípio, esta revisão tem por objetivo avaliar a eficácia da metformina em melhorar as taxas de ovulação e de gravidez clínica, seja como tratamento isolado ou combinado ao CC.(AU)

The polycystic ovary syndrome (PCOS) is a complex endocrine disease characterized by reproductive and metabolic disorders. It is the most common cause of ovarian infertility and has a prevalence of 5-10% in reproductive age women. Its etiology remains unclear, and the variability of phenotypic expression continues to yield clinical care and research on the heterogeneity of this challenging condition. Although life style changes as well as the use of clomiphene citrate (CC) is a standard treatment of infertility in these patients; metformin use has been highlighted in recent years as a treatment for this purpose due its effectiveness in treating PCOS. Based on this principle, this review aims to assess the metformin effectiveness in improving ovulation rates and clinical pregnancy, either alone or in combination as the CC treatment.(AU)

Síndrome de ovario poliquístico / Polycystic ovary syndrome

El síndrome de ovario poliquísticos (SOP) representa una de las endocrinopatías más frecuentes en la mujer y es la principal causa de hiperandrogenismo (HA). Se trata de un trastorno complejo, multifactorial, poligénico con influencias ambientales. Aunque se han propuestos diferentes criterios para su diagnóstico, se prefiere el uso del más abarcativo (Criterio de Rotterdam) con la presencia de 2 de 3 de los siguientes: 1) HA clínico o bioquímico, 2) oligoanovulación crónica (OA), 3) poliquistosis ovárica por ecografía, excluyendo otras etiologías. Es frecuente su asociación con comorbilidades metabólicas (obesidad, diabetes 2, dislipidemia, apnea del sueño, etc.) y trastornos reproductivos (hiperplasia endometrial e infertilidad), sobre todo en los fenotipos clásicos, con HA y OA. El tratamiento estará orientado a las características clínicas de cada paciente y al deseo reproductivo. La pérdida de peso en aquellas con sobrepeso u obesidad o ambos factores puede restaurar los ciclos menstruales y disminuir el riesgo metabólico y representa la primera línea de tratamiento. Los anticonceptivos orales (ACO) son el tratamiento farmacológico de elección ya que atenúan las manifestaciones de HA y ofrecen protección endometrial. En las pacientes con oligoanovulación que buscan embarazo, el citrato de clomifeno es el tratamiento aconsejado en primera instancia. La metformina podría usarse en aquellas con intolerancia a la glucosa o diabetes 2 y también como segunda línea de tratamiento para restaurar los ciclos e inducir la ovulación. (AU)

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women, the main cause of hyperandrogenism (HA). It is a complex, multifactorial polygenic disorder with environmental influences. Although there have been proposed different criteria for diagnosis, using the most comprehensive (Criteria Rotterdam) with the presence of 2 of 3 of the following is preferred: 1) HA clinical or biochemical, 2) oligo-anovulation chronic (OA), 3) polycystic ovaries by ultrasound, excluding other etiologies. It is frequently associated with metabolic comorbidities (obesity, type 2 diabetes, dyslipidemia, sleep apnea, etc.) and reproductive disorders (endometrial hyperplasia and infertility), especially in the classical phenotypes, with HA and OA. The treatment will be oriented to the clinical characteristics of each patient and reproductive desire. Weight loss in those who are overweight and / or obesity can restore menstrual cycles and decrease metabolic risk and represents the first line of treatment. Oral contraceptives (OC) are the pharmacological treatment of choice as it attenuates the manifestations of HA and offer endometrial protection. In patients seeking pregnancy with oligo-anovulation, clomiphene citrate would be used at first instance. Metformin may be used in those with impaired glucose tolerance or type 2 diabetes and also as a second-line treatment to restore cycles and induce ovulation. (AU)

