Adolescent androgen abnormalities

PURPOSE OF REVIEW: Polycystic ovary syndrome is one of the most common endocrinopathies affecting premenopausal women. This review focuses on this major cause of hyperandrogenism in adolescents and young women, highlighting new diagnostic and therapeutic strategies that are under investigation. The pathophysiologic role in the disorder are the subject of several recent reports. RECENT FINDINGS: Recent studies have found a 33% prevalence of abnormal glucose tolerance in a cohort of affected adolescents, higher fasting insulin levels and lower insulin sensitivity, and that glucose tolerance testing appears to be necessary for routine screening. The effects of hyperinsulinism may be counteracted by insulin sensitizing agents. In adult women with polycystic ovary syndrome, metformin treatment reduced hyperinsulinemia and hyperandrogenemia. In some obese adolescents, metformin therapy resulted in declines in body mass index, insulin, and glucose. Restoration of regular menses may also occur after metformin treatment. Thus, data is accumulating that insulin-sensitizing agents may be helpful in decreasing the pathophysiologic effects of hyperinsulinism and insulin resistance associated with polycystic ovary syndrome. Other hormonal alterations in polycystic ovary syndrome have also been the subject of recent reports. Leptin secretion was found to be markedly irregular in these women. Elevated LH secretion may be secondary to accelerated gonadotropin-releasing hormone pulse generator activity, although the etiology of the pulse alterations is unclear. SUMMARY: Although polycystic ovary syndrome is the most common endocrine disorder affecting young women, it is one of the least understood, reflected by the wealth of research in this area. One area of focus has been the pathophysiologic link between insulin resistance and this disorder, including the effects of promising new agents to counteract these effects.     

No more surrogate end-points in randomised trials: the PCOSMIC trial protocol for women with polycystic ovary syndrome using metformin for infertility with clomiphene

Current data supporting the effectiveness of metformin as a fertility treatment for women with polycystic ovary syndrome have been misinterpreted. Still unproven for women with polycystic ovary syndrome is, first, whether metformin adds to the standard first-line fertility management in all women, second, whether metformin is an effective fertility treatment for overweight women, and third, the relative fertility efficacy of metformin and clomiphene citrate as a first-line treatment in women with a lower body weight. The PCOSMIC (polycystic ovary syndrome: metformin for infertility with clomiphene) trial is an ongoing New Zealand multicentre double-blind placebo-controlled parallel randomised trial assessing these questions.     

Surgical treatment in polycystic ovary syndrome

PURPOSE OF REVIEW: The purpose of this review is to provide a critical summary of current knowledge on the role and effectiveness of ovarian surgery in the treatment of polycystic ovary syndrome. RECENT FINDINGS: Clomiphene citrate is used as a first-line treatment for ovulation induction in infertile anovulatory patients with polycystic ovary syndrome. In clomiphene citrate-resistant women, other treatment modalities such as laparoscopic electrocautery or ovulation induction with gonadotropins have been proposed as alternative therapies. Although gonadotropin treatment and laparoscopic ovarian drilling have demonstrated similar reproductive outcomes, laparoscopic ovarian drilling has some advantages over gonadotropin treatment such as lower cost per pregnancy, improvement in menstrual regularity, and better long-term reproductive performance. On the other hand, knowledge about the pathogenesis of polycystic ovary syndrome has been growing and insulin-sensitizing drugs have gained popularity as a new treatment option. SUMMARY: According to current data, metformin has gained popularity as first-line management in clomiphene citrate-resistant women with polycystic ovary syndrome. If ovulation does not occur within several months after treatment with metformin, after the evaluation of all pros and cons related to each treatment, laparoscopic ovarian drilling or gonadotropins may be considered as an effective option according to patient choice.     

