Natural Treatment for Polycystic Ovary Syndrome Discovered

The Natural Pcos Diet

The Natural Pcos Diet, By Jenny Blondel, A Leading Australian Naturopath In Response To Thousands Of Requests For Professional Information To Help Women Suffering From Pcos. Real Solutions To Naturally Overcome PCOS. Naturally balance your hormones Increase your chances of conceiving Help you lose weight and feel good Curb your cravings for sugary foods Turn your fatigue around Achieve clearer, glowing skin See improvements in your mood. Do You Feel PCOS Is. Ruling Your Life? At Last! The Natural PCOS Diet. A Naturopath’s Easy Step-by-Step Guide to Overcoming PCOS Is. Now Available! More here...

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Backgroundsummary 21 Insulin Resistance and PCOS

The role of insulin resistance in the pathogenesis of PCOS has been extensively reviewed in Chapter 24. Briefly, insulin resistance is an intrinsic and virtually universal feature of PCOS. Insulin resistance exists in PCOS independent of obesity, as evidenced by the presence of insulin resistance even in lean women with PCOS (1). In addition, about 50-80 of women with PCOS are obese. Hence, in PCOS obesity further induces an added burden of insulin resistance and hyperinsulinemia in addition to the component of insulin resistance that is intrinsic to the disorder (2).

Mechanism Linking Obesity and PCOS

The mechanisms linking obesity and PCOS are unclear but may be related to insulin resistance and hyperandrogenism, both of which are commonly documented in lean and obese women with this condition. Insulin resistance is a common but not universal feature of PCOS, although women with insulin resistance appear to be more clinically affected (2). Because insulin resistance is strongly influenced by obesity in non-PCOS subjects, it was initially debated whether insulin resistance and hyperinsulinemia are a primary metabolic disturbance of PCOS or a symptom of the obesity commonly observed in PCOS. Hyperandrogenemia and insulin resistance appear to be independent features of PCOS, with hyperinsulinemia enhancing the expression of hyperandrogenemia by increasing bioavailability of androgens (4) (Fig. 1). Obese women with PCOS show decreased insulin sensitivity and hyperinsulinemia to an extent greater than can be explained by obesity alone (4,5). A synergistic interaction appears to exist...

Lifestyle Modification in the Infertile Patient With PCOS

Obesity is a very common feature of women with PCOS, with an estimated prevalence of 35-63 among women with the disorder (3). Ghrelin homeostasis and measures of hunger and satiety are significantly impaired in subjects with PCOS, although not affected by dietary composition (4). Abdominal obesity, characterized by a waist-to-hip ratio of more than 0.8, has been reported in 63 of women with PCOS whether they are obese or not (5,6). Obesity, particularly abdominal, is often associated with insulin resistance and hyperinsulinemia, which stimulates the biosynthesis of androgens and the decreased hepatic production of sex hormone-binding globulin (SHBG). Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, and, possibly, high dietary lipid intake may be mechanisms by which obesity worsens the degree of hyperandrogenism and ovulatory function in PCOS (7). Obesity is associated with a reduced chance...

Effect of Hyperinsulinemia on Hyperandrogenism in PCOS

Several lines of evidence suggest that the compensatory hyperinsulinemia associated with insulin resistance is critical to the pathogenesis of hyperandrogenism in PCOS. In in vitro cultures of isolated human ovarian thecal cells, ovarian testosterone biosynthesis stimulated by insulin was fourfold greater in cells from women with PCOS than those of normal women, and in a dose-response study insulin stimulated thecal androgen production at physiological concentrations (3). This stimulation of testosterone production was almost fully prevented by antibody blockade of the insulin receptors. This suggests that insulin stimulates ovarian thecal testosterone biosynthesis via activation of its homologous receptor. In vivo data also suggest that hyperinsulinemia is associated with an increased level of circulating testosterone in PCOS. When pancreatic insulin secretion was suppressed in women with PCOS by diazoxide, both serum total and free testosterone levels decreased (8). However,...

Choice of Insulin Sensitizing Agent in PCOS

Currently, the commercially available insulin-sensitizing agents include metformin and the thiazolidinediones (rosiglitazone and pioglitazone). Most of the clinical studies in women with PCOS have been conducted with metformin. In addition, for several decades metformin has been used worldwide to treat diabetes, and thus its side effect profile has been well described. Adverse effects of metformin include gastrointestinal distress, such as diarrhea and nausea. More serious toxicity includes a documented, but rare, risk of lactic acidosis. Nearly all reports of lactic acidosis occurred in patients with renal insufficiency (plasma creatinine 1.4 in women), hepatic dysfunction, heart failure, or other pulmonary and circulatory dysfunctions that can by themselves lead to hypoxia and lactic aci-dosis (70,71). Careful attention to these contraindications will prevent most occurrences of lactic acidosis. As discussed in a previous section, metformin is classified by FDA as Pregnancy Category...

Long Term Health Consequences of PCOS

Insulin resistance is associated with diabetes, hypertension, dyslipidemia, endothelial dysfunction, a procoagulant state, and cardiovascular disease (see Chapters 28 and 29). Recently, the National Cholesterol Education Program Adult Treatment Panel defined the metabolic syndrome as the presence of three of the five following risk factors waist circumference greater than 88 cm in females fasting serum glucose 110 mg dL or more, fasting serum triglycerides greater than 150 mg dL serum high-density lipoprotein cholesterol less than 50 mg dL and blood pressure greater than 130 85 mmHg (60). The metabolic syndrome has been found to be present in 43-46 of women with PCOS, a twofold higher prevalence compared with women in the general population of the same age (61,62).

Medical History and Physical Examination in Patients With Possible Androgen Excess

Modified Ferriman Gallwey Score

We outline here the basics of the medical history and physical exam in the patient suspected of suffering from androgen excess. The timing and pace of pubertal development and its relation to complaints of unwanted hair growth, hair loss, acne, and or obesity should be established. The onset and progression of these complaints should also be established. Drug or medication use and exposure or use of skin irritants should be elicited. A detailed menstrual history should be obtained, with an emphasis on determining whether evidence of ovulatory function (e.g., premenstrual molimina) is present. Change in skin pigmentation or texture, extremity or head size, and changes in facial contour should be noted. A detailed family history of endocrine, reproductive, or metabolic disorders should be obtained. A family history of similar hyperandrogenic signs and symptoms is a powerful clue to the inherited basis of the disorder, although a familial association can be noted for PCOS, HAIR-AN...

