Clasificación de los fenotipos de síndrome de ovario poliquístico de acuerdo a los criterios de Rotterdam: ¿una condición estática o variable? / Effects of pregnancy and changes in body weight on polycystic ovary syndrome phenotypes according to the Rotterdam criteria

Background: Polycystic Ovary Syndrome (PCOS) is tightly associated with insulin resistance and obesity and characterized by hyperandrogenism, chronic oligo-anovulation and polycystic ovarian morphology when fully expressed. The 2003 Rotterdam consensus proposed that two or three of these features were necessary to make the diagnosis, which generated four phenotypes. Several studies have suggested that these phenotypes could differ in their metabolic and endocrine characteristics and that they could vary in the same patient when analyzed throughout life. Aim: To determine if the initial classification of PCOS phenotypes is modified by different physiological conditions. Material and Methods: We performed a non-concurrent prospective analysis of 88 women with PCOS according to the Rotterdam criteria. The effect of physiological conditions such as changes in body weight, pregnancy and ageing more than five years on PCOS phenotype expression was analyzed. Results: Twenty four percent of women became pregnant, 37% decreased and 24% increased their body weight during follow up. These conditions modified significantly the proportion of the different phenotypes (c2 = 32.2, p < 0.001). For instance, weight reduction was associated with a change to a better phenotype (p = 0.047) and even a normalization of the PCOS condition in 27% of the patients. On the other hand, an increase in body weight modifying body mass index in one unit, conferred an 8% probability of changing to a worst phenotype. Conclusions: Pregnancy and changes in body weight significantly modify PCOS phenotypes.

¿Qué hay de nuevo en el síndrome de ovario poliquístico? / What’s new in polycystic ovary syndrome

Polycystic ovary syndrome is recognized as a risk factor for the development of type 2 diabetes and metabolic syndrome. The prevalence of the condition is 6 to 10 percent in different populations. Its etiology is not well known and there are genetic and epigenetic phenomena involved. Due to its association with insulin resistance, it has been incorporated as another component of Reaven plurimetabolic syndrome. Therefore polycystic ovary syndrome evolved from an ovarian disease to a multisystem disorder and it must be considered a public health problem.

Síndrome de ovario poliquístico y embarazo / Polycystic ovary syndrome and pregnancy

Background: Polycystic ovary syndrome (PCOS) is a common endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications and prenatal programming of the offspring. The aim of this review is to report our experience in PCOS patients who became pregnant and were followed during the whole pregnancy. Firstly, we analyzed the effect of pregnancy on PCOS pathophysiology and secondly the role of PCOS in pregnancy outcomes. Regarding the firstpoint, during normal pregnancy a progressive insulin resistance, serum lipid changes and an increase in androgen levels is observed, which is exacerbated in the PCOS condition. This adverse intrauterine environment could have a prenatal programming effect with detrimental consequences for female or male fetuses. Regarding the second point, PCOS is associated with an increased risk for maternal complications such as gestational diabetes (GDM) and pregnancy-induced hypertension. Moreover, these adverse pregnancy outcomes are more frequently associated with an increase in low birth weight and high birth weight newborns. According to our clinical experience, PCOS patients who became pregnant and were not treated with metformin during the whole pregnancy, showed a higher prevalence of gestational diabetes and SGA newborns, which was improved with metformin treatment. In summary, pregnancy may constitute a period in which an abnormal condition is established or aggravated in the fetus of a PCOS mother. Moreover, PCOS enhanced adverse obstetric and neonatal outcomes.

Caracterización del síndrome de ovarios poliquísticos desde el término de la edad reproductiva hasta la menopausia / Ovarian function during late reproductive age and early menopausal transition in women with polycystic ovary syndrome

The higher life expectancy and prevalence of obesity among women has increased the prevalence of diseases associated to metabolic syndrome such as polycystic ovary disease and cardiovascular diseases. Polycystic ovary disease is common among women of reproductive age and the main cause of hyperandrogenism. Multiple growing follicles and increased ovarian stroma are observed. Hyperinsulinemia, commonly associated with the syndrome, stimulates follicle development, ovarian volume and cardiovascular risk. After the age of 35 years, the late reproductive ages ensues in healthy women with a reduction in the number of ovarian follicles. This is accentuated after the age of 40, when menopausal transition starts. Women with polycystic ovary syndrome could experience a delay in the onset of menopause due to their elevated androgen and insulin levels and their increased follicular mass. This is a review about the endocrine and metabolic changes experienced by women with polycystic ovary syndrome from the end of their reproductive life to their menopause. The mechanisms that differentiate these women from their healthy counterparts are discussed.