Polycystic ovary syndrome and metformin in pregnancy

The diagnostic criteria of polycystic ovary syndrome incorporate hyperandrogenism, polycystic ovaries, anovulation and irregular menstrual bleeding and the syndrome is a recognized reason behind infertility. The biguanide metformin has encouraging effects on several metabolic aspects of the syndrome, including insulin sensitivity, plasma glucose concentration and lipid profile. Moreover, metformin improves the ovarian function in women diagnosed with polycystic ovary syndrome. Hence, metformin is considered an agent for ovulation induction among these patients. However, even higher ovulation frequencies have been observed when metformin has been adjuvant to clomifene therapy. Metformin-induced ovulation presumably brings about resumption of regular menstrual cycles and improved conception rates. Polycystic ovary syndrome patients are presumably more likely than healthy women to suffer from pregnancy-related problems like early pregnancy loss, gestational diabetes mellitus and hypertensive states in pregnancy. Recent data suggest sparing effects of continued metformin therapy throughout pregnancy on early pregnancy loss and gestational diabetes mellitus, but its impact on hypertensive complications to pregnancy appears less evident. Instead, metformin might even induce pre-eclampsia or exert no effect on blood pressure. CONCLUSION: So far, evidence for safety of continued therapy throughout gestation is insufficient, and existing papers are limited in design and might mask for fetal toxic outcomes due to metformin therapy. Prior to a recommendation of sustained metformin therapy throughout pregnancy, randomized placebo-controlled double-blinded clinical trials are awaited with interest, so that present assumptions on efficiency can be clarified, in order to assure efficient and safe management of pregnant polycystic ovary syndrome patients.     

Homocysteine levels are unaffected by metformin treatment in both nonpregnant and pregnant women with polycystic ovary syndrome

BACKGROUND: Women with polycystic ovary syndrome have elevated homocysteine levels. Elevated homocysteine levels associate with pregnancy complications. Women with polycystic ovary syndrome are often treated with metformin, a drug that may increase homocysteine levels. Hence, we investigated the effect of metformin treatment on homocysteine levels in nonpregnant and pregnant women with polycystic ovary syndrome. METHODS: Two prospective randomized placebo-controlled studies included women with polycystic ovary syndrome in a university hospital setting. Sixty-three infertile women were treated with metformin 1,000 mg bid or placebo for 16 weeks and 38 pregnant women with metformin 850 mg bid or placebo from the first trimester and throughout pregnancy. All the women had polycystic ovary syndrome and all participants received diet and lifestyle advice, and oral folate and vitamin B12 substitution, and a daily oral multivitamin tablet. The main outcome measures were serum levels of homocysteine, folate, and vitamin B12. RESULTS: Serum homocysteine levels were unaffected by metformin treatment both in nonpregnant and pregnant women with polycystic ovary syndrome. However, in nonpregnant women both serum folate and vitamin B12 levels decreased with treatment. At inclusion in nonpregnant women, serum homocysteine levels associated negatively with serum levels of folate and methyl malonic acid and positively with free testosterone index. No such associations were seen in pregnant women. CONCLUSIONS: Metformin treatment in women with polycystic ovary does not increase serum homocysteine levels in the nonpregnant or the pregnant state.     

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.     

Metformin in polycystic ovary syndrome

PURPOSE OF REVIEW: Metformin has become an established treatment for women with polycystic ovary syndrome, although controversy remains as to how effective it is and in which populations it should be used. This review examines the recent literature in order to ascertain the evidence for the benefits and disadvantages of using metformin in women with polycystic ovary syndrome. RECENT FINDINGS: A Cochrane systematic review and metaanalysis examined the evidence for metformin in treating polycystic ovary syndrome. Since this was published there have been a number of new trials, some of which have been reasonably large involving participants from many different countries. SUMMARY: Evidence shows that metformin is effective in inducing ovulation, has some marginal benefit in improving aspects of the metabolic syndrome, improves objective measures of hirsutism, and seems to be effective in both obese and lean individuals. However, it has significant side effects, and the high levels of effectiveness that were reported by some early trials have not been replicated. Metformin should always be used as an adjuvant to general lifestyle improvements, and not as a replacement for increased exercise and improved diet.     