Anovulation Is A Characteristic Feature Of Pcos. It Manifests As Menstrual Disturbance 80 Amenorrhoea Oligoamenorrhea

Patient With Hyperandrogenism

The features of PCOS may be elicited when obtaining the medical history or upon the physical examination. The ovarian morphological and the biochemical and metabolic features of the disorder are discussed in Chapters 16 and 17. The evaluation of patients with androgen excess, including PCOS, is discussed in Chapter 33. In this section, we will outline important information that the medical history will elicit concerning the features of PCOS, including the presenting complaint, the onset and progression of hyperandrogenic signs and symptoms, menstrual dysfunction and irregularity, weight gain, symptoms of obstructive sleep apnea, and the family history. Patients with PCOS may present complaining of irregular or unpredictable menstrual cycles, unwanted hair growth, acne or scalp hair loss, or unexplained weight gain or overweight (see Section 2.1.4.). Another frequent presenting complaint of PCOS may be infertility, possibly associated with recurrent first trimester miscarriages....

Effect of Hyperinsulinemia on Anovulation in PCOS

Numerous studies have demonstrated that hyperinsulinemia contributes to the chronic anovulation of PCOS. In the largest long-term study, 305 women with PCOS were randomized to the insulin sensitizer troglitazone (150, 300, or 600 mg daily) or placebo for 44 weeks (10). Women receiving troglitazone at doses of 300 and 600 mg daily had a significantly higher ovulation rate (0.42 and 0.58) than those receiving placebo (0.32 p 0.05 and 0.0001, respectively). This increase in ovulation rate was dose dependent, suggesting that the improvement in ovulatory function was at least in part accounted for by the improvement in insulin sensitivity.

Pharmacological Options for Ovulation Induction in PCOS

In women with PCOS who are not obese or overweight, who are obese but unable to lose weight, or who fail to ovulate despite weight loss, ovarian stimulation with pharmacological agents is the next step in the treatment of oligo-ovulatory infertility. Clomiphene citrate is currently the first-line pharmacological therapy for ovulation induction, although metformin appears to also be a promising agent for first-line therapy, at least in some patients. Studies are currently ongoing to address which first-line agent (clomiphene or metformin) is of greater benefit and or which subpopulations of patients with PCOS will benefit from either treatment alone or in combination. Alternatively, glucocorticoids do not result in consistent ovulation and have significant side effects. Patients who are resistant to ovulation with clomiphene may benefit from the addition of metformin or may proceed to laparoscopic ovarian drilling or exogenous pulsatile GnRH treatment. However, the most commonly used...

Estimating the Economic Burden of PCOS

We calculated the health care-related economic burden in PCOS based on the above prevalences of disease (64). We restricted the calculation to the United States only, although we recognize that PCOS is an international disorder. However, we should note that our estimation is highly conservative because we did not include a number of costs for which we did not have accurate and present-day prevalence and monetary estimates (Table 1). We did include the costs of the initial evaluation, detailed in Table 2. The overall costs associated with the treatment and, if appropriate, the diagnosis of the various morbidities evident in the premenopausal women with PCOS are outlined in Table 3. This conservative estimate of the health care-related economic burden of premenopausal women with PCOS exceeded 4 billion annually in the United States alone. Approximately 40 of the burden is a result of the increased prevalence of diabetes associated with PCOS 30 arises from the treatment of the associated...

Pcos And Risk For Cardiovascular Disease

At this moment there is no single and universally accepted definition for PCOS. This is probably the pivotal reason why published studies on PCOS cannot be easily reanalyzed in order to provide a conclusive assessment of the CVR or CVD in this group of patients. Nevertheless, several lines of evidence (11-15) indicate alterations in intermediate endpoints for CVR in women with PCOS and provide evidence for an association between CVR factors in PCOS and CVD (Table 1). Most studies Evidence for Association Between Polycystic Ovary Syndrome, Cardiovascular Risk (CVR) Factors and Cardiovascular Disease (CVD) TeT-1) impaired fibrinolysis (TpAI-1) Increased clinical CVD No increased mortality from CVD documented to date in PCOS how on CVD in PCOS used criteria adopted at the 1990 National Institute of Child Health and Human Development (NICHD) conference to diagnose PCOS (16). Patients with PCOS diagnosed by the NICHD criteria, which include androgen excess as a sine qua non, should have a...

Metformin Weight Loss and PCOS

The initial use of metformin in the treatment of PCOS has now been widely accepted to be a valuable and inexpensive therapeutic modality. Recent systematic reviews have indicated that metformin is highly effective in inducing ovulation and increasing pregnancy rates (8,9). The numbers needed to treat for ovulation are around four patients, and there is an improvement in serum insulin levels and a reduction in free testosterone in response to metformin. The drug appears to be safe in early pregnancy with respect to congenital abnormalities, although it is controversial whether miscarriage rates are reduced. The predictors of success of metformin have not been established, although there is some evidence that patients who are substantially overweight do not respond as well. Side effects of metformin include nausea, vomiting, diarrhea, and other forms of gastrointestinal intolerance, and patients need to be warned about the interaction between metformin and alcohol. The ovulatory...

Chronic Therapy in PCOS with Insulin Sensitizers

Both metformin and the thiazolidinediones have been shown to reduce blood pressure and inflammatory markers. Obese women on metformin also tend to lose weight while on metformin in a dose-dependent manner (63). Although the insulin sensitizers' effects on cardiovascular risk factors are favorable, currently there are no prospective randomized outcome trials examining the use of insulin sensitizers in the prevention of diabetes or cardiovascular events in women with PCOS. Although not specifically conducted in women with PCOS, there are several outcome studies indicating that interventions to improve insulin sensitivity may decrease the incidence of diabetes in individuals at high risk. The Diabetes Prevention Project was a prospective study sponsored by the National Institutes of Health (64). The study included 3234 patients at high risk of diabetes (history of gestational diabetes or presence of impaired glucose tolerance and a first-degree relative with diabetes). Subjects were...

