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Dopaminergic treatments for hyperprolactinaemia.

Hyperprolactinaemia is a frequent cause of anovulatory sterility, although spontaneous pregnancy may occur occasionally. Dopaminergic treatment is highly effective for the treatment of both idiopathic and tumoral hyperprolactinaemia. If the only cause of infertility is chronic anovulation due to hyperprolactinaemia, an 80% pregnancy rate can be anticipated. Because of these results, surgical treatment is still needed only rarely. Pregnancy, either spontaneous or drug-related, is usually uneventful for the mother and is not associated with any increase in abortion, twins or malformations. Pregnancy-related tumour growth occurs rarely and can be treated successfully with dopaminergic drugs. On the contrary, there is more frequently improvement after pregnancy of the biochemical and clinical disorders associated with hyperprolactinaemia.

Adolescent↗

The use of gonadotrophin-releasing hormone antagonists in polycystic ovarian disease.

Polycystic ovarian disease (PCOD) is characterized by anovulation, eventually high luteinizing hormone (LH) levels, with increased LH pulse frequency, and hyperandrogenism. As the aetiology of the disease is still unknown, gonadotrophin-releasing hormone (GnRH) antagonists, competitive inhibitors of GnRH for its receptor, are interesting tools in order to study and treat the role of increased LH levels and pulse frequency in this disease. Their administration provokes a rapid decrease in bioactive and immunoactive LH followed by a slower decrease in follicle-stimulating hormone (FSH). In patients with PCOD, the suppression of gonadotrophin secretion eradicates the symptoms of the disease as long as the treatment lasts. Several authors have suggested that increased plasma LH levels have deleterious effects on the fertility of women with PCOD. Indeed, fewer spontaneous pregnancies with more miscarriages are observed when plasma LH levels are high. Assisted reproduction techniques such as in vitro fertilization (IVF) have provided other clues to the role of the LH secretory pattern in women with PCOD. The number of oocytes retrieved, the fertilization rate and the cleavage rate are lower in PCOD patients undergoing IVF and this is inversely correlated with FSH:LH ratio. These abnormalities are corrected when endogenous secretion of LH is suppressed. On the other hand, implantation and pregnancy rates after IVF are similar to those observed in control women. New GnRH antagonists are devoid of side effects and suppress LH secretion within a few hours without a flare-up effect. This action lasts for 10-100 hours. When GnRH antagonists are associated with i.v. pulsatile GnRH, this combination both suppresses the effect of endogenous GnRH and because of the competition for GnRH receptors restores a normal frequency of LH secretion. We have studied two women with PCOD, administering first 10 mg s.c. every 72 hours for 7 days of the GnRH antagonist Nal-Glu, then adding on top i.v. pulsatile GnRH: 10 micrograms/pulse every 90 minutes for 15 days. We thus succeeded in normalizing LH secretion pattern and observed a significant decline in testosterone levels. We failed to induce appropriate ovarian response and ovulation. In conclusion, the combination of GnRH antagonist and GnRH pulsatile treatment can re-establish normal LH secretory pattern in patients with PCOD. The failure to induce ovulation with this regimen suggests the existence of an inherent ovarian defect in women with PCOD.

Adult↗

The role of lifestyle modification in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine condition with reproductive and metabolic consequences, including anovulation, infertility and an increased prevalence of diabetes mellitus. Obesity, central obesity and insulin resistance are strongly implicated in its etiology and reduction of these risk factors should be a central treatment focus. Short-term weight loss has been consistently successful in reducing insulin resistance and restoring ovulation and fertility. However, problems arise with maintaining weight loss and precisely quantifying the associated long-term benefits of risk factor change. Although recent research indicates modest long-term lifestyle changes might reduce the extent of impaired glucose tolerance and delay the conversion to diabetes mellitus in the general population, this has not yet been examined in women with PCOS. Current conservative treatment should emphasize sustainable weight loss through dietary modification and exercise. Modifying additional lifestyle factors, including alcohol consumption, psychosocial stressors and smoking, are also crucial in long-term treatment of PCOS.