Síndrome de ovario poliquístico: nuevas perspectivas / New perspectives on polycystic ovary syndrome

Currently there are two definitions for polycystic ovary syndrome (PCOS). One was proposed by the NIH Consensus Conference (1990), which defined it as the presence of hyperandrogenism and oligo-ovulation in the absence of other specific causes of ovarian, adrenal, or hypophyseal origin. The other proposed by the Rotterdam ESHRE/ASRM Consensus Conference (2003), which incorporates ovarian morphology to the definition generating four different phenotypes. Most women with PCOS exhibit peripheral insulin resistance, which plays a major role in the long-term metabolic consequences of the syndrome, among which type 2 diabetes and cardiovascular disease should be highlighted. Therefore, this syndrome is currently defined as a mainly endocrine metabolic disorder. PCOS could have a genetic predisposition that may manifest itself even before menarche. On the other hand, environmental factors during prenatal or postnatal life could lead to clinical and biochemical expressions of the syndrome in adult life. At present, it is accepted that prenatal exposure to androgens during fetal life is implicated in the origin of this syndrome. We have demonstrated that PCOS mothers may offer a hyperandrogenic and hyperinsulinemic milieu to the female and male fetus. This adverse intrauterine milieu could induce fetal programming consequences, which are evidenced by a high frequency of low-birth weight infants and changes in the testicular and ovarian function. Moreover, some of the metabolic features of PCOS are present in the offspring of PCOS women. Therefore, these children are a high risk group for metabolic and reproductive alterations. Consequently the treatment for this syndrome must not only be symptomatic but also fundamentally preventive. For this reason, PCOS should be considered a marker of a family pathology, a pathway to type 2 diabetes, and a public health problem.

Síndrome de ovario poliquístico (SOP) y embarazo: Experiencia clínica / Polycystic ovary syndrome and pregnancy: Clinical experience

Background: Polycystic ovary syndrome (PCOS) is an endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications. Aim: To report a prospective clinical experience in PCOS patients who became pregnant after diet, exercise and metformin treatment intervention, and were followed up during the whole pregnancy. Patients and Methods: Seventy pregnant PCOS (PPCOS) women and forty normal pregnant (NP) women of similar age and with singleton pregnancies were included in the study. During gestational ages 10-16 and 22-28 weeks, a 2h, 75 g oral glucose tolerance test (OGTT) was performed with measurement of glucose and insulin in each sample. Results: No differences were found in duration of gestation, weight gain during pregnancy, or systolic and diastolic blood pressure between PPCOS and NP women. There were significant differences in body mass index (BMI) at the initiation and in the third trimester of pregnancy between both groups. The incidence of gestational diabetes was significantly higher (p <0.01) in the PCOS group (35.2 percent) compared to the control group (5.0 percent). The prevalence of small for gestational age (SGA) infants tended to be higher (p =0.09) in the PCOS group. During pregnancy, 2h glucose and insulin were significantly higher in PPCOS than in NP women. Conclusions: PCOS mothers showed a higher prevalence of gestational diabetes and SGA newborns, which cannot be attributed to the weight gain during pregnancy, and seems to be more related to the BMI at the initiation of pregnancy, and to the PCOS condition of the mothe.

Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep

Although evidence is accumulating that prenatal testosterone (T) compromises reproductive function in the female, the effects of excess T in utero on the postnatal development of male reproductive function has not been studied. The aim of this study was to assess the influence of prenatal T excess on age-related changes in pituitary and gonadal responsiveness to GnRH in the male sheep. We used the GnRH agonist, leuprolide (10 µg/kg), as a pharmacologic challenge at 5, 10, 20 and 30 weeks of age. These time points correspond to early and late juvenile periods and the prepubertal and postpubertal periods of sexual development, respectively. LH and T were measured in blood samples collected before and after GnRH agonist administration. The area under the response curve (AUC) of LH increased progressively in both controls and prenatal T-treated males from 5 to 20 weeks of age (P<0.01). The LH responses in prenatal T-treated males were lower at 20 and 30 weeks of age compared to controls (P<0.05). AUC-T increased progressively in control males from 5 through 30 weeks of age and prenatal T-treated males from 5 to 20 weeks of age. The T response in prenatal T-treated males was higher at 20 weeks compared to controls of same age but similar to controls and prenatal T-treated males at 30 weeks of age (P <0.05). Our findings suggest that prenatal T treatment advances the developmental trajectory of gonadal responsiveness to GnRH in male offspring.