Background On Polycystic Ovarian Syndrome Among Adolacents

Recently, the concept of intrauterine programming has been extended to include possible fetal influences on androgen production in the peripubertal period. For example, Ibanez et al. (12) found evidence for precocity, ovarian androgen excess, and hyperinsulinism among some girls who had experienced restricted fetal growth. Other investigators have also found evidence for differences in the androgenic milieu of low-birthweight infants during childhood and beyond. For example, Korhonen et al. (13) reported significantly increased levels of DHEAS and androstenedione at age 7 among previously growth-restricted infants compared to normal infants. Szathmari et al. (14) reported increased levels of DHEA, DHEAS, and A4 during young adulthood in formerly low-birthweight girls no such effects were seen among formerly low-birthweight males, however. Future studies of these relationships are obviously required.

Ovarian Stimulation for IVF in Polycystic OvaryPCOS

Ovarian stimulation with gonadotropins for IVF in polycystic ovaries and or PCOS is a particular problem and is indeed a challenge for the physician and patient. The long GnRH agonist-suppression protocol accompanied by pretreatment with combined oral contraceptive pills has been widely accepted as the most effective stimulation protocol for polycystic ovary PCOS patients (Fig. 2). Pituitary suppression takes longer for polycystic ovary PCOS patients (22). Although the optimal time to commence GnRH agonist is not clearly determined, commencement in the early follicular phase combined with oral contraceptive pills would avoid the risk of inadvertent administration during early pregnancy. The GnRH agonist protocol has been found to suppress elevated LH and androgen levels and prevent a premature LH surge, which appears to improve the pregnancy rate and reduce the miscarriage rate in PCOS patients undergoing IVF treatment (23-26). It is very important to select the appropriate dose of...

Effect of Metformin on Anovulation and Infertility 2211 Metformin Monotherapy in PCOS

Numerous clinical trials have evaluated the effect of metformin on ovulation in women with PCOS. Nester et al. reported the first randomized, placebo-controlled trial evaluating the use of metformin to reestablish ovulation (11). Sixty-one obese women with PCOS were randomized to metformin 500 mg three times daily or placebo for 35 days. If spontaneous ovulation did not occur, they were entered into the second phase of the study and were given clomiphene 50 mg daily for 5 days while continuing to take the metformin or placebo for another month. During the first 35 days in which metformin monotherapy was compared to placebo, 24 of the women (12 in 35) taking metformin ovulated spontaneously, whereas only 4 (1 in 26) in the placebo group had spontaneous ovulation. Other studies have corroborated the above findings. The Cochrane library has published a systematic review of the use of metformin in PCOS (12). The review included only the most rigorously performed clinical trials for...

Polycystic Ovaries

Overall, polycystic ovaries are observed in 20-30 of the unselected female population (4,3538). The prevalence of polycystic ovaries in the general population decreases with age and was observed in only 7.8 of women older than 35 years (37). The prevalence of androgen excess disorders among women with polycystic ovaries is less clear. Considering only the prevalence of PCOS, and assuming that 25 of unselected reproductive-aged women have polycystic ovaries, that the overall prevalence of PCOS in this population is 7 , and that about 75 of patients with PCOS will have polycystic ovaries on ultrasound, we can estimate that approximately 21 of women having polycystic ovaries will have PCOS. Although this represents about a threefold higher prevalence than in the general population (i.e., 6.5 ), it also indicates that about 80 of the pool of women with polycystic ovaries will not have PCOS. Consistent with this estimation, in their study of 224 college women Michelmore and colleagues...


Exercise Pco Treatment

PCOS is the most common cause of anovulatory infertility. As described in Chapters 35 and 37, the treatment of anovulation comprises lifestyle modification through diet, exercise, and weight loss, insulin sensitizers, oral ovulation induction agents, surgical treatments, and gonadotropins. Patients who have not conceived with other treatment approaches or couples who have additional infertility factors may require IVF. In vitro fertilization treatment outcomes for PCO PCOS patients may even be better than for patients with normal ovaries. After three cycles of IVF treatment, the odds of achieving a pregnancy with polycystic ovaries were 69 higher than those of a woman with normal ovaries (9). PCOS has been shown to exist in 4-10 of the general population and can be found in even higher incidences in certain populations. Polycystic ovary is a morphological definition based on ultrasound without any manifestation of the syndrome and can be defined as the presence of 12 or more follicles...

Future Avenues Of Investigation

The effect of androgens on a PCOS endometrial cell-line growth and development and on gene expression in these conditions 2. Microarray analysis of gene expression in endometrium from women with PCOS with differing clinical presentations and biochemical parameters 3. Creation of a central database of women with PCOS who develop endometrial hyperplasia or cancer, to permit advances in the pathogenesis and prevention of neoplasia in these women 4. Long-term studies examining the effects of lifestyle interventions in women with PCOS 5. Association between PMS and PCOS, as this will help the understanding of the much-studied, but little-understood subject of PMS

Menstrual and Ovulatory Dysfunction

The prevalence of PCOS among women with clinically evident menstrual dysfunction can be estimated from four studies evaluating the prevalence of PCOS in the general population (2,3,5,6). These studies noted that the overall prevalence of menstrual dysfunction approximated 20 of the women studied, very similar to the rate of 22.9 reported by 101,073 women participating in the Nurses Health Study II (34). Of the women complaining of menstrual dysfunction, between one-fourth and one-third had androgen excess, notably PCOS (using the National Institutes of Health NIH 1990 criteria).

Comparative Efficacy of Different Insulin Sensitizing Agents

Few studies have directly compared the utility of the various insulin-sensitizing drugs in women with PCOS. Ortega-Gonzalez et al. studied 52 obese (BMI 28 kg m2), insulin-resistant women with PCOS who had not been previously treated and randomized them to either pioglitazone 30 mg day or metformin 850 mg three times daily for 6 months (35). Both metformin and pioglitazone significantly improved AUC-insulin and fasting glucose-to-insulin ratio despite a significant increase in weight (from BMI of 32.2 1.0 kg m2 at baseline to 34.0 1.2 kg m2 at 6 months) in the pioglitazone group. At 6 months, fasting AUC-insulin was significantly lower in the women treated with pioglitazone compared with those treated with metformin. However, women in the metformin group also had a higher AUC-insulin at baseline, and hence whether there was a true difference in the reduction of AUC-insulin between pioglitazone and metformin is unknown. Ovulation rates were not evaluated in this study. The above two...