Clomiphene citrate treatment for late onset hypogonadism: rise and fall

ABSTRACT Objective: Previous series have demonstrated that Clomiphene Citrate (CC) is an effective treatment to increase Total Testosterone (TT) in Late Onset Hypogonadism (LOH) patients. However, what happens to TT levels after ending CC treatment is still debatable. The objective of this study is to evaluate TT levels 3 months after the discontinuation of CC in patients with LOH who were previously successfully treated with the same drug. Materials and Methods: Twenty-seven patients with LOH that were successfully treated (achieved TT levels >11nmol/l) with CC 50mgs daily for 50 days were prospectively recruited in our Andrological outpatient clinic. CC was then stopped for 3 months and TT levels were measured at the end of this period. Results: Mean TT level before discontinuation of CC was 22.7±8.1nmol/L (mean±SD). Three months after discontinuation, mean TT level significantly decreased in all patients, 10.2±3.9nmol/l (p<0.01). Twenty-one patients (78%) decreased TT levels under 11nmol/L. Six patients (22%) had TT levels that remained within the normal recommended range (≥11nmol/l). No statistical significant differences were observed between both groups. Conclusion: In the short term LOH does not seem to be a reversible condition in most patients after CC treatment. More studies with longer follow-up are needed to evaluate the kinetics of TT in LOH.

Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice

Polycystic ovary syndrome represents 80% of anovulatory infertility cases. Treatment initially includes preconception guidelines, such as lifestyle changes (weight loss), folic acid therapy to prevent the risk of fetal neural tube defects and halting the consumption of tobacco and alcohol. The first-line pharmacological treatment for inducing ovulation consists of a clomiphene citrate treatment for timed intercourse. The second-line pharmacological treatment includes the administration of exogenous gonadotropins or laparoscopic ovarian surgery (ovarian drilling). Ovulation induction using clomiphene citrate or gonadotropins is effective with cumulative live birth rates of approximately 70%. Ovarian drilling should be performed when laparoscopy is indicated; this procedure is typically effective in approximately 50% of cases. Finally, a high-complexity reproduction treatment (in vitro fertilization or intracytoplasmic sperm injection) is the third-line treatment and is recommended when the previous interventions fail. This option is also the first choice in cases of bilateral tubal occlusion or semen alterations that impair the occurrence of natural pregnancy. Evidence for the routine use of metformin in infertility treatment of anovulatory women with polycystic ovary syndrome is not available. Aromatase inhibitors are promising and longer term studies are necessary to prove their safety.

Clinical Practice Guidance for the Use Of Clomiphene Citrate in Male Hormone Replacement Therapy (HRT).

Introduction: Inhibition of pituitary gonadotropin secretion in men by testosterone (T) is principally mediated by aromatization to estrogen (E), which inhibits hypothalamic secretion of gonadotropin-releasing hormone (GnRH). Material and Methods: Longitudinal clinical investigation unit-based evaluation of the clinical and biochemical response to E-receptor blockade. Initial monotherapy with 50 mg of clomiphene citrate (CC) daily for a period of 9 months, with diurnal morning peak testosterone and luteinizing hormone (LH) levels evaluated at three-month intervals thereafter. Th e patient then resumed hormone replacement therapy (HRT) using T cream with adjuvant CC therapy. Main Outcome Measures were Baseline and stimulated T and LH levels; eff ect on sexual function. Result(S): CC therapy resulted in complete normalization of pulsatile gonadotropin secretion, serum T level, and sexual function. Conclusion(S): Isolated hypogonadotropic hypogonadism (IHH) may result from an acquired defect of enhanced hypothalamic sensitivity to E-mediated negative feedback. Whereas direct T replacement therapy can further suppress endogenous gonadotropin secretion, treating IHH men with gonadotropins can stimulate endogenous T secretion and enhance fertility potential. Reversal of gonadotropin defi ciency with CC was found to have a similar biological eff ect.

Hiperprolactinemia y disfunción sexual en el varón / Hyperprolactinemia and sexual dysfunction among males