La exposición prenatal a andrógenos como factor de reprogramación fetal / Prenatal exposure to androgens as a factor of fetal programming

Both epidemiological and clinical evidence suggest a relationship between the prenatal environment and the risk of developing diseases during adulthood. The first observations about this relationship showed that prenatal growth retardation or stress conditions during fetal life were associated to cardiovascular, metabolic and other diseases in later life. However, not only those conditions may have lasting effects after birth. Growing evidence suggests that prenatal exposure to steroids (either of fetal or maternal origin) could be another source of prenatal programming with detrimental consequences during adulthood. We have recently demonstrated that pregnant women with polycystic ovary syndrome exhibit elevated androgen levels compared to normal pregnant women, which could provide an androgen excess for both female or male fetuses. We have further tested this hypothesis in an animal model of prenatal androgenization, finding that females born from androgenized mothers have a low birth weight and high insulin resistance, that starts at an early age. On the other hand, males have low testosterone and LH secretion in response to a GnRH analogue test compared to control males and alterations in seminal parameters. We therefore propose that our efforts should be directed to modify the hyperandrogenic intrauterine environment to reduce the potential development of reproductive and metabolic diseases during adulthood.

Response to the gonadotropin releasing hormone agonist leuprolide in immature female sheep androgenized in utero

Similar to women with Polycystic Ovary Syndrome (PCOS), female sheep treated prenatally with testosterone (T-females) are hypergonadotropic, exhibit neuroendocrine defects, multifollicular ovarian morphology, hyperinsulinemia and cycle defects. Hypergonadotropism and multifollicular morphology may in part be due to developmentally regulated increase in pituitary responsiveness to GnRH and may culminate in increased ovarian estradiol production. In this study, we utilized a GnRH agonist, leuprolide, to determine the developmental impact of prenatal testosterone exposure on pituitary-gonadal function and to establish if prenatal exposure produces changes in the reproductive axis similar to those described for women with PCOS. Eight control and eight T-females were injected intravenously with 0.1 mg of leuprolide acetate per kilogram of body weight at 5, 10 and 20 weeks of age. Blood samples were collected by means of an indwelling jugular vein catheter at 0, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 hours after leuprolide. Area under the curve (AUC) of LH response to leuprolide increased progressively between the three ages studied (P<0.05). AUC of LH in T-females was higher than in control females of the same age at 5 and 10 weeks of age (P<0.05), but similar at 20 weeks of age. AUC of estradiol response was lower at 10 but higher at 20 weeks of age in T-females compared to controls of the same age (P<0.05). Our findings suggest that prenatal T treatment alters the pituitary and ovarian responsiveness in a manner comparable to that observed in women with PCOS.

Síndrome de ovario poliquístico: modelo de exposición prenatal a andrógenos / Polycystic ovary syndrome: model of prenatal androgen exposure

It has been proposed that androgen excess during fetal life either experimentally, accidentally or pathologically will produce changes in the reproductive axis and glucose homeostasis of the adult female which resemble those observed in the polycystic ovary syndrome (PCOS). Although androgen excess during pregnancy has been proposed to be involved in the development of PCOS, it has not been established if PCOS mothers could provide a potential source of androgen excess for the fetus. In women with a classical 21-hydroxylase deficiency, the fetal suprarrenal cortex of the fetus will be the source of the androgen excess. In the case of the PCOS, this origin is uncertain. We have recently demonstrated a significant increase in serum androgen concentrations during pregnancy in PCOS women compared to normal pregnant women, which opens the possibility that children of PCOS women could be exposed to an abnormal steroid milieu during fetal life affecting either the female or male fetus. Further studies are needed to evaluate the potential long effect of this prenatal androgen excess on baby girls and boys born to PCOS mother in order to establish if PCOS women should be treated during pregnancy in order to avoid the androgen excess.

Se ha propuesto que la exposición prenatal a andrógenos (EPA) durante la vida fetal en forma experimental, accidental o patológica podría producir una serie de cambios del eje reproductivo y de la homeostasis glucídica del feto femenino que se harían evidentes en su vida posnatal y semejarían aquellos descritos en el síndrome de ovario poliquístico (SOP). Si bien la EPA podría estar involucrada en el desarrollo del SOP no se ha establecido si la madre con SOP podría constituir una fuente de exceso de andrógenos para el feto. En la hiperplasia virilizante congénita, un modelo clásico de EPA, podría ser la corteza suprarrenal hiperandrogénica del propio feto el origen del exceso prenatal de andrógenos, mientras que en el SOP este origen parece más incierto. Recientemente, hemos podido establecer que las embarazadas con SOP presentan niveles androgénicos significativamente más altos que las embarazadas normales, lo que abre la posibilidad que los hijos de estas mujeres pudiesen haber estado sometidos a un ambiente esteroidal anormal durante su vida fetal, el cual podría afectar tanto al feto femenino como masculino. Futuros estudios permitirán evaluar el efecto a largo plazo de este exceso de andrógenos prenatales sobre la descendencia de madres con SOP con el fin de establecer si el SOP debería ser tratado durante el embarazo con el fin de evitar el exceso de andrógenos.