Abnormal Estrogen Production

In normally cycling women the predominant site of estrogen production is the granulosa cells of the ovarian follicle. In ovulatory cycles in PCOS, the dominant follicle secretes estradiol in sufficient quantities to trigger the midcycle surge of LH, but in the anovulatory cycles typical of PCOS, follicle development is arrested at the small antral stage when selection of a dominant follicle would normally occur and the aromatase enzyme would be expressed (30). Consequently, the granulosa cells fail to express aromatase, and estrogen production from the ovary is minimal. PCOS, however, is not a hypoestrogenic condition. The high concentrations of androstenedione secreted by the theca cells are metabolized to estrone in the peripheral tissues, in particular the adipose stromal cells, leading to a chronic elevation of estrogen in the circulation. The chronic elevation of estrogen in PCOS contributes to the frequently observed increase in LH-to-follicle- stimulating hormone (FSH) ratio...

Differentiation of Functional Disorders

Once specific disorders are excluded, the remaining patients (the vast majority of patients with androgen excess) are considered to have androgen excess resulting from a functional abnormality, principally PCOS or IH. It is important to note that the classification of these patients will depend to a great extent on the definition used, particularly for PCOS (see Chapter 13). Hyperandrogenic women in whom specific disorders have been excluded and who have evidence of ovarian dysfunction (either oligo-anovulation or polycystic ovarian morphology) are generally considered to have PCOS. Only a minority of women suspected of androgen excess will have IH, if strictly defined (including the absence of ovulatory dysfunction, polycystic ovarian morphology, and hyperandrogenemia, in the face of evident hirsutism see Chapter 12). Also, depending on diagnostic criteria, a variable proportion of androgen excess patients will be classified as having nonspecific hyperandrogenism (e.g., patients with...

Insulin Sensitizing Drugs

In the past decade, several studies reported th+at insulin sensitization may be effective in improving several abnormalities of PCOS. In particular, metformin has been proposed as the first-line therapy for both reproductive and metabolic abnormalities in these women. Insulin sensitizers also lower serum testosterone, and a few controlled studies assessed the efficacy of these drugs on hirsutism. These studies, carried out with either metformin or troglitazone, showed limited effect of this approach on established hirsutism (26,27), suggesting that the treatment of hirsutism should not be a primary indication for using insulin sensitizers. However, it can be hypothesized that these drugs might be helpful in hirsute women with PCOS for the maintenance of the clinical improvement obtained with antiandrogen treatment.

Summary of Predictive Value of Clinical Markers

Overall, between 50 and 75 of women with evidence of hirsutism or the complaint of unwanted hair growth will have androgen excess, notably PCOS. Alternatively, only 20 and 40 of patients with acne as their sole presenting complaint and only about 10 of women complaining of hair loss will have androgen excess. Between one-fourth and one-third of women with oligo- amenorrhea have androgen excess, and only about one-fifth of women with polycystic ovaries on ultrasonogra-phy will have androgen excess.

Gonadotropin Ovulation Induction

Exogenous gonadotropins have traditionally been used in PCOS patients who are resistant to ovulation induction with clomiphene and more recently those not responding to the addition of metformin or laparoscopic ovarian drilling. Gonadotropin preparations derived from hMG, a mixture that contains FSH, LH, and large quantities of urinary proteins, have been in use since the early 1960s (97). Other gonadotropin preparations in use today include purified urinary FSH (uFSH) and recombinant FSH (rFSH). Highly purified uFSH contains a reduced amount of LH and very small amounts of urinary proteins. The lack of urinary proteins in this preparation reduces adverse reactions such as local allergy or hypersensitivity (98). Preparations of rFSH were recently developed with a complete absence of LH and co-purified proteins, giving high specific bioactivity. These preparations share similar pharmacokinetic characteristics with purified uFSH (99). Whereas hMG is administered intramuscularly, uFSH...

Identification of Associated Morbidities

Once the diagnosis (specific or functional) is established, related morbidities should be identified. For example, PCOS and the HAIR-AN syndrome are associated with important metabolic dysfunction, including the metabolic syndrome. As such, it is recommended that patients diagnosed with these disorders undergo measurement of fasting lipids and insulin and glucose levels following an oral glucose load (75 g). The results of the oral glucose tolerance test (OGTT) will allow the detection of impaired glucose tolerance (IGT) or type 2 diabetes mellitus (DM). Although many patients can be diagnosed as having DM by a fasting glucose of greater than 126 mg dL (40), patients with PCOS frequently require Women with longstanding ovulatory dysfunction, particularly those not having received long-term progestogen therapy or hormonal contraception, will be at increased risk for endometrial hyperplasia and or carcinoma (see Chapter 27), although the extent of this risk is unclear (46). Current...

Estrogen Progestogen Combinations

In women who are hyperandrogenic, suppression of ovarian androgens by estrogen-progestogen combinations is widely used (1). This strategy is effective in lowering circulating free androgens resulting from the decrease in luteinizing hormone and androgen secretions and via an estrogen-induced increase in sex hormone-binding globulin. In addition, there is some evidence of a mild reduction in adrenal androgen secretion, attributed to the effect of the progestin. Despite the fact that these drugs have been used for hirsutism treatment for decades, there have been few controlled studies assessing their efficacy on the cutaneous manifestation of androgen excess. In addition, there are pros and cons in using oral contraceptives for the treatment of hyperandrogenism in PCOS. These medications counteract the risk of endometrial cancer as a result of unopposed estrogen. Furthermore, they ensure contraception, which may be very useful in these women, who have in many cases reduced but...

Confirmation of Ovulatory Function in Eumenorrheic Women

Approximately 75 women with androgen excess have overt oligo-menorrhea or menstrual dysfunction, signaling the presence of ovulatory abnormalities. Alternatively, a history of regular Prevalence of Abnormally Elevated Androgen Measures in 858a Patients With Androgen Excess Prevalence of Abnormally Elevated Androgen Measures in 858a Patients With Androgen Excess

Exclusion of Specific Disorders

Approximately 6 of androgen excess patients suffer from a specific disorder, including classic and nonclassic 21-hydroxylase deficiencies, the HAIR-AN syndrome, or an ASN, among others (12). In patients clinically suspected of having an ASN, a computed tomography or magnetic resonance imaging scan of the adrenals and transvaginal ovarian ultrasonography should be obtained to assess for adrenal or ovarian masses, respectively. Importantly, measurement of a basal 17-hydroxyprogesterone serum level should be obtained in the follicular phase of the menstrual cycle, preferably in the morning, to exclude 21-hydroxylase-deficient NCAH (39). In patients suspected of having Cushing's syndrome, it will also include a 24-hour urinary free cortisol level or a cortisol level following an overnight dexamethasone (1.0 mg at 11 pm) test. If the HAIR-AN syndrome is suspected, a basal or preferably a glucose-stimulated insulin level should be obtained. Growth hormone levels should be obtained in...