Alcohol Drinking↗

Toward a new approach: primary and preventive care of the woman with polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS), characterized by chronic anovulation and hyperandrogenism, affects approximately 5%-10% of reproductive-age women. The reproductive consequences of this syndrome, such as menstrual irregularities and infertility, are well understood and managed by obstetrician/gynecologists. However, less is known about the metabolic consequences of PCOS. As primary physicians for women, we are obligated to promote disease prevention. This can be done by recognizing the significant impact that the metabolic consequences of PCOS have on long-term health while continuing to recognize and treat the reproductive abnormalities. This article reviews the metabolic consequences of PCOS, discusses the use of insulin-sensitizing agents in PCOS, and discusses the role of the obstetrician/gynecologist in the primary and preventive care of women with PCOS.

Journal Article↗

Novel aspects of estrogen action.

The discovery of a second estrogen receptor, ER beta, in 1996 introduced a new paradigm in our understanding of estrogen action. ER alpha predominates in the uterus and mammary gland, whereas ER beta has significant roles in the central nervous, cardiovascular, and immune systems, urogenital tract, bone, kidney, and lung. ER beta appears to be the only from expressed in the embryonal central nervous system. Photoestrogens may be good candidates for physiologic ligands of ER beta. Coactivator proteins play critical roles in regulating estrogen. Female ER beta-deleted mice (beta ERKO) develop follicular arrest and anovulation.

Animals↗

Treatment of polycystic ovary disease with laparoscopic low-watt bipolar electrocoagulation of the ovaries.

STUDY OBJECTIVE: To assess the efficacy of laparoscopic low-watt bipolar electrocoagulation of the ovaries in women with polycystic ovary disease (PCOD). DESIGN: Prospective case series. SETTING: Hospital-based infertility clinic. PATIENTS: Seventy-four consecutive infertile women with PCOD resistant to conventional ovulation-induction regimens. INTERVENTIONS: Laparoscopic bipolar low-watt electrocoagulation of the ovarian surface (25 W for 5-12 sec/cyst). MEASUREMENTS AND MAIN RESULTS: Postoperative follow-up ranged from 18 months to 7 years. Menstrual rhythm returned to normal in all 74 women. All 40 women in whom infertility was solely due to anovulation eventually conceived. Overall, 62 (84%) of the 74 women conceived, 42 spontaneously after surgery and 20 after supplementation with clomiphene. These 62 women had a total of 93 pregnancies: 79 singleton live births, 4 sets of twins, and 10 miscarriages. Twenty-five women conceived twice and three conceived three times. At second-look laparoscopy or cesarean section in 20 women, fine stringlike adhesions on the ovaries were found in 2. CONCLUSION: Laparoscopic low-watt bipolar electrocoagulation of the ovaries is an effective treatment for women with PCOD who fail medical therapy.

Adult↗

[Role of luteinizing hormone in follicular and corpus luteum physiology].

Luteinizing hormone (LH) is an hypophyseal glycoprotein involved in both follicular maturation and corpus luteum function. During the follicular phase, effects of LH must be considered according to the stages of follicular development: in the early follicular phase, LH acts through specific receptors, constitutively present on thecal cells, for stimulating androgen production. Androgens seem to be positively involved in the folliculogenesis in primates. Indeed, a positive correlation has been recently established between androgen receptor expression and follicular cell proliferation. Furthermore, androgens are active through a conversion to estrogens in granulosa cells. Estrogens are needed for achieving pregnancy. Thus, a question remains: what in the minimal amount of endogenous LH required for an optimal production of oestradiol? Several models have been investigated in clinical situations with hypogonadotrophic hypogonadism: WHO type I anovulation or GnRH analog-induced hypogonadisms. A large majority of these studies conclude that the minimal amount of LH needed during the follicular phase is probably low (< 1.5 IU/L of plasma LH level). Recent availability of GnRH antagonist will give a new opportunity for evaluating this minimal LH threshold. During the late follicular phase, LH plays a biphasic role, with a positive effect on steroidogenesis but a negative effect on cell proliferation. As suggested by S. Hillier, this negative effect on cell proliferation may be relevant to control the rate of follicular growth. One study, performed in WHO type I anovulatory patients, seems to confirm this assumption but further evaluation is needed to give support to this concept. Finally, LH is also involved in corpus luteum function. Due to the short half-life of LH as compared to hCG, the role of LH must be evaluated according to the adjunct therapies. For example, following a long-term GnRH aganist administration that constantly induces a profound hypophyseal desensitization, LH administration must be repeated to adequately sustain the corpus luteum function. This conclusion must be reconsidered with the recent introduction of GnRH antagonists. Indeed, according to their short-term effects on LH secretion, it may be presumed that a single injection of LH may be effective to maintain an adequate corpus luteum function.