Hyperprolactinemic males usually have a hypoactive libido and less commonly, erectile dysfunction and disturbances of orgasm and ejaculation. Hyperprolactinemia alters the balance between neurotransmitters, neuropeptides and hormones involved in libido and erection, affecting dopaminergic tone. An imbalance between dopamine, that stimulates sexual function and serotonin that inhibits it, is generated. In the central nervous system, hyperprolactinemia inhibits centers controlling sexual desire and erection. At the neuroendocrine level, it decreases GnRH, LH and testosterone pulses, resulting in a hypogonadotrophic hypogonadism. Erection is also inhibited peripheral actions of low testosterone and high prolactin levels. There is a disturbance of penile smooth muscle relaxation and of the parasympathetic sacrum-penis reflex arch. In experimental animals, acute hyperprolactinemia hampers the central erection mechanism whereas in chronic conditions, peripheral disturbances also occur. Even correcting low testosterone levels, the adverse effects of hyperprolactinemia on sexual function persist. The use of dopaminergic agonists may achieve normal prolactin and testosterone levels resulting in normal sexual function. Chronic hyperprolactinemia results in progressive deterioration of sexual function and a higher hypothalamic damage that does not respond to clomiphene. In this situation and in the presence of sellar tumors that destroy gonadotrophic cells, there is indication of androgenic replacement maintaining the use of dopaminergic agonists...

Comparison of treatment outcomes of infertile women by clomiphene citrate and letrozole with gonadotropins underwent intrauterine insemination

This study was designed to compare the effect of clomiphene and letrozole in ovulatory stimulation in infertile women under intrauterine insemination who referred to Mahdiyeh infertility clinic during 2008-2009. 106 infertile women were randomly divided into two equal groups. Patients were treated with 5 mg of letrozole daily [in letrozole group] or 100 mg of clomiphene citrate daily [in clomiphene group] for five days starting on day 3 of their menses. Dose and time of FSH was similar in the two groups. Number of follicles, endometrial thickness, Pregnancy rate and prevalence of complications were compared in the two groups. Mean [ +/- SD] of age in letrozole and clomiphene groups was 26.3 +/- 3.9 and 25.2 +/- 4.9 respectively [P=0.186]. Average number of follicles was 2.5 +/- 1.65 in letrozole group and 2.36 +/- 1.4 in clomiphene group [P=0.764]. Beta-hCG was positive in 11 [20.8%] in letrozole and 12 [22.6%] in clomiphene groups [P=0.814]. Pregnancy rate was 20.8% and 22.6% in letrozole and clomiphene group respectively [P=0.814]. There was no difference in rate of abortion between groups. Endometrial thickness [ET] at the time of hCG administration in the letrozole [6.8 +/- 1.5 mm] and in clomiphene [6.6 +/- 1.2 mm] [P=0.615]. But ET>7.4 mm was found in 2 cased [3.8%] in clomiphene group and 12 cases [%22.8] in letrozole groups [P=0.01]. It appears that letrozole and clomiphene have similar outcome infertile women under intrauterine insemination and these drugs are good alternative for each others

Clomiphene fails to revert hypogonadism in most male patients with conventionally treated nonfunctioning pituitary adenomas / Clomifeno não reverte o hipogonadismo na maioria dos homens com adenomas pituitários não funcionais tratados de forma convencional

OBJETIVE: To evaluate the effect of clomiphene in men with hypogonadism and conventionally treated nonfunctioning pituitary adenomas (NFPA). PATIENTS AND METHODS: Open label, single-arm, prospective trial. Nine hypogonadal men (testosterone < 300 ng/dL and low/normal LH) with previously treated NFPA. Clomiphene (50 mg/day orally) for 12 weeks. Testosterone, estradiol, LH, FSH, prolactin and erectile function were evaluated before and after 10 days, 4, 8 and 12 weeks of clomiphene treatment. RESULTS: After clomiphene treatment, testosterone and erectile function improved in only one patient. In the remaining eight patients, testosterone levels decreased whereas LH, FSH, and estradiol remained unchanged. Insulin sensitivity increased in unresponsive patients. CONCLUSIONS: Compared with hypogonadal men with prolactinomas under dopaminergic therapy, clomiphene treatment failed to restore normal testosterone levels in most patients with conventionally treated NFPA.