Effects of metformin on insulin resistance and on ovarian steroidogenesis in women with polycystic ovary syndrome]

BACKGROUND: Polycystic ovary syndrome is considered the most frequent endocrine abnormality during the fertile age. Hyperinsuli-nemia, typical of this syndrome, alters the functionality of the cytochrome P450 c 17 alfa and this causes an exaggerated secretion of male hormones produced by the female gonad. Objective of this study was to verify if the reduction of the circulating insulin levels, obtained through therapy with metformin, caused the reduction of LH levels, LH:FSH ratio, of testosterone and androstenedione levels, but also of cholesterolemia, triglyceridemia, BMI, and naturally of insulinemia, glycemia, as well as an increase in HDLC (high density lipoprotein cholesterol). METHODS: The presence of insulin-resistance and hyperinsulinemia, in 15 women aged between 20 and 30 with BMI >26 kg/m2, has been verified with test loaded with glucose; 500 mg of metformin have been given to these women three times a day before meals for 12 weeks. LH and FSH levels, LH:FSH ratio testosterone, androstenedione, progesterone, estradiol levels, cholesterolemia, trygliceridemia, HDLC and BMI have been considered in each patient before and after therapy. RESULTS: A statistically significant modification of all measured parameters was observed but the most important data is the reduction of the androgens. CONCLUSIONS: The reduction of insulinemia seems to be actually associated with a reduction of circulating androgens in women with polycystic ovary syndrome. As well as the reproductive function, this insulin-sensitizing agent has the further advantage of a possible favourable effect also on the complications of the polycystic ovary syndrome specifically connected with: glucose-intolerance, dislipidemia, arteriosclerosis and hypertension. To consider the effects on the complications of the syndrome it would be necessary to give the drug for a period longer than 12 weeks.     

Use of metformin in polycystic ovary syndrome: a meta-analysis

OBJECTIVE: To update the state of evidence on the efficacy of metformin, used either alone or in combination with clomiphene citrate in women with polycystic ovary syndrome, by examining three outcomes: ovulation, pregnancy, and live birth. Sources of heterogeneity among the published randomized controlled trials are systematically assessed. DATA SOURCES: An electronic literature search was performed using MEDLINE, EMBASE, SCOPUS, CENTRAL, Cochrane, and U.S. Food and Drug Administration databases, restricted to studies conducted on humans and published in English. METHODS OF STUDY SELECTION: Of the 406 potentially relevant articles identified, 17 met criteria for inclusion in the meta-analysis, rendering a total sample of 1,639 women. Study quality was examined in terms of randomization scheme, masking process, adequacy of allocation concealment, statistical power, and loss to follow-up; publication bias was also assessed. Meta-analytic procedures were used to compare metformin with placebo, and metformin plus clomiphene with clomiphene alone, for all study outcomes. Exploratory analyses were conducted to assess differences in treatment effects between clomiphene-resistant and nonresistant patients, obese and nonobese patients, and trials with long and short durations of follow-up. TABULATION, INTEGRATION, AND RESULTS: Metformin improved the odds of ovulation in women with polycystic ovary syndrome when compared with placebo (odds ratio [OR] 2.94; 95% confidence interval [CI] 1.43-6.02; number-needed-to-treat 4.0) and appears more effective for non-clomiphene-resistant women. Metformin and clomiphene increased the likelihood of ovulation (OR 4.39; 95% CI 1.94-9.96; number-needed-to-treat 3.7) and pregnancy (OR 2.67; 95% CI 1.45-4.94; number-needed-to-treat 4.6) when compared with clomiphene alone, especially in clomiphene-resistant and obese women with polycystic ovary syndrome. These treatment effects were greater for trials with shorter follow-up. CONCLUSION: Using all available evidence, this meta-analysis suggests that metformin increases the likelihood of ovulation and, in combination with clomiphene, increases the odds of both ovulation and pregnancy in women with polycystic ovary syndrome.     