Animals↗

[Benefits and risks of ovarian stimulation before intrauterine insemination].

Performance of intra-uterine insemination (IIU) is generally advocated as a first line therapy for infertility related to cercical hostility, male factor, unexplained infertility or mild endometriosis. IIU are usually performed following stimulation of ovulation, even in absence of anovulation. However the rationale for such a systematic ovulation induction is still questionable. Indeed, while an overall assessment of ovarian stimulation tends to conclude to a beneficial effect of these treatments in unexplained or some male infertility, it is clear that no definitive conclusion can be drawn. Indeed, the methodology in many published series is mostly inadequate, data are usually not analysed according to the type of infertility or to the female hormonal features. Finally, adverse effects are imperfectly descripted. A more accurate analysis of these data in relation to the number of recruited follicles definitively shows that, if a bifollicular development is associated with a significant increase in the pregnancy rates, there is no advantage to stimulate further the ovary. Indeed, surpassing the recruitment of two follicles would lead to dramatically increase the risk of OHSS and multiple pregnancies. Thus, further investigations including prospective, randomized studies are needed to better define what should be the most adequate regimen of ovulation induction. Specifically, tailoring the rate of multifollicular development according to the duration, the type of infertility (etiology; primary or secondary; female age) would prove to be a safer approach for getting pregnancy as well as avoiding adverse effects. Such a policy remains to be determined in the light of further clinical studies conducted in the more appropriate manner.

Female↗

[Polycystic ovary syndrome: recent genetic contributions].

Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. It is characterized by hyperandrogenism, chronic anovulation and it is often associated with hyperinsulinemia, insulin resistance and dyslipidaemia. The pathophysiology of polycystic ovary syndrome seems to implicate primary defects in ovarian steroidogenesis, influenced by environment, insulin action and obesity. Polycystic ovary syndrome is probably both a multigenetic and environmental disease. Knowing the genes of polycystic ovary syndrome would be helpful to develop therapeutics and prevention. Genes of gonadotrophins, steroid hormone synthesis and insulin resistance seem not to be directly involved, except perhaps the CYP 11 a gene. On the other hand, identification of the signal transduction pathways involved in these genes may provide valuable information that can be applied to other clinical manifestations of polycystic ovary syndrome (follicular growth arrest, insulin resistance, obesity and endometrial cancer...).

Cholesterol Side-Chain Cleavage Enzyme↗

[Insulin resistance and polycystic ovary syndrome].

Polycystic ovary syndrome (PCOS) is a frequent disease, characterized by disturbed ovarian function with hyperandrogenism. Anovulation is secondary to an absence of follicular dominance. Apart from a primary ovarian defect, insulin resistance is observed in PCOS women, even in the absence of overweight. This insulin resistance could be secondary to a defect in the insulin transduction pathway, mainly by a defect in receptor phosphorylation. It enhances hyperandrogenism as it increases ovarian androgen production. Therefore treating insulin resistance by weight loss or drugs reducing insulin resistance might improve fertility of PCOS women. Metformin has been shown to reduce ovarian production, enhance ovulatory cycles and in some cases increase fertility. However, there are few randomized studies on large numbers of patients to prove an effect on pregnancies as well as on the occurrence of early pregnancy loss. There are currently no recommendation on dose and duration of metformin treatment. It is noteworthy that metformin has no authorization in France to be prescribed apart from diabetic patients' care. Considering the medical care of PCOS women, the cardiovascular risk needs to be taken into account. Therefore hypertension, dyslipidemia and diabetes must be treated in those women who need to be followed carefully all over their life.

Female↗

[Should infertile women with polycystic ovarian syndrome be treated with metformine?].