Wiesner G. Vaz M. Collier G. Y Col. Leptin Is Released From The Human Brain Influence Of Adiposity And Gender. J. Clin.

Polycystic ovary syndrome. N Engl J Med 2005 352 1223-1236. 2. Dunaif A. Insulin resistance and the polycystic ovary syndrome mechanisms and implications for pathogenesis. Endocr Rev 1997 18 774-800. 4. Gambineri A, Pelusi C, Vicennati V, Pagotto, U, Pasquali R. Obesity and the polycystic ovary syndrome. Int J Obes Rel Metab Dis 2002 26 883-896. 13. Cresswell JL, Barker DJ, Osmond C, Egger P, Phillips DI, Fraser RB. Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet 1997 350 1131-1135. 14. Abbott DH, Dumesic Da, Franks S. Developmental origin of polycystic ovary syndrome a hypothesis. J Endocrinol 2002 174 1-5. 15. Eisner JR, Dumesic DA, Kemnitz JW, Abbott DH. Timing of prenatal androgen excess determines differential impairment in insulin secretion and action in adult female rhesus monkeys. J Clin Endocrinol Metab 2000 85 1206-1210. 17. Yen SSC. The polycystic ovary syndrome. Clin Endocrinol (Oxf) 1980 12 177-208. 18. Pasquali R, Casimirri F....

Effect of Insulin Sensitizers on Hirsutism

Current data on the effect of insulin sensitizers on hirsutism are conflicting. In an open-label study of 39 women with PCOS, metformin 500 mg three times daily significantly decreased Ferriman-Gallwey hirsutism scores at the end of the 12-week study period (32). However, in a more rigorous randomized, placebo-controlled, 44-week trial, metformin at the same dose did not significantly reduce clinical hirsutism scores (17). In another randomized controlled 12-month study, metformin 500 mg three times daily was compared to Dianette (ethinyl estradiol 35 ig and cyproterone acetate 2 mg) in 52 women (33). Both groups demonstrated significant reductions in the Ferriman-Galwey scores, with a significantly greater reduction in the metformin arm (p 0.01). In addition, in patient self-assessment, women taking metformin scored their hirsutism as having improved significantly more than the contraceptive group (p 0.01). In the long-term, placebo-controlled study using troglitazone, a significant...

Ovarian Hyperstimulation Syndrome

Ovarian Hyperstimulation Syndrome

OHSS is a potentially serious iatrogenic complication of ovarian stimulation with gonadotropins. A controlled study comparing patients with and without polycystic ovaries undergoing IVF showed that 10.5 of the polycystic ovary patients developed moderate severe OHSS compared with none of the controls (13). OHSS is characterized by increased vascular permeability and transudation of protein-rich fluid from the vascular space into the peritoneal cavity. The incidence of severe OHSS ranges between 0.6 and 1.9 but may occur as frequently as 6 in women with polycystic ovary PCOS (34-36). Severe OHSS is characterized by ascites, plural effusion, and electrolyte imbalances. While there is no successful strategy to completely predict and prevent this potentially life-threatening complication, patients are commonly identified when the serum E2 concentration is high (10,00015,000 pmol L) and the number of ovarian follicles is greater than 20. Although follicular puncture 8. Metformin...

Glucocorticoids for Ovulation Induction

The role of adrenal hyperandrogenism in producing oligo-ovulation is unclear, because both dehydroepiandrosterone and dehydroepiandrosterone sulfate (DHEAS) are relatively weak androgens. Nevertheless, DHEAS circulates in a concentration 10,000 times that of testosterone, and thus may result in significant androgenicity. Furthermore, circulating DHEAS has been found to be the precursor for almost 50 of testosterone within follicular fluid in women being treated with menotropins (48). Thus, it is possible that excess circulating DHEAS results in elevated levels of intrafollicular testosterone and a higher risk of follicular atresia. Consistent with this, a number of investigators have suggested a beneficial effect of glucocorticoid administration, alone or in combination with other agents, on ovulatory function in these patients (49-51). We prospectively studied the impact of dexamethasone 0.5 mg day for 4 months in 36 hirsute oligo-ovulatory patients (58). Ovulatory function was...

Dermatological Abnormalities Hirsutism Acne and Androgenic Alopecia

We should note that hirsutism is one of the more common signs of androgen excess, in particular in PCOS (10), which has significant psychosocial and quality-of-life implications (56,57). The prevalence and degree of hirsutism, however, is dependent on the ethnicity of the patients apparently it is less prevalent in women with PCOS of East Asian extraction or Pacific Islanders (58,59) but more prevalent in women of Asian Indian origin (e.g., Bengali, Gujarati, or Dravidian Indian) (60). Overall, approximately 70 of white and black women with PCOS will be hirsute, a figure we used to calculate economic burden. Acne has been reported to affect 12-14 of white PCOS patients (10,60), although the prevalence of this dermatological abnormality also varies with ethnicity. It is reportedly higher in Asian Indians (60) and lower in Pacific Islanders (58). Androgenic alopecia is a recognized sign of PCOS (61-63) however, in a study of 257 androgen excess patients undergoing treatment, only 12...

Background 21 Cosmetic Procedures

Self-reported severity of facial hair and time spent on hair removal in a randomized controlled trial carried out in 88 women with PCOS (9). A retrospective study assessed 242 patients with hirsutism who received diode laser treatments over 4 years (10). After an average of two treatments (range 16), a sufficient reduction in terminal hairs was achieved for a mean period of 8 months, and the hair-plucking interval was raised from a mean of 3.7 days before treatment to 15.2 days after laser epilation. The procedure was well accepted by about 80 of the subjects. At least in the short term, ruby, alexandrite, and diode lasers or the intense pulsed light resulted in similar success rates. The long-pulsed diode and Nd YAG wavelength-based laser systems are best suited to treat patients with darker skin.