Laparoscopic treatment of polycystic ovaries: is its place diminishing?

PURPOSE OF REVIEW: The purpose of this review is to provide a critical discussion on the place of laparoscopic ovarian drilling and medical treatment with metformin for polycystic ovary syndrome. RECENT FINDINGS: Laparoscopic ovarian drilling remains popular. It is associated with an ovulation rate of approximately 80% and a pregnancy rate of 50-60% within 1 year of the procedure. The technique results in a decrease in ovarian stromal blood flow. An increasing amount of data, however, suggests that treatment with metformin is equally as effective. The use of metformin in pregnancy appears to be safe; it decreases the miscarriage rate and possibly the incidence of gestational diabetes. SUMMARY: Laparoscopic ovarian drilling and metformin improve ovulatory dysfunction and pregnancy rate to a similar extent. The advantages of metformin continue beyond conception. It reduces the miscarriage rate and also decreases the likelihood of developing gestational diabetes. A randomized trial comparing the effects of metformin and laparoscopic ovarian drilling in women with polycystic ovary syndrome is recommended.     

Body morphology and its impact on adolescent and pediatric gynecology, with a special emphasis on polycystic ovary syndrome

PURPOSE OF REVIEW: To provide the reader with a timely review of studies investigating the impact of body morphology and weight on pubertal maturation, impact of pubertal maturation on adult body morphology, and recent developments in the diagnosis and management of polycystic ovary syndrome. RECENT FINDINGS: The temporal trends in age of onset of puberty and menarche, and prevalence of obesity, are presented. Timing of pubertal maturation and initial manifestations of puberty may impact adult adiposity and ponderosity, as well as predispose to conditions associated with adult morbidity. The polycystic ovary syndrome is the most common endocrinologic disorder, occurring in up to 10% of women. It is associated with insulin resistance, and substantial proportions of women with polycystic ovary syndrome, regardless of age or obesity status, have impaired glucose tolerance. Clinical and biochemical abnormalities seen in polycystic ovary syndrome may improve through utilization of insulin-sensitizing agents, although lifestyle changes provide more profound clinical improvements. SUMMARY: We now understand better those factors associated with initiation of puberty, and pathophysiology of polycystic ovary syndrome. However, further longitudinal studies are needed.     

Effects of metformin on body mass index,menstrual cyclicity,and ovulation induction in women with polycystic ovary syndrome

OBJECTIVE: Metformin has been used as a treatment in many studies of the infertility associated with polycystic ovary syndrome (PCOS). We will review the literature on this topic as it specifically relates to changes in body mass index (BMI), improvement in menstrual cyclicity, and effects on ovulation and pregnancy rates. DESIGN: Review of studies addressing biochemical and clinical changes in women with PCOS on metformin. MAIN OUTCOME MEASURE(S): Changes in BMI, menstrual cyclicity, ovulation rate, and pregnancy rate. RESULT(S): Metformin has been shown to produce small but significant reductions in BMI. Multiple observational studies have confirmed an improvement in menstrual cyclicity with metformin therapy. The studies addressing the concomitant use of metformin with clomiphene citrate initially predicted great success, but these have been followed by more modest results. There is little data in the literature concerning the use of metformin and hMGs. CONCLUSION(S): Some (but not all) women with PCOS have improvements in their menstrual cycles while on metformin. The data supporting the use of metformin in ovulation induction with clomiphene citrate and hMG remain to be confirmed by large, randomized, prospective studies.     

