Association of obesity and anovulatory infertility.

OBJECTIVE: To verify the association of obesity and infertility related to anovulatory issues. METHODS: This case-control study was carried out with 52 women, aged 20 to 38 years, divided into two groups (infertile - cases - and fertile - control), seen at outpatient clinics, in the period from April to December, 2017. RESULTS: We found significant evidence that obesity negatively affects women's fertility (p=0.017). The group of infertile women was 7.5-fold more likely to be obese than fertile women. CONCLUSION: Strategies that encourage weight control are indicated for women with chronic anovulation, due to hight metabolic activity of adipose tissue.

Association of obesity and anovulatory infertility / Associação entre obesidade e infertilidade anovulatória

ABSTRACT Objective To verify the association of obesity and infertility related to anovulatory issues. Methods This case-control study was carried out with 52 women, aged 20 to 38 years, divided into two groups (infertile − cases − and fertile − control), seen at outpatient clinics, in the period from April to December, 2017. Results We found significant evidence that obesity negatively affects women's fertility (p=0.017). The group of infertile women was 7.5-fold more likely to be obese than fertile women. Conclusion Strategies that encourage weight control are indicated for women with chronic anovulation, due to hight metabolic activity of adipose tissue.

RESUMO Objetivo Verificar em mulheres a associação entre obesidade e infertilidade relacionada a questões anovulatórias. Métodos Estudo de caso-controle com 52 mulheres, de 20 a 38 anos, divididas em dois grupos (mulheres inférteis − casos − e férteis − controles), atendidas em ambulatórios, no período de abril a dezembro de 2017. Resultados Verificou-se evidência significativa de que a obesidade afeta negativamente na fertilidade das mulheres (p=0,017). O grupo de mulheres inférteis teve 7,5 vezes mais chances de serem obesas quando comparadas às mulheres férteis. Conclusão Estratégias que estimulem o controle do peso são indicadas para mulheres com anovulação crônica devido à elevada atividade metabólica do tecido adiposo.

[Polycystic ovary syndrome: is there a rise in the prevalence?]. / Síndrome de ovario poliquístico: Ha aumentado su prevalencia?

OBJECTIVE: To determine the prevalence of polycystic ovary syndrome (PCOS) according to the three major diagnostic criteria previously described in an unselected group of women from Spain and to identify the most common phenotypes of the disease. MATERIAL AND METHOD: An observational, transversal prevalence study was carried out between July 1 2014 and October 31 2014. All participants received a questionnaire and underwent a physical and trans-vaginal ultrasound examination. Blood samples were also collected for analysis of metabolic markers and hormones. PCOS was diagnosed according to three major criteria: NIH, Rotterdam and AE-PCOS criteria. Following diagnosis women with PCOS were assigned to one of four phenotypes. RESULTS: A total of 242 women were involved in the study. The prevalence for each major criteria was as follows: National Institute of Health (NIH) criteria had a prevalence of 1 4.88%, Rotterdam criteria had a prevalence of 29.34% and Androgen Excess and PCOS Society criteria presented a prevalence of 17.36%. The prevalence for each phenotype was: A, 40.85%; B, 25.35%; C, 8.45%; and D, 25.35%. PCOS women had more prevalence of hirsutism (36.61 %), infertility (25.35%), obesity (21.1 2%) and metabolic syndrome (11 .26%) than controls (7.01%, 6.43%, 5.84% and 2.33% respectively). CONCLUSION: There is a rise in the prevalence of PCOS in Caucasian population with the classic phenotype (oligo-anovulation, hyperandrogenism, polycystic ovaries) being the most common presentation of the syndrome.

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.

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.

Involvement of GDF-9, leptin, and IGF1 receptors associated with adipose tissue transplantation on fertility restoration in obese anovulatory mice.