Effect of Thiazolidinediones on Anovulation and Infertility 2221 Effects of Thiazolidinedione Monotherapy

As described earlier, the largest long-term study evaluating the use of an insulin-sensitizing agent in PCOS has been conducted with troglitazone. In this study, troglitazone (150, 300, or 600 mg daily) was compared to placebo in 305 women with PCOS for 44 weeks (10). Women receiving troglitazone daily at the 300- and 600-mg doses had significantly higher ovulation rates than those receiving placebo. This increase in ovulation rate was dose dependent, suggesting that improvement in insulin sensitivity ameliorated the anovulation in PCOS. However, because of liver toxicity, troglitazone is on longer commercially available. The newer thiazolidinediones rosiglitazone and pioglitazone have subsequently been evaluated in women with PCOS. In a small study involving 12 obese women with PCOS, rosiglitazone 4 mg daily was administered for 4 months (28). Rosiglitazone therapy restored regular ovulatory cycles in 11 of the 12 women studied. Serum androgen levels and insulin sensitivity also...

Insulin Sensitizers and Pregnancy Outcomes

Although ovulatory dysfunction is an important etiological feature of the infertility of PCOS, ovulation is only one aspect of fertility. In addition to ovulatory problems, women with PCOS suffer a high rate of early pregnancy loss (EPL) during the first trimester (30-50 in PCOS vs 10-15 in normal women) (38-42). It is possible that insulin resistance may contribute to EPL by adversely affecting the endometrial environment and or endometrial function. The effect of metformin on endometrial function has been studied using surrogate markers, such as circulating levels of glycodelin and insulin-like growth factor binding protein-1(IGFBP-1) (43). Glycodelin is secreted by endometrial glands (44,45) to lessen the endometrial immune response against the developing embryo (46,47). Decreased endometrial secretion of glycodelin has been associated with EPL (48,49). IGFBP-1 modulates adhesion processes at the feto maternal interface (50,51) and hence may be important in the peri-implantation...

When Should Insulin Sensitizers Be Used for Ovulation Induction

In the scenario where a woman with PCOS desires pregnancy but time to achieving pregnancy is not of essence, current evidence suggests it would be reasonable to use metformin as an initial therapy combined with lifestyle intervention. If metformin therapy is not successful in increasing ovulation, clomiphene should be added to metformin therapy. While waiting for the results of prospective randomized studies, the addition of metformin may be beneficial for the establishment and maintenance of pregnancy in women with PCOS who have a prior history of spontaneous abortions after conceiving with clomiphene. In order to establish the optimal therapy or combination of therapies to achieve pregnancy most efficiently, the National Institutes of Health's Reproductive Medicine Network is conducting the Pregnancy in Polycystic Ovary Syndrome (PPCOS) study. The PPCOS study is a randomized, doubleblind controlled trial comparing three regimens in women with PCOS desiring pregnancy (a) monotherapy...

Conclusion And Future Avenues Of Investigation

The diagnosis of drug-induced androgen excess is often evident except in the case of illegal administration of anabolic androgenic steroids. However, other etiologies of hyperandrogenism should not be ignored, particularly an androgen-secreting tumor or PCOS (which may also be induced or worsened by certain drugs). Our knowledge of the physiological mechanisms underlying drug-induced hyperandrogenism continues to develop, particularly concerning VPA. Indeed, this common antiepileptic drug has been suggested to induce a PCOS-like phenotype. The role of the weight gain often associated with VPA treatment in the development of reproductive disturbances is still unclear. Further investigations are required to elucidate the mechanism underlying the interaction between VPA and ovarian theca cells. These studies have the potential for improving our understanding of the mechanisms underlying ovarian hyperandrogenism in PCOS, because this molecule induces alteration of ovarian steroidogenic...

Hirsutism and Unwanted Hair Growth

Complaints of unwanted hair growth or clinical evidence of hirsutism are important predictors of an androgen excess disorder. In studies of large populations of hirsute women seeking care, 50-75 demonstrate PCOS (12,25,27,28). It is also important to note that the sole complaint of unwanted hair growth in the absence of frank hirsutism on physical examination may also signal the presence of PCOS. In one study, approximately 50 of 288 women complaining of unwanted excess facial or body hair growth with minimal hair growth on examination (i.e., a modified Ferriman-Gallwey mFG score of 5 or less) demonstrated PCOS on further evaluation (29).

Insulin Sensitizing Agents

Insulin resistance with compensatory hyperinsulinemia is a prominent feature of PCOS diagnosed in both lean and obese patients (see Chapter 24). The exact mechanisms for abnormalities of insulin action in the syndrome have yet to be elucidated (65). However, hyperinsulinemia has been show to increase ovarian androgen biosynthesis (66) and decrease hepatic synthesis of SHBG (67), leading to increased bioavailability of free androgens. The increase in local ovarian androgen production mediated by hyperinsulinemia can also result in premature follicular atresia and anovulation (68). The strong association between PCOS and insulin resistance and the role of hyperinsulinemia in hyperandrogenism and disrupted folliculogenesis provide the rationale for the use of insulin sensitizers in the treatment of the syndrome. It seems logical that the therapeutic interventions directed at increasing insulin sensitivity, thereby decreasing hyperinsulinemia, would ameliorate the hyperandrogenism and...

Differential Diagnosis Of Polycistic Ovaran Syndrome

Pugeat M, Nicolas MH, Craves J, et al. Androgens in polycystic ovary syndrome. Ann NY Acad Sci 1993 687 124-135. 33. Rosenfield RM, Cohen RM, Talemran A. Lipid cell tumor of the ovary in reference to adult onset congenital adrenal hyperplasic and polycystic ovary syndrome. J Reprod Med 1987 32 363-366. 34. Kaltsa GA, Isidori AM, Kola BP, et al. The value of the low-dose dexamethasone suppression test in the differential diagnosis of hyperandrogenism in women. J Clin Endocrinol Metab 2003 88 2634-2643. 42. Kaltas GA, Isidori A, Besser GM, Grossman AB. Secondary forms of polycystic ovary syndrome. Trends Endocrinol Metab 2004 15 204-210.