Metformin for the treatment of polycystic ovary syndrome

OBJECTIVE: To familiarize obstetrician-gynecologists with the use of metformin for the treatment of polycystic ovary syndrome (PCOS). DATA SOURCES: Using OVID, 94 English-language articles published after 1966 indexed with the key words "metformin" and "polycystic ovary syndrome" were identified. METHODS OF STUDY SELECTION: Studies were excluded if they did not have a control group, did not use the National Institutes of Health definition of PCOS, did not have a clinical outcome as an end point, and were not in the English language. Reviews were also excluded, leaving 21 articles for inclusion. TABULATION, INTEGRATION, AND RESULTS: Three clinical trials reported that for the treatment of anovulatory infertility caused by PCOS, metformin plus clomiphene is more effective than clomiphene alone in inducing ovulation. For the treatment of irregular menses caused by PCOS in women not attempting conception, metformin therapy may restore ovulatory menses in the majority of women. However, most women will require 4-6 months of metformin therapy before they achieve ovulatory menses. In obese women, metformin plus a low-calorie diet may be associated with more weight loss than a low-calorie diet alone. CONCLUSION: Polycystic ovary syndrome is a common gynecologic endocrine disorder. Obstetrician-gynecologists should be familiar with the indications and contraindications for the use of metformin in their practice.     

Effects of short-term and long-term metformin treatment on menstrual cyclicity in women with polycystic ovary syndrome

The purpose of this retrospective study was to compare the frequency of menstrual cyclicity between two groups of patients with polycystic ovary syndrome: women who were followed while on metformin for 3-6 months and those who were followed for >6 months. The results showed that metformin is highly effective in normalizing menstrual cyclicity in women with polycystic ovary syndrome (the overall response rate was 69%, with 88% of responders achieving normal cyclicity), especially with a treatment duration of 6 months or longer (the response rate was 40% higher for women who were treated with metformin for >6 months vs. 3-6 months, 77% vs. 55%).     

Polycystic ovarian syndrome--prognosis and treatment outcomes

PURPOSE OF REVIEW: Polycystic ovarian syndrome is the commonest endocrine disorder of reproductive-age women. It may have implications for women with regard to anovulatory infertility, insulin resistance and elevated androgens. Furthermore, patients are prone to health problems in later life, including diabetes and cardiovascular risk. This review provides an update of recent findings for the management of polycystic ovarian syndrome. RECENT FINDINGS: Studies have been performed to determine the best first-line medication for ovulation induction in polycystic ovarian syndrome. Meta-analyses have been performed to determine whether metformin should be used as an adjunct in IVF in women with this syndrome and to determine whether metformin or the oral contraceptive pill should be used for symptom control. Adverse features of this syndrome can be improved by diet and exercise. Evidence for the longer-term use of metformin to protect against adverse cardiovascular outcomes, and for its pregnancy use to reduce gestational diabetes, preeclampsia, and fetal macrosomia is lacking, although evidence for a reduction in miscarriage in insulin-resistant patients is accumulating. SUMMARY: Recent studies have sought to clarify the serious short-term clinical problems faced by women with polycystic ovarian syndrome; however, studies looking to the long term to address cardiovascular and diabetic conversion are still required.     

Insulin-sensitizing agents and reproductive function in polycystic ovary syndrome patients

PURPOSE OF REVIEW: To review the current reproductive advances in insulin-sensitizing agents for treatment of polycystic ovary syndrome patients. RECENT FINDINGS: To date, among insulin-sensitizing drugs, only metformin should be used to improve reproductive function in well selected polycystic ovary syndrome patients. Preliminary data seem to show beneficial effects of thiazolidinediones in improving metabolic and hormonal patterns and in restoring regular menses. SUMMARY: The use of insulin-sensitizing drugs offers a new perspective for the treatment of polycystic ovary syndrome-related reproductive disorders. However, further data are needed before we can draw definitive conclusions regarding their clinical role.     