The aim was to analyze the effect of adipose tissue transplantation on growth differentiation factor-9 (GDF-9), insulin growth factor 1 receptor (IGF1R), and leptin receptor (LEPR) protein expression in ovaries of obese anovulatory mice. Leptin-deficient female (ob/ob) and wild-type mice were divided into untreated ob/ob mice and gonadal white adipose tissue transplanted ob/ob mice, with evaluation after 7, 15, and 45 days and compared to control wild-type mice. The corporal weight and glycemia levels increased in the obese group concomitant with polymicrocyst formation and abundant estrone, mimicking anovulatory disease. In the treated group after 45 days, glycemia, weight, ovarian size, and number of follicles were decreased and corpora lutea were decreased. The analysis of GDF-9 revealed that, whereas control ovaries presented follicular localization, the obese ovary lacked this protein. On the other hand, obese ovaries showed elevated expression of IGF1R that was normalized after the transplantation. Finally, LEPR was reduced in obese ovaries, and adipose tissue transplantation was efficient in returning it to normal levels. In conclusion, the adipose tissue transplantation, especially after 45 days, seems to stimulate ovulation, supported by the fact that several proteins involved in ovulation returned to basal levels.

Anovulación y disfunción ovulatoria e infertilidad / Anovulation, ovulatory disfunction and infertility

La anovulación crónica es una de las alteraciones más frecuentes que ven los ginecólogos en la consulta. Ciclos menstruales irregulares, sangrados uterinos anormales, amenorrea e infertilidad son los síntomas clínicos más frecuentemente observados. El objetivo principal en la evaluación de estas pacientes es identificar la causa que está provocando la anovulación crónica. Para propósitos de esta revisión, las causas potenciales se han agrupado en: a) amenorreas hipotalámicas, b) Anovulación crónica funcional, c) Síndrome de ovario poliquístico, d) hiperprolactinemia, e) Disfunción tiroídea, f) Falla ovárica prematura. El tratamiento está enfocado en corregir la condición que pueda estar causando el problema, optimizar la calidad de vida de la paciente y su salud, y reestablecer ciclos normales o inducir la ovulación si es que fuera necesario. Respecto a este último punto, los diferentes medicamentos y protocolos más comúnmente usados para inducción de la ovulación se analizan endetalle.

Chronic anovulation is one of the most frequent disorders seen by gynaecologists. Irregular cycles, abnormal uterine bleeding, amenorrhea and infertility are the most common clinical symptoms. The main target during the evaluation of these patients is to identify the disorders that cause chronic anovulation. For the purpose of this review, the potential causes have been grouped as follows: a) Hypothalamic amenorrhea, b) Hypothalamic functional anovulation, c) Polycystic ovary syndrome (PCO), d)Hyperprolactinemia, e) Thyroid dysfunction and f) Premature ovarian failure. The treatment of this conditionaims to correct any underlying disorder, to optimize the patient´s health and, to re-establish normal cycles or to induce regular ovulation, if required. With respect to the latter, the different drugs and protocols most commonly used for ovulation induction are reviewed in detail.

Síndrome dos ovários policísticos: uma visão atual / Polycystic ovary syndrome: an updated view

Este trabalho trata-se de uma revisão da síndrome dos ovários policísticos (SOP) em relação aos seus aspectos etiopatogênicos, clínicos, diagnósticos e terapêuticos. Tecem-se considerações sobre a importância não só de efetivo tratamento médico como também de abordagem e apoio psicológico, no sentido de melhorar ainda mais o bem-estar e a qualidade de vida dessas mulheres

The authors have reviewed the main aspects of the polycystic ovary syndrome (PCOS) with respect to its etiopathogenic, clinical, diagnostic and therapeutic features. They also make considerations on the importance of an effective clinical treatment as well as on the approaches and psychological support, aiming to improve women's well-being and quality of life

Structural evaluation of type 3 dopaminergic receptor gene (DRD3) in chronic anovulatory women.