Secretory Patterns of Leptin and Luteinizing Hormone in Food-Restricted Young Female Sheep

Leptin, the product of the ob gene, has been proposed as a metabolic signal that regulates the secretion of GnRH/LH. This may be critical during prepubertal development to synchronize information about energy stores and the secretion of GnRH/LH. This study aimed to assess the effect of food restriction on the episodic secretion of leptin and LH in young female sheep. Five 20-week-old prepubertal females were fed a low-level diet for 10 weeks to maintain the body weight. Control females of the same age received food ad libitum. Blood samples were collected at 10-min intervals for six hours at 20, 26, and 30 weeks of age, and plasma leptin, LH, insulin and cortisol concentrations were measured. In the control group, no changes were found in pulsatile LH secretion characteristics. Mean LH concentrations and LH amplitude were lower in the food-restricted group than in the control group at 26 and 30 weeks of age. In the control group, pulsatile leptin secretion did not change. When compared to control lambs of the same age, the food-restricted group showed lower mean plasma leptin concentrations, pulse amplitude and plasma insulin levels, after 6 weeks of restriction (week 26), although by week 30, plasma leptin concentrations and plasma insulin rose to those of the control group. Leptin pulse frequency did not change, nor did mean plasma levels of insulin in the control group at any age studied. Mean plasma concentration of cortisol did not change within or between groups. These data suggest that plasma leptin concentrations may not be associated with the onset of puberty under regular feeding and natural photoperiod in lambs. Prolonged food restriction, however, induces metabolic adaptations that allow an increase of leptin during the final period, probably related to the development of some degree of insulin resistance..

Prevalencia familiar de patologías metabólicas en paciente con síndrome de ovario poliquístico / Prevalence of metabolic disorders among family members of patients with polycystic ovary syndrome

Background: About 60 percent of patients with polycystic ovary syndrome (PCOS) have insulin resistance, predisposing them to the premature coronary disease and type 2 -diabetes mellitus. However, the history of metabolic disorders in family members of patients with PCOS has been seldom documented in the literature. Aim: To evaluate the family profile of metabolic disorders of PCOS patients and to determine their relative risk of developing one of them in comparison to a control group. Patients and Methods: Sixty PCOS patients were evaluated. The control group were 60 normal women. The data were obtained from the clinical history and personal interview with the patients, the controls and their relatives (brothers, parents and grandparents). The metabolic disorders considered were: dyslipidemia, obesity, hypertension and diabetes. Results: The ages were similar between groups (PCOS: 24.0 ñ 6.3; control group: 24.8 ñ 6.2 years). The prevalence of metabolic disorders was 62 percent in the relatives of the PCOS patients and 27.8 percent in the relatives of the control group (p <0.005). The probability to develop a metabolic disorder within the family was 2.7 (2.2-3.3) fold higher in the PCOS group compared to the control group. The risk of developing hypertension, dyslipidemia, obesity and diabetes was 2.1 (1.5-2.9); 1.8 (1.5-2.7); 3.6 (2.6-4.9) and 2.7 (1.8-3.9), respectively, in the PCOS group compared to the control group. Conclusions: The probability of finding a metabolic disorder in the families of PCOS patients, is 2.7 fold higher than in the control group families. The metabolic disorders are more frequent in parents and grandparents of the PCOS patients than in those of normal women

Síndrome de ovario poliquístico: la importancia de establecer su diagnóstico / Polycystic ovary syndrome: the importance of establishing diagnosis

Polycystic ovary syndrome (PCOS) is a very common disorder that occurs up to 10 percent of premenopausal women. Although PCOS is known to be associated with a higher reproductive morbility and increased risk of hormone dependent-cancer, its diagnosis is particularly important because PCOS is strongly linked to insulin resistance. This involves a major risk of early metabolic and cardiovascular complications. On the other hand, the prevalence of metabolic disorders associated with insulin resistance is higher in family members of patients with PCOS than in those of normal women, which suggests that the treatment of this syndrome should be preventive rather than symptomatic. For that reason, PCOS might be considered a signal of a family disorder, a route to diabetes and a public health problem

Insulinorresistencia: generalidades e implicancias clínicas / Insulin resistance generalties and clinical approach