OBJETIVO: Avaliar o efeito do clomifeno em homens com hipogonadismo e adenoma hipofisário não funcionante (NFPA) previamente tratados. PACIENTES E MÉTODOS: Aberto, braço único, prospectivo. Nove homens hipogonádicos (testosterona < 300 ng/dL e LH normal/baixo) com NFPA previamente tratados. Clomifeno (50 mg/dia oral) por 12 semanas. Testosterona, estradiol, LH, FSH, prolactina e função erétil foram avaliados antes e após 10 dias, 4, 8 e 12 semanas de clomifeno. RESULTADOS: Após clomifeno, a testosterona e a função erétil melhoraram em um paciente. Em outros oito pacientes, os níveis de testosterona reduziram enquanto os níveis de LH, FSH, e estradiol permaneceram inalterados. A sensibilidade à insulina aumentou nos não respondedores. CONCLUSÕES: Em contraste com homens hipogonádicos com prolactinomas tratados com agonistas dopaminérgicos, a maioria dos hipogonádicos com NFPA falha em restaurar os níveis de testosterona durante o uso de clomifeno.

Uso de la metformina en el tratamiento de pacientes infértiles con síndrome de ovarios poliquísticos / Use of metformin in the treatment of infertile patients with polycystic ovary syndrome

Determinar el efecto de la terapia con metformina en pacientes infértiles con síndrome de ovarios poliquísticos. Estudio clínico, prospectivo y descriptivo. Incluyó pacientes con diagnóstico de síndrome de ovarios poliquísticos, infertilidad y resistencia a la insulina, a las que se les administró tratamiento con metformina por 3 meses. Las pacientes que no se embarazaron en ese período recibieron tratamiento con citrato de clomifeno, hasta un máximo de 6 meses. En el Servicio de Fertilidad Maternidad "Concepción Palacios". Caracas. Resultados: Se completó un total de 62 pacientes. La tasa de embarazo de 25,8 por ciento (19 pacientes). Un 57,9 por ciento de las pacientes lograron embarazo con 3 meses de tratamiento, con una P= 0,492 lo cual no fue estadísticamente significante. La tasa de embarazos con citrato de clomifeno fue de 23,5 por ciento (8 pacientes), P=0,684. El 63,2 por ciento (12) tuvo un embarazo a término. La tasa de aborto fue de 26,3 por ciento (5). La metformina induce ovulación espontánea en pacientes con síndrome de ovarios poliquísticos. No existe diferencia estadística entre la tasa de embarazos con la terapia con metformina sola y metformina con citrato de clomifeno. La metformina mejora la evolución de embarazo

To determine the effect of treatment with metformin in infertile patients with polycystic ovary syndrome. Clinical, prospective and descriptive study. Infertile anovulatory patients with polycystic ovary syndrome and insulin resistant were included, and all of them, were treated with metformin for 3 months. Patients who did not ovulate in this time, received clomiphene citrate for 6 months. Fertility Service of Maternidad "Concepcion Palacios". 62 infertile patients were included in this study. The pregnancy rate was 25.8 percent (19 patients). The 57.9 percent of women became pregnant with metformin administration for 3 months, with P= 0.492, it was not statistical significance. The pregnancy rate with clomiphene citrate was 23.5 percent (8 patients), P= 0.684. The abortion rate was 26.3 percent (5). The metformin induce ovulation in anovulatory polycystic ovary syndrome women, whereas the pregnancy rate resulted similar in both treatment groups: metformin alone and metformin and clomiphene citrate

Inducción de ovulación: conceptos básicos / Ovulation induction: basic concepts

La concepción sin éxito es uno de los trastornos crónicos más prevalentes que involucra adultos jóvenes. Desde el año 1978, cuando nació la primera bebé producto de técnicas de reproducción asistida, el manejo de la infertilidad femenina ha sido transformada por la Fertilizaciòn In Vitro. Los trastornos de la ovulación representan el 15% de las causas de infertilidad en las parejas y el 40% de infertilidad en las mujeres.

Tratamiento con metformina en pacientes con síndrome de ovario poliquístico, no obesa, no insulinorresistentes y durante el embarazo / Metformin treatment and pregnancy outcome in non-obese, non-insulinresistant patients with policystic ovarian syndrome