Dopamine receptor type 3 (DRD3) expressed in the limbic system sites involved in the regulation of GnRH seems to play a role in neuroendocrine control. We hypothesized that women with chronic anovulation should show exacerbated secretion of prolactin (PRL) after thyrotropin-releasing hormone (TRH) stimulation test, having more chances for dopamine inhibitory dysfunction due to alterations in the structure of DRD3. The DRD3-coding region was evaluated in 60 women with chronic anovulation (35 without and 25 with hyperresponse of PRL after TRH stimulation), and in 34 controls. Statistically similar frequencies of homozygous AGC polymorphism (43.4 and 33.4%) and heterozygous polymorphism (33.4 and 47.9%) at position 9 were found in controls and patients, respectively. Homozygous GCG polymorphism at position 17 was identified in 3.4% of the patients, while heterozygosis occurred in 20.8% of the patients and in 6.6% of the controls. The novel 41563_41567delTAAGT polymorphism of DRD3 was identified in 14.7% of the controls and 8.6% of the women with chronic anovulation displaying hyperresponse of PRL after TRH stimulation. Alteration 41563_41567delTAAGT of DRD3 was not found in patients who did not show hyperresponse of PRL after TRH stimulation. Normal baseline and peak levels of PRL and thyroid-stimulating hormone were similar for women with and without 41563_41567delTAAGT in the DRD3 gene. It is concluded that the novel polymorphism in DRD3 identified in this study is not associated with the response of PRL to TRH stimulation in women with chronic anovulation.

Structural evaluation of type 3 dopaminergic receptor gene (DRD3) in chronic anovulatory women

Dopamine receptor type 3 (DRD3) expressed in the limbic system sites involved in the regulation of GnRH seems to play a role in neuroendocrine control. We hypothesized that women with chronic anovulation should show exacerbated secretion of prolactin (PRL) after thyrotropin-releasing hormone (TRH) stimulation test, having more chances for dopamine inhibitory dysfunction due to alterations in the structure of DRD3. The DRD3-coding region was evaluated in 60 women with chronic anovulation (35 without and 25 with hyperresponse of PRL after TRH stimulation), and in 34 controls. Statistically similar frequencies of homozygous AGC polymorphism (43.4 and 33.4%) and heterozygous polymorphism (33.4 and 47.9%) at position 9 were found in controls and patients, respectively. Homozygous GCG polymorphism at position 17 was identified in 3.4% Type 3 dopaminergic receptor in chronic anovulationof the patients, while heterozygosis occurred in 20.8% of the patients and in 6.6% of the controls. The novel 41563_41567delTAAGT polymorphismof DRD3 was identified in 14.7% of the controls and 8.6% of the women with chronic anovulation displaying hyperresponse of PRL after TRH stimulation. Alteration 41563_41567delTAAGT of DRD3 was not found in patients who did not show hyperresponse of PRL after TRH stimulation. Normal baseline and peak levels of PRL and thyroid-stimulating hormone were similar for women with and without 41563_41567delTAAGT in the DRD3 gene. It is concluded that the novel polymorphism in DRD3 identified in this study is not associated with the response of PRL to TRH stimulation in women with chronic anovulation.

Tratamento da infertilidade em mulheres com síndorme dos ovários policísticos / Infertility management in women with polycystic ovary syndrome

Infertilidade por anovulação é uma característica prevalente na síndrome dos ovários policísticos (SOP). A retomada da ovulação pode ser alcançada pela estimulação ovariana ou pela redução das concentrações de insulina e de LH. Citrato de clomifeno é freqüentemente utilizado para indução da ovulação, por excitação direta com hormônio fóliculo estimulante (FSH). As complicações prevalentes da síndrome da hiperestimulação ovariana e gravidezes múltiplas podem ser evitadas em grande parte pela administração de baixas doses de FSH em protocolos individualizados de indução de ovulação. A hiperinsulinemia pode ser corrigida com perda de peso, ou por meio de agentes sensibilizadores da insulina como a metformina, que isolada ou em combinação com outros agentes é capaz de restabelecer a ovulação. O aconselhamento sobre a perda de peso é um passo essencial nas condutas atuais para o tratamento da SOP. A fertilização in vitro (FIV) pode ser usada com resultados excelentes, no caso de falhas dos outros métodos. O uso de inibidores da aromatase, sensibilizadores de insulina e maturação in vitro de oócitos são procedimentos alternativos para a mesma finalidade. A pletora de opções de tratamentos disponíveis que existem hoje assegura que a grande maioria das mulheres com problemas de fertilidade devido à SOP possa ser tratada prosperamente

Manifestaciones clínicas del síndrome del ovario poliquístico / Clinics manifestations of the polycystic orvaries syndrome