Metformin reduces abortion in pregnant women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are considered to be at increased risk of miscarriage. Since metformin has beneficial effects on the risk factors contributing to first-trimester abortion in PCOS patients, we hypothesized that metformin - owing to its metabolic, endocrine, vascular and anti-inflammatory effects - may reduce the incidence of first-trimester abortion in PCOS women. MATERIALS AND METHODS: A prospective cohort study was set up to determine the beneficial effects of metformin on PCOS patients during pregnancy. Two hundred non-diabetic PCOS patients were evaluated while undergoing assisted reproduction. One hundred and twenty patients became pregnant while taking metformin, and continued taking metformin at a dose of 1000-2000 mg daily throughout pregnancy. Eighty women who discontinued metformin use at the time of conception or during pregnancy comprised the control group. RESULTS: Both groups were similar with respect to all background characteristics (age, body mass index, waist/hip ratio, follicle-stimulating hormone, luteinizing hormone, estradiol and dehydroepiandrosterone sulfate levels). Rates of early pregnancy loss in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11-0.42). CONCLUSIONS: Administration of metformin throughout pregnancy to women with PCOS was associated with a marked and significant reduction in the rate of early pregnancy loss.     

Polycystic ovary syndrome in adolescence and early adulthood

Polycystic ovaries and the associated syndrome are recognized as the most common cause of endocrine disturbances in adult women, but much less research has been performed to examine how polycystic ovary syndrome (PCOS) presents in girls and young women. Polycystic ovaries have been demonstrated in childhood, and there is evidence to show that even very young women may show symptoms and signs of the associated syndrome. Closer examination of younger populations (less-than-or-eq, slant 25 years of age), and in particular, studies of girls during the transition from puberty into early adulthood (adolescence), may provide new insights into the pathogenesis and natural history of polycystic ovaries and PCOS, and may indicate whether polycystic ovaries could potentially be considered as a marker for health screening. Consideration should be given to the management of girls and young women with polycystic ovaries and PCOS as this group may have different needs and health risks compared with older women.     

Should we continue or stop insulin sensitizing drugs during pregnancy?

PURPOSE OF REVIEW: The use of insulin sensitizing drugs such as metformin in polycystic ovary syndrome has been increasingly popular and validated by systematic reviews. There has also been an interest in the use of metformin for gestational diabetes. However, administration of metformin to prevent miscarriage is controversial and widespread use of this drug in early pregnancy requires investigation. RECENT FINDINGS: There are claims that miscarriage and gestational diabetes are more common in polycystic ovary syndrome and that use of insulin sensitizers improves outcomes dramatically. This review suggests there is no evidence for increased risk of miscarriage solely due to polycystic ovary syndrome and that there are insufficient data for promoting therapy with metformin. There is some reason for use of metformin in mid-pregnancy for gestational diabetes but better evidence from randomized controlled trials is urgently needed. SUMMARY: The use of metformin in early pregnancy for reducing the risk of miscarriage should be avoided outside of the context of properly designed prospective randomized trials. Safety in early pregnancy appears to be reassuring but not completely proven. The use of metformin in mid-pregnancy for gestational diabetes appears more logical but also needs adequate trials before general use is advocated.     

Should insulin-sensitizing drugs be used in the treatment of polycystic ovary syndrome?

Insulin resistance is a central feature of polycystic ovary syndrome (PCOS). Hyperinsulinaemia contributes to anovulation, hyperandrogenism, infertility and early pregnancy loss in women with PCOS. Chronic hyperinsulinaemia also predisposes women with PCOS to increased risks of diabetes and cardiovascular events. Current data indicate that metformin, either as monotherapy or in combination with clomiphene in clomiphene-resistant patients, is an effective treatment for anovulation in PCOS. Initial evidence also suggests that insulin sensitizers may have a role in preventing early pregnancy loss. Of the available insulin-sensitizing agents, metformin has been the agent most frequently studied in PCOS, and has the least undesirable pregnancy safety profile. Ameliorating the metabolic syndrome associated with insulin resistance in PCOS with metformin may also prevent long-term cardiovascular and diabetes complications, pending further evidence. Based on these data, metformin should be a first-line therapy for women with PCOS.