La insulinorresistencia, es la base fisiopatológica de múltiples enfermedades de alta prevalencia, entre las que se destacan: la obesidad androide, la intolerancia a la glucosa, la diabetes mellitus, la hipertensión arterial y la dislipidemia. Además, se presenta en otras situaciones patológicas frecuentes, entre otras, diabetes gestacional, ovario poliquístico y en sujetos pequeños para la edad gestacional. Finalmente, está presente en una serie de condiciones fisiológicas y patológicas poco frecuentes o muy excepcionales, ya sea de origen genético, congénitas o adquiridas. Quizás más que por su prevalencia, el principal problema reside en, que esta condición puede permanecer desconocida y el daño metabólico puede ocurrir mucho antes que un exámen fortuito o el cuadro florido de una diabetes 2 nos lleve finalmente a su diagnóstico. El propósito de esta revisión es dar una orientación diagnóstica práctica de este síndrome tanto desde el punto de vista clínico como de las metodologías actualmente en uso

Ciclo sueño vigilancia y obesidad / Sleep wake cycle and obesity

La relación entre el hombre y su ambiente requiere, necesariamente, ajustes fisiológicos y comportamentales indispensables para el mantenimiento de la homeostasia. Para ejercer estas adecuaciones, el ser humano está dotado de dos tipos de adaptaciones funcionales: a) las reactivas, que son modificaciones del organismo en respuesta a un cambio que ya ocurrió, y b) las anticipatorias o predictivas, que suceden antes de que intervengan los predecibles cambios en las claves ambientales (homeostasia anticipatoria). Enfatizamos, entonces, el marco temporal de 24 horas en que fluctúan las diversas variables fisiológicas producto de los relojes biológicos, y, en particular, el ciclo sueño/vigilia (CSV). La relación de fase de las diversas variables del organismo, constituye el orden temporal interno (OTI). La preservación de este OTI es parte fundamental de nuestra fisiología, pues asegura el establecimiento de una adecuada eficiencia funcional y promueve una armoniosa interacción con nuestro entorno. La ruptura incluso transitoria de este OTI, determina una desincronización interna. Postulamos que la transgresión del OTI gatilla y/o magnifica las disfunciones conducentes a enfermedades crónicas, incluyendo la obesidad y sus complicaciones clínicas

Evaluación del efecto agudo de la administración de GnRH sobre la secreción de leptina en mujeres sanas e hiperandrogénicas / Assessment of acute effect of GnRH administration on leptin secretion in normal and hyperandrogenic women

Background: Several studies suggest that leptin modulates the reproductive axis function. Leptin may stimulate release of GnRH from hypothalamus and of gonadotrophins from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women and in patients with polycystic ovarian syndrome (PCOS), suggesting a relationship between the episodic secretion of LH and leptin. In vitro experimental studies have demonstrated that leptin administration promotes GnRH-LH release. However it is not established whether GnRH promotes the episodic secretion of leptin. Aim: To assess the response of LH and leptin to the administration of a GnRH bolus in hyperandrogenic and healthy women. Patients and methods: Eleven hyperandrogenic and eleven healthy women of similar age and body mass index (BMI) were studied. Under basal conditions three blood samples were collected every 30 min before and after the administration of a GnRH bolus (100 µg). LH and leptin concentrations were measured in all samples. Testosterone, SHBG and estradiol were determined in the first sample. For data analysis, the increment of LH and leptin between 0-30 and 0-60 min. was calculated. The LH and leptin areas under the curve (AUC) before and after GnRH administration were also calculated in both groups. Results: After GnRH administration. an increment in LH concentrations was observed in both groups; however, leptin concentrations were not modified. In both groups LH area under the curve increased after GnRH administration; however, the leptin area was not modified. Conclusions: These results suggest that circulating leptin concentration is not modulated by GnRH-LH

Leptina y sistema reproductivo / Leptin and the reproductive system

La leptina es una hormona proteica recientemente descubierta, la cual es producida por los adipocitos. Esta actúa regulando el apetito, el peso corporal y la termogénesis. Su posible rol como modulador en el eje reproductivo se ha inferido de una cepa de ratas carentes de leptina, que se caracterizan por ser obesas, diabéticas e infértiles y en las que el administrar esta hormona se producen cambios como disminución del apetito, aumento del gasto energético y recuperación de la fertilidad. Estos fenómenos han motivado una gran cantidad de estudios para establecer el rol la leptina en el sistema reproductivo. Se revisa la literatura existente sobre leptina y su acción sobre los cambios de peso corporal, pubertad, sistema nervioso central y periférico, ovarios y embarazo