El SOP es el trastorno endocrino más frecuente en mujeres jóvenes. Desde 1976 Kahm describe la relación entre el andogenismo ovárico y la resistencia a la insulina. Bergen, en 1980, establece la asociación ovarios poliquísticos, hiperandogenismo e hiperinsulinemia, visiualizando que el SOP no solo es causa de infertilidad y anovulación, sino que tiene riesgos metabólicos asociados. La explicación del SOP fue redefinida por un taller de consenso en Holanda, en 2003. Esta patología se presenta si existen al menos dos de los tres criterios siguientes: irregularidades menstruales, signos bioquímicos o clínicos de exceso de andrógenos y la presencia de la morfología de ovario poliquístico. Los ginecólogos frecuentemente diagnostican esta patología y por tal motivo se debe tener un conocimiento adecuado sobre sus manifestaciones clínicas y sus posibles riesgos en el largo plazo. La evidencia de la supuesta asociación con el cáncer de endometrio y predisposición a enfermedad coronaria es incompleta, pues la variedad de definiciones del SOP hace difícil su comparación. Dunaif refiere que la prevalencia de resistencia a la insulina es una función de la población estudiada y la sensibilidad y especificidad del método usado para medir este parámetro. También menciona que las mujeres con SOP son hiperinsulémicas y resistentes a insulina, independientemente de la obesidad, comparadas con mujeres normales. Legro demostró que entre el 25 y el 30 por ciento de las mujeres con el SOP tienen intolerancia a la glucosa a los 30 años, y el 8 por ciento desarrollarán franca Diabetes Mellitus tipo 2, anualmente. Descriptores: prevalencia, anovulación, hiperandrogenismo, ovarios poliquísticos, resistencia a insulina. Diabetes Mellitus tipo 2, enfermedad coronaria.

Neonatal handling induces anovulatory estrous cycles in rats.

Since previous work has shown that stimulation early in life decreases sexual receptiveness as measured by the female lordosis quotient, we suggested that neonatal handling could affect the function of the hypothalamus-pituitary-gonadal axis. The effects of neonatal handling on the estrous cycle and ovulation were analyzed in adult rats. Two groups of animals were studied: intact (no manipulation, N = 10) and handled (N = 11). Pups were either handled daily for 1 min during the first 10 days of life or left undisturbed. At the age of 90 days, a vaginal smear was collected daily at 9:00 a.m. and analyzed for 29 days; at 9:00 a.m. on the day of estrus, animals were anesthetized with thiopental (40 mg/kg, ip), the ovaries were removed and the oviduct was dissected and squashed between 2 glass slides. The number of oocytes of both oviductal ampullae was counted under the microscope. The average numbers for each phase of the cycle (diestrus I, diestrus II, proestrus and estrus) during the period analyzed were compared between the two groups. There were no significant differences between intact and handled females during any of the phases. However, the number of handled females that showed anovulatory cycles (8 out of 11) was significantly higher than in the intact group (none out of 10). Neonatal stimulation may affect not only the hypothalamus-pituitary-adrenal axis, as previously demonstrated, but also the hypothalamus-pituitary-gonadal axis in female rats.

Efecto de la reducción de peso en la condición clínica y hormonal de mujeres anovulatorias obesas / Neight reduction effect in clinical and hormonal condition of obese anovulatory women

La obesidad se asocia a una gran variedad de trastornos endocrinos hipotálamo-hipófisio-ováricos que pueden llevar a una anovulación persistente. La reducción de peso puede mejorar el perfil hormonal y por lo tanto recuperar la función ovulatoria. El objetivo del presente estudio fue valorar el efecto de la reducción de peso en la condición clíonica y hormonal de mujeres anovulatorias obesas en el Instituto de Medicina Reproductiva del Bajío en el Hospital Aranda de la Parra de la ciudad de León, Guanajuato. Se analizaron un total de 30 pacientes entre 18 y 35 años de edad con obesidad, anovulación crónica y sin patología tiroidea. Previo y posterior a un tratamiento de reducción de peso, con pérdida de al menos 5 por ciento de peso inicial, se analizaron hormona luteinizante (LH), hormona folículo estimulante (FSH), estradiol, prolactina, testosterona, dihidroepiandrostendiona-sulfato (DEA-S), curva de tolerancia oral a la glucosa y progesterona en día 21, peso, IMC, relación cintura/cadera y porcentaje de grasa por suma de pliegues. La pérdida media de peso fue de 9.5 ñ 4.3 kg. lo que representa una pérdida de peso de 10.96 por ciento con respecto al inicial. Se presentó ovulación espontánea en 26 pacientes (86.6 por ciento). Hubo una reducción significativa en los niveles basales de LH, estradiol, testoterona, DHEA-S, así como un aumento en los niveles de progesterona. De 12 pacientes con curva de tolerancia a la glucosa alterada, nueve (75 por ciento) observaron mejoría la final del tratamiento. Los resultados obtenidos demuestran que la disminución de peso y de porcentaje corporal de grasa puede mejorar el perfil hormonal y la función ovulatoria de pacientes anovulatorias obesas por lo que estas mujeres deberían someterse a un tratamiento de reducción de peso antes de comenzar con inductores de ovulación