Polycystic ovary syndrome is a frequent endocrine disorder often associated with insulin resistance and hyperinsulinaemia which may play a role in hyperandrogenism and anovulation. The use of "insulin sensitizing" agents has been suggested to reduce insulin resistance and hyperandrogenism. In that respect, the use of metformin in polycystic ovary syndrome is reviewed. Although its mechanism of action is still unclear, metformin proved to be effective to restore cyclicity and spontaneous ovulation. The synergistic effect of clomiphene citrate and metformin was demonstrated in some studies, suggesting that metformin could be helpful for women with clomiphene citrate resistance. However, the potential effect of metformin administration for reducing hyperstimulation in women treated with exogenous FSH, or for preventing early miscarriages has to be confirmed. Here, we propose a guideline for the use of metformin, as an adjuvant therapy, to restore cyclicity and ovulation in women with polycystic ovary syndrome.

Clomiphene↗

Genetics of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is a reproductive system disorder characterized by irregular menses, anovulation, clinical and/or biochemical signs of hyperandrogenism (hirsutism and/or acne), ovarian micropolycystic appearance and metabolic abnormalities, such as hyperinsulinaemia and obesity. The aetiopathogenesis of this syndrome is not well known. Several pathogenetic hypotheses have been proposed to explain the full array of symptoms and signs, but with elusive results. A genetic abnormality causing PCOS is supported by the observation that different members of the same family are often affected, and about half of the sisters of PCOS women have elevated serum testosterone concentrations. Therefore, the presence of gene abnormalities in women with PCOS has been widely explored in the attempt to establish whether their mutations or polymorphisms may cause PCOS. The main genes evaluated are those involved in steroidogenesis, steroid hormone effects, gonadotrophin release regulation and action, insulin secretion and action, and adipose tissue metabolism. Despite the vast body of literature produced, none of the genes evaluated seems to play a key role in PCOS pathogenesis. It is likely that PCOS may represent the final outcome of different, deeply inter-related genetic abnormalities that influence each other and perpetuate the syndrome.

Adipose Tissue↗

Impact of androgens on fertility - physiological, clinical and therapeutic aspects.

Ovarian androgen synthesis and regulation are essential to ensure adequate steroidogenesis and folliculogenesis. In primates, there is evidence for a direct impact on the number of small antral follicles and on the process of chronic anovulation. Therefore, serum androgen should be more carefully assessed in infertile women. Accurate measurements of serum androgen are required to better identify patients with androgen excess or deficiency. Medical or surgical interventions are able to decrease ovarian androgen excess and to reduce the risk of hyperstimulation. Conversely, androgen supplementation should be considered in women at risk of low ovarian response to gonadotrophins, related to androgen deficiency. This review supports a specific and broad role of androgen in reproductive physiology.

Androgens↗

IUI in male subfertility: are we able to select the proper patients?

There is at this time no indication as to which semen parameters from the fertility work-up discriminate between couples with male subfertility who will and will not benefit from intrauterine insemination (IUI). This study evaluated the predictive capacity of semen parameters (both pre- and post-wash) and antisperm antibodies (ASA) obtained during the fertility workup on IUI outcome in couples with male subfertility in a retrospective cohort study. It included 290 couples, who underwent 722 IUI cycles. The overall ongoing pregnancy rate was 9% per cycle. Model I, with female age, duration of subfertility, secondary subfertility, the presence of anovulation, cervical hostility and cycle number had an area under the curve (AUC) of 0.59. Adding the presence of ASA to this model improved the AUC to 0.65 (model II). Further addition of the post-wash total motile count (TMC) to the model with ASA (model III) improved the AUC to 0.67. Using the models to exclude couples from IUI due to low expected pregnancy rates would increase the pregnancy rate to 11% per cycle with model I, and to 14% per cycle for model II and for model III. In conclusion, in the selection of patients with male subfertility for IUI, the use of prediction models including ASA can increase the efficiency of IUI.