Intároducción:el síndrome de ovario poliquístico (SOP) se caracteriza por anovulación crónica e hiperandrogenismo y en nuestro medio afecta el 12% de las mujeres. No existen dudas de la función que cumple la metformina en pacientes con SOP, obesidad e insulinorresistencia (IR), sin embargo, al no conocer íntegramente su mecanismo de acción, no estamos en condiciones de predecir cual es su rol en el grupo de no obesas, no IR. Se trata del 80% de nuestras pacientes con diagnóstico de PCO que solo presentan oligoamenorrea-anovulación y ovarios ecográficamente poliquísticos. Objetivo: investigar la efectividad de la metformina en la restauración de los ciclos menstruales y la ovulación, así como también en el logro del embarazo en mujeres con SOPQ no obesas, no IR, y reportar la evolución de los embarazos con metformina. Materiales y métodos: se realizó un trabajo prospectivo, desde julio de 2005 a marzo de 2007, en 59 pacientes con diagnóstico de SOP, según los criterios del Consenso de Rotterdam, todas con deseo de fertilidad, oligomenorreicas-anovuladoras, no obesas, no IR (mediana del peso: 60kg, mediana de talla:165 cm, BMI 22,8 de mediana. Indice HOMA:143 de mediana) El estudio se dividió en 3 etapas. En la primera etapa se utilizó metformina en dosis crecientes hasta la dosis de 1700mg/día, durante 6 meses. En la segunda, se sumó citrato de clomifeno, 50 mg/día entre el 5º y 9º días. La tercera etapa la constituyó el seguimiento de embarazos con el uso de metformina. Resultados: se observó un franco cambio en el ritmo menstrual y en la ovulación, con eumenorrea en un 72% de los casos post-metformina y dosaje de progesterona dentro de rango ovulatorio en el día 21 del ciclo. La tasa de embarazo global fue del 52,5% (31/59), de los que el 74% fue solo con metformina, más un 25,8% con el agregado de citrato de clomifeno. El 58% de embarazos (18/31) ocurrió en los 2 primeros meses. De los 31 embarazos, se logró seguimiento completo de 24, ...

Síndrome do ovário policístico: aspectos atuais das abordagens terapêuticas: parte 2 / Polycystic ovary syndrome: current aspects of the therapeutic interventions: part 2

A segunda parte desta revisão inclui as demais opções de tratamento da síndrome do ovário policístico (SOP). O citrato de clomifeno (CC) é utilizado na dose de 50 a 200 mg/dia durante cinco dias a partir do segundo ao quinto dia do ciclo menstrual. A taxa de ovulação após o tratamento com CC é de aproximadamente 73 por cento e a de gravidez em torno de 36 por cento. Com os análogos do GnRH ocorre redução dos níveis de gonadotrofinas e diminuição da secreção de estrógenos e androgênios. O principal risco da estimulação com gonadotrofinas é a gestação múltipla. Anastrazole e letrozole pertencem à classe dos inibidores da aromatase de terceira geração. As taxas de ovulação e gestação com letrozole variam de 54,5 a 82,4 por cento e 9 a 25 por cento, respectivamente. Não ocorreu diferença significativa nas taxas de ovulação e gestação entre o uso de 2,5 mg de letrozole em comparação com 1 mg de anatrozole. O uso da N-acetilcisteína (NAC) sugere melhora significativa da sensibilidade à insulina em mulheres com SOP. Os contraceptivos hormonais orais combinados permanecem como tratamento predominante para redução do hiperandrogenismo e das irregularidades menstruais em mulheres que não desejam engravidar. Os antiandrógenos são utilizados principalmente para diminuir as queixas de hirsutismo e o efeito será percebido em 9 a 12 meses de tratamento. Muitas mulheres se submetem à cauterização ovariana ou a laser por videolaparoscopia tendo restauração espontânea da ovulação com gravidez subsequente. Porém, os benefícios potenciais destas intervenções tendem a ser atenuados devido à formação de aderências.

The second part of this review includes other treatment options for polycystic ovary syndrome (PCOS). The clomiphene citrate (CC) is used in a dose of 50 to 200 mg/day for five days, begining from the second to fifth day or the menstrual cycle. The ovulation rate after the treatment with CC is approximately 73 percent and the pregnancy rate is about 36 percent. With GnRH analogues, there is a reduction in gonadotrophin levels and a decrease of androgen and estrogen secretion. The major risk due to stimulation with gonadotrophins is the multiple gestation. Anastrozole and letrozole belong to the class of third-generation aromatase inhibitors. The rates of ovulation and pregnancy with letrozole vary from 54.5 to 82.4 percent and from 9 to 25 percent, respectively. There was no significant difference in ovulation and pregnancy rates with the use of 2.5 mg of letrozole compared to 1 mg of anastrozole. The use of N-acetyl Cysteine (NAC) suggests significant improvement in insulin sensibility in women with PCOS. The combined oral hormonal contraceptives are still the predominant treatment to decrease hyperandrogenism and menstrual irregularities in women who do not want to get pregnant. Anti-androgens are used mainly to diminish complaints of hirsutism and the effect will be noted after 9 to 12 months of treatment. Several women undergo ovarian cauterization of with laser by videolaparoscopy having their ovulation spontaneously restored with subsequent pregnancy. However, the potential benefits of these interventions might be attenuated due to adhesion formations.