Neonatal handling induces anovulatory estrous cycles in rats

Since previous work has shown that stimulation early in life decreases sexual receptiveness as measured by the female lordosis quotient, we suggested that neonatal handling could affect the function of the hypothalamus-pituitary-gonadal axis. The effects of neonatal handling on the estrous cycle and ovulation were analyzed in adult rats. Two groups of animals were studied: intact (no manipulation, N = 10) and handled (N = 11). Pups were either handled daily for 1 min during the first 10 days of life or left undisturbed. At the age of 90 days, a vaginal smear was collected daily at 9:00 a.m. and analyzed for 29 days; at 9:00 a.m. on the day of estrus, animals were anesthetized with thiopental (40 mg/kg, ip), the ovaries were removed and the oviduct was dissected and squashed between 2 glass slides. The number of oocytes of both oviductal ampullae was counted under the microscope. The average numbers for each phase of the cycle (diestrus I, diestrus II, proestrus and estrus) during the period analyzed were compared between the two groups. There were no significant differences between intact and handled females during any of the phases. However, the number of handled females that showed anovulatory cycles (8 out of 11) was significantly higher than in the intact group (none out of 10). Neonatal stimulation may affect not only the hypothalamus-pituitary-adrenal axis, as previously demonstrated, but also the hypothalamus-pituitary-gonadal axis in female rats

Upper body obesity and hyperinsulinemia are associated with anovulation.

The objective of this study was to determine the effect of body fat distribution and hyperinsulinemia on the occurrence of ovulation. Fifty-six women (20-35 years old) either with overweight or obesity (body mass index >/=25) were studied. They were classified in two groups according to waist/hip ratio (WHR); one with predominance of adiposity in the upper body segment (n = 29, WHR >0.85) and the other with predominant adiposity in the lower body segment (n = 27, WHR

[Has oligomenorrhea a pathological meaning? The importance of this symptom in internal medicine]. / Tiene la oligomenorrea un significado patológico? Importancia de este síntoma en medicina interna.

BACKGROUND: Oligomenorrhea, defined as a menstrual cycle lasting 36 to 90 days, can be a normal condition in the first years after the menarche. When it persists or appears after a period of normal menstrual cycles, an underlying illness must be sought. AIM: To assess ovulation and causes of anovulatory cycles in women with oligomenorrhea, compared with causes of secondary amenorrhea. PATIENTS AND METHODS: One hundred one women of less the 35 years old, presenting with oligomenorrhea persisting 5 years after menarche or lasting more than two years after a period of normal menstrual cycles, were studied. Ovulation was studied measuring serial plasma progesterone during normal or induced (with intramuscular progesterone) menstrual cycles. RESULTS: Eighty nine percent of women had anovulatory oligomenorrhea. The main causes were polycystic ovarian disease in 51% and hypothalamic dysfunction in 31%. Thirty percent of women with secondary amenorrhea had polycystic ovarian disease and 14% had hyperprolactinemia. Women older than 20 years old or with more than 10 years of gynecological age had a higher frequency of polycystic ovarian disease and a lower prevalence of hypothalamic dysfunction. CONCLUSIONS: There is a high frequency of anovulatory oligomenorrheas. Therefore, this symptom deserves a thorough endocrinological assessment to uncover underlying diseases. Special attention must be paid to polycystic ovary syndrome, due to its importance in internal medicine as a risk factor for myocardial infarction, high blood pressure, and type 2 diabetes mellitus.