Second Edition

Androgen Excess Disorders in Women F. Kushner and Daniel H. Bessesen, 2007 Androgen Excess Disorders in Women Polycystic Ovary Syndrome and Other Disorders, Second Edition, edited by Ricardo Azziz, John E. Nestler, and Didier Dewailly, 2006 Androgen Excess Disorders in Women


Male-like hair growth and masculinization of women and the ambiguity of genders has fascinated mankind for millennia, frequently appearing in mythology and the arts. The earliest reports of androgen excess, beginning 400 years bc, focused on the appearance of male-like hair growth and features in women, often accompanied by menstrual cessation. The first etiologies identified as a cause of androgenization in the female were adrenal disorders, primarily adrenocortical neoplasms, but also eventually adrenal hyperplasia. The first report of a patient with nonclassic adrenal hyperplasia (NCAH) was made in 1957. The Achard-Thiers syndrome, which was originally reported in 1921 and was felt to primarily affect postmenopausal women, included the development of diabetes mellitus, hirsutism, and menstrual irregularity or amenorrhea in conjunction with adrenocortical disease. Androgen production by the ovary was not recognized until the early 1900s, with the first case of a patient with glucose...


Tumor Kupferstich

Hyperandrogenism in Mythology and the Arts Hyperandrogenized women have frequently been held as a curiosity for all to view. Caufield recounts the story told by one D. George Sagari describing the case of the 22-year-old Augustina Barbara, daughter of Balthazer Ursler (or Ulster), whose whole body and face was covered by yellowish hair, including a thick beard that reached her girdle he noted that her husband had married her . . . merely to make a shew of her, for which purpose he traveled into various countries . . . (6). The famous Julia Pastrana, the Nondescript or Bearded and Hairy Lady, a 23-year-old of Mexican origin, attracted throngs of gawkers during her tour of Britain in 1857 (7). However, it is likely that neither of these cases represented women solely with hyperandrogenism, as they appeared to suffer far more extensive hair growth and, at least in the case of Pastrana, facial distortion (8). 2.2. Hyperandrogenism in Ancient Medicine 2.4. Insulin Resistance, Glucose...


A promoter VNTR was linked and associated with PCOS and or insulin sensitivity in women with polycystic ovaries in some studies but not others. Analysis of multiple data sets showed no association of the VNTR with PCOS or testosterone levels. An SNP in the tyrosine kinase domain was associated with PCOS, particularly in lean women. Other studies of the insulin receptor in women with PCOS have identified only common, silent polymorphisms. Two independent studies have reported linkage and association of the micro satellite marker D19S884 with PCOS. A study of Italian and Spanish women with PCOS failed to confirm this association. Variants of both IRS1 and IRS2 were found to influence fasting insulin and postload glucose levels, respectively, in women with PCOS. IRS1 was associated with PCOS and with adolescent hyperandrogenism and obese insulin-resistant PCOS. IRS1 genotype influenced response to metformin in PCOS. IRS1 was not found to be linked or associated with PCOS or...


Whereas menstrual irregularity is a common and defining feature of PCOS and other androgen excess conditions in women, the understanding of the pathophysiology of these conditions will help to create newer treatment modalities that address not only the patients' concerns for immediate care, but also the long-term risks associated with it, for which the physician is ultimately responsible. With PCOS now encompassing a wide variety of heterogeneous presentations, work needs to be done to identify which subsets are at greatest risk of endometrial neoplasia, and hence requiring prophylactic measures to prevent associated morbidity and mortality.

Pulsatile GnRH

Exogenous pulsatile GnRH has been used in an attempt to simulate the physiological pattern of pulsatile gonadotropin secretion, with the expected outcome of monofollicular development. It was suggested that this approach was more physiological, potentially avoiding the risks of OHSS and multiple gestation. However, the results in women with PCOS have not been promising (94,95). Exogenous GnRH stimulation often caused brisk gonadotropin secretion that resulted in the maturation of more than a single dominant follicle with a high risk of multiple pregnancy. Even after pre-treatment with a GnRH agonist, the rates of ovulation and pregnancy were low and miscarriage rates were as high as 45 (95). Thus, pulsatile GnRH therapy is rarely used today for ovulation induction in women with PCOS (96).

Seborrhea andor Acne

The prevalence of androgen excess among acneic-only patients (excluding patients with hirsutism) is less than among hirsute women. In small studies, between 20 and 40 of patients with treatment-resistant acne and without menstrual disturbance, alopecia, or hirsutism are reported to have androgen excess, principally PCOS (30-33). Alternatively, data regarding the predictive ability of seborrhea for androgen excess is lacking. Large populational studies of acneic or hyperseborrheic patients, particularly those without other evidence of hyperandrogenism (e.g., hirsutism), are then still needed to better define this prevalence.

Clomiphene Citrate

The antiestrogenic compound clomiphene citrate currently represents the first-line medical treatment of ovulatory dysfunction in PCOS. This easy-to-use, convenient, inexpensive, and relatively safe drug has been used extensively since the first report of clomiphene-induced ovulation in 1961 (18) and its first approval for clinical use by the US Food and Drug Administration (FDA) in 1967. Clomiphene is an oral synthetic triphenylethylene derivative with estrogen agonist antagonist characteristics (19). The clinically available preparations contain an approximate 3 2 mixture of two stereoisomers, enclomiphene and zuclomiphene, which show distinctly different patterns of agonistic and antagonistic activity in vitro (20). Clomiphene is metabolized in the liver, and its biological half-life is reported to be 5 days (21). The drug is contraindicated in patients with liver disease, endometrial carcinoma, undiagnosed abnormal uterine bleeding, ovarian cysts not rrelated to PCOS, and during...

Pregnancy Rates

Most early studies were of an observational nature and have also been reported in the context of large reviews (2,3). An unfortunate feature of many of the papers that describe laparoscopic treatment wedge resection is the poor characterization of the patients such that many appear to have been ovulating prior to treatment. Furthermore, as the polycystic ovary becomes more sensitive to either endogenous or exogenous FSH after LOD, many practitioners have taken a pragmatic approach by commencing ovarian stimulation with either clomiphene or gonadotropins if ovulatory activity is not immediately induced (30,31). The first RCT suggested that LOD was as effective as routine gonadotropin therapy in the treatment of clomiphene-insensitive PCOS (29). In this study 88 patients were randomized prospectively to receive either human menopausal gonadotropin, FSH, or LOD. There were no differences in the rates of ovulation or pregnancy between the two groups, although those treated with LOD had...