Medical management of male infertility.

Management of male infertility is always a difficult task. In recent years booming of artificial reproductive technologies (ART) has put infertologists and andrologists in front of a million dollar question whether to treat the person or the gametes. A basic andrology laboratory at present has become part and parcel of an infertility clinic. Hence treatment of male infertility has become institutional and collective for clinicians and basic scientists. The basic approach towards management of male infertility includes confirmation of diagnosis and to find out the cause for which pathological, endocrinological and biochemical tests are essential. In this series specific defects causing seminopathy has been found in 18% cases where treatment is straightforward and towards the cause. The main bulk of idiopathic seminal defects (82%) really poses challenge to the infertologists so far management is concerned. In this study commonest seminal defect has been found to be oligoasthenozoospermia which amounts to 63% cases. For medical management purpose drugs commonly used are clomiphene, gonadotrophins, bromocriptine, L-thyroxine, vitamin E, B12, etc. When they fail the main approach remains to be intra-uterine insemination (IUI) and ART eg, in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI).

Effects of metformin treatment on luteal phase progesterone concentration in polycystic ovary syndrome

The causes of luteal phase progesterone deficiency in polycystic ovary syndrome (PCOS) are not known. To determine the possible involvement of hyperinsulinemia in luteal phase progesterone deficiency in women with PCOS, we examined the relationship between progesterone, luteinizing hormone (LH) and insulin during the luteal phase and studied the effect of metformin on luteal progesterone levels in PCOS. Patients with PCOS (19 women aged 18-35 years) were treated with metformin (500 mg three times daily) for 4 weeks prior to the test cycle and throughout the study period, and submitted to ovulation induction with clomiphene citrate. Blood samples were collected from control (N = 5, same age range as PCOS women) and PCOS women during the late follicular (one sample) and luteal (3 samples) phases and LH, insulin and progesterone concentrations were determined. Results were analyzed by one-way analysis of variance (ANOVA), Duncan's test and Karl Pearson's coefficient of correlation (r). The endocrine study showed low progesterone level (4.9 ng/ml) during luteal phase in the PCOS women as compared with control (21.6 ng/ml). A significant negative correlation was observed between insulin and progesterone (r = -0.60; P < 0.01) and between progesterone and LH (r = -0.56; P < 0.05) concentrations, and a positive correlation (r = 0.83; P < 0.001) was observed between LH and insulin. The study further demonstrated a significant enhancement in luteal progesterone concentration (16.97 ng/ml) in PCOS women treated with metformin. The results suggest that hyperinsulinemia/insulin resistance may be responsible for low progesterone levels during the luteal phase in PCOS. The luteal progesterone level may be enhanced in PCOS by decreasing insulin secretion with metformin.

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.

Terapia con metformina y embarazo en pacientes con síndrome de ovario poliquístico / Metformin therapy for polycystic ovary syndrome during pregnancy

Estudio prospectivo de seguimiento de 15 pacientes con síndrome de ovario poliquístico (SOP) e hiperinsulinemia que se embarazaron con el uso de metformina, y que se siguieron hasta el parto. Diez continuaron metformina durante el embarazo, hasta las 14 semanas y cinco hasta las 32 semanas. Las 5 pacientes que usaron más tiempo el medicamento no desarrollaron diabetes gestacional a diferencia de las que lo tomaron hasta las 14 semanas que presentaron diabetes gestacional en tres de diez. No encontramos abortos en estas pacientes, y tampoco presentaron problemas con el medicamento. No hubo malformaciones en los recién nacidos.