Adult↗

Effects of lifestyle modification in polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is a common endocrine condition with reproductive and metabolic consequences, including anovulation, infertility and an increased prevalence of diabetes mellitus. Obesity, central obesity and insulin resistance are strongly implicated in its aetiology. Dietary weight loss is recommended as the primary treatment strategy; however, effective means of achieving and maintaining weight loss and reproductive and metabolic improvements are unknown. Lifestyle modification programmes with an emphasis on behavioural management and dietary and exercise interventions have been successful in the general population in reducing the risk of diabetes and the metabolic syndrome, and have had some initial success in improving fertility outcomes in PCOS. However, the literature on effective diet and exercise programmes for PCOS has been sparse, and structured advice for implementing components of lifestyle modification programmes should be assessed in this population.

Appetite↗

Physical activity and its effects on reproduction.

The reproductive system is tightly coupled with energy balance, and thereby changes in the status of energy balance through changes in physical activity can impact on the reproductive system. In light of the new physical activity for health recommendations, it is therefore important to understand the inherent effects, both positive and negative, of physical activity on the reproductive system. At both extremes of the energy spectrum, disorders of chronic energy excess and energy deficiency are characterized by a wide range of reproductive disorders, including menstrual irregularity, anovulation, polycystic ovarian syndrome, and infertility in women, and erectile dysfunction and altered spermatogenesis in men. Although laboratory research indicates that individuals may be able to prevent or reverse reproductive disruptions, either by increasing energy expenditure in cases of energy excess or by dietary reform in cases of energy deficits, there is an acute need for applied research to confirm this idea and to identify mechanisms by which the availability of energy per se regulates reproductive function in humans.

Energy Metabolism↗

Influence of oral contraceptive pills on phenotype expression in women with polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is characterized by a heterogeneous phenotype including chronic anovulation, hyperandrogenism and polycystic ovaries. The use of oral contraceptive pills (OCP) alters features characteristic for the syndrome. In the present study, PCOS features were compared between women using or not using OCP at the time of the study. One hundred and one women diagnosed with normogonadotrophic anovulatory infertility were included. A total of 81 (80%) women were diagnosed with PCOS (revised 2003 criteria). From these women, a total of 54 did not use OCP, whereas 27 women did. Corrected for age, women taking OCP had increased serum concentrations of sex hormone-binding globulin (P < 0.001). Serum concentrations of testosterone (P = 0.04) and androstenedione (P = 0.01) were decreased. These differences resulted in a decreased free androgen index for women currently taking OCP compared with women without (P < 0.001). The mean ovarian volume/ovary and the mean follicle number/ovary were not different. Use of OCP influences phenotype expression (the observable trait) of individual women known to suffer from PCOS by reducing hyperandrogenism. Despite taking OCP, women still fulfilled the revised 2003 criteria for the syndrome, as PCO morphology was still present. Hence, OCP use does not appreciably affect the PCOS phenotype.

Adult↗

Clomiphene citrate and ovulation induction.

Clomiphene can be used to treat anovulation due to hypothalamus or pituitary gland dysfunction, and it normalizes the luteal phase in stimulated patients. It can be used to estimate ovarian follicle reserve, and may be predictive of ovulation in women aged >/=35 years or with failed IVF. Contraindications include risk of congenital anomalies, chronic liver disease and visual disorders. Clomiphene may impair fertility through its effects on cervical mucus and in causing various endometrial dysfunctions. However, if clomiphene is administered in 50 mg doses, side-effects are avoided and efficacy is similar to that of a 100 mg dose, although daily dosages of 200 mg/day over 5 days can induce ovulation in approximately 70% of treated patients. Gonadotrophin concentrations increase up to days 5-9 when follicles are selected, and clomiphene is effective in patients with polycystic ovary syndrome (PCOS). Fifty percent of normal patients conceive, a value perhaps biased by the antagonistic effects of clomiphene on cervical mucus in some women. Clomiphene is valuable for IVF, and is used by some clinics in combination with HMG or recombinant FSH. Resistance to clomiphene can develop, and human chorionic gonadotrophin may be needed to induce ovulation in clomiphene cycles. Corticosteroids and human menopausal gonadotrophin (HMG) can be combined with clomiphene for stimulation, its combination with HMG long having been a standard protocol in assisted reproduction. PCOS patients may become insulin resistant, a condition improved by the administration of metformin. Other adverse effects include multiple pregnancies, an increase in the rate of multiple births, ovarian hyperstimulation and unsubstantiated claims of ovarian cancer.

Adrenal Cortex Hormones↗