Alternatively, spironolactone may sometimes improve amenorrhea in women with PCOS. In this regard, a recent study reported similar rates of improvement in menstruation with spironolactone or metformin therapy (19). However, when using this drug, the frequency of menstruation cannot be used as a surrogate marker of improved ovulation. Increased diuresis, breast tenderness, and abdominal discomfort are other frequently reported mild side effects of spironolactone, at least with high


Wedge resection of the ovaries was initially described by Stein and Leventhal (1) at the time that polycystic ovaries were diagnosed during a laparotomy. It was found that ovarian biopsies taken to make the diagnosis led to subsequent ovulation. The rationale was to normalize ovarian size and hence the endocrinopathy by removing between 50 and 75 of each ovary. A large review of 187 reports summarized data on 1079 ovarian wedge resections, with overall rates of ovulation of 80 and pregnancy of 62.5 (range 13.5-89.5 ) (2). Another 30 or so years later, Donesky and Adashi (3) were able to increase the summarized experience in the literature to 1766 treatments, with an average pregnancy rate of 58.8 . Because of the realization that significant postoperative adhesion formation occurred and that initial favorable reports of pregnancy rates were not sustained, wedge resection became less popular in the 1970s the same time medical therapies for ovulation induction appeared more successful.

Laboratory Analysis

The laboratory analysis has multiple objectives, including the confirmation of androgen excess (i.e., by the presence of hyperandrogenemia), which we briefly discuss here. We should note that laboratory testing will also be used for the exclusion of related or specific androgen excess disorders and the identification of associated morbidities. Androgen excess can be determined by measuring the circulating androgen levels, with supranormal levels (i.e., hyperandrogenemia) constituting evidence of androgen excess. However, a number of pitfalls should be considered when measuring androgens (Table 3). (The nuances and limitations of the currently used androgen assays are discussed in detail in Chapter 5.) Consequently, it is preferable to rely on the measurement of androgens primarily in those patients without clinical evidence of hyperandrogenism, i.e., without clinically apparent hirsutism. These may include adolescents and women of certain Asian ethnic origins. The choice of androgen...


Androgen-secreting neoplasms are generally associated with distinct clinical features and presentations, and are associated with rapidly progressive symptoms of hyperandrogenism that generally result in various degrees of virilization. The patient's history and clinical presentation are strong predictors for ASNs. A plasma concentration of testosterone greater than 200 ng dL (8.7 nmol L) (or two to three times the upper normal range) with a normal DHEAS level is highly suggestive of an ovarian ASN. A combined increased testosterone of greater than 200 ng dL (8.7 nmol L) with an elevated DHEAS level of more than 600 g dL (16.3 mol L) is highly suggestive of an adrenal ASN. Suppression and stimulation testing has a high degree of sensitivity, albeit low specificity, for the diagnosis of ASNs and is generally of limited value in the diagnosis of these neoplasms. Ovarian and adrenal venous catheterization and sampling should be reserved for patients in whom the presence of a small ovarian...

Ovarian Sonography

The nuances of ovarian morphology have been reviewed in Chapter 16. It is important here to note that because polycystic ovarian morphology has become an integral part of the diagnosis of PCOS, patients suspected of having androgen excess should undergo transvaginal sonography when possible. Importantly, the definition of polycystic-appearing ovaries is relatively uniform and specific. It should also be understood that although virginal women and others who do not tolerate a transvaginal ultrasound probe can undergo transabdominal ultrasonography for ovarian examination, this latter method is considerably less sensitive than the transvaginal approach (26). 2.4. Predictive Value of the Clinical Features Observed in Patients With Possible Androgen Excess Clinical experience has indicated that the majority of women with signs of virilization (i.e., mas-culinization of body muscular, severe or extreme male-pattern balding or hirsutism, clitoromegaly, etc.) will have androgen excess....

In Vitro Maturation

Transvaginal Oocyte Recovery

The recovery of immature oocytes (Fig. 4) followed by IVM and IVF is an attractive alternative to conventional IVF treatment in which controlled ovarian stimulation with gonadotropins is used to increase the number of available oocytes and embryos (41). Significant progress has been made in improving implantation and pregnancy rates from in vitro matured oocytes (Fig. 4). The high numbers of antral follicles in patients with polycystic ovaries or PCOS make them prime candidates for IVM treatment, even if the appearance of polycystic ovaries in the scan is not associated with an ovulation disorder. Indeed, the main determinant of clinical success rates of IVM treatment is antral follicle count (42). When hCG priming is used before oocyte retrieval, it has been found that immature oocytes retrieved from normal ovaries, polycystic ovaries, or women with PCOS have a similarly high maturation, fertilization, and cleavage potential (43). However, although the implantation rate was lower,...


PCOS, polycystic ovary syndrome IGT, impaired glucose tolerance. (Adapted from ref. 8.) PCOS, polycystic ovary syndrome IGT, impaired glucose tolerance. (Adapted from ref. 8.) weight in kg divided by height in m2 ), women with PCOS have a higher percentage of body fat and a larger waist-to-hip ratio (7) than their matched controls. Clinical manifestations of PCOS are different in obese women with PCOS compared with lean women with PCOS (8) (Table 1). Obese women with PCOS report more menstrual irregularities and more oligo- amenorrhea than their lean counterparts. Obesity is also associated with an increased prevalence of infertility in PCOS and in the general population as well. The risk of miscarriage is also increased in obese women, whether or not they have PCOS. Moreover, obesity increases the risk of complications during pregnancy, such as gestational diabetes and pre-eclampsia (9). Finally, obese women with PCOS tend to have higher hirsutism and acne scores than lean PCOS...


Androgenization of women has captivated humankind for millennia, with early recognition of the relationship between menstrual dysfunction and the development of hirsutism and other virilizing features. Most early patients described appeared to suffer from ovarian or adrenal neoplasms, such that the hyperandrogenic symptoms were generally marked. Not until the early 20th century were lesser degrees of hyperandrogenism recognized as meriting medical evaluation, and only in the past century have significant strides been made in elucidating the etiology and pathophysiology underlying these disorders. Initially the adrenal cortex was recognized as a potential cause of androgen excess, with androgen-secreting neoplasms and frequently concomitant cushingoid features and later adrenal hyperplasia identified as a cause. Many of these women were also found to develop glucose intolerance or diabetes, a disorder known as diabetes of the bearded woman or the Achard-Thiers syndrome. NCAH was...


Some studies reported that this drug is more effective than spironolactone or finasteride in the treatment of hirsutism. However, differences were small, and all these medications gave similar results in a controlled comparative trial (18). Anecdotal evidence suggests that flutamide is more effective than other drugs in treating androgen-dependent acne, although no controlled study has been specifically designed to assess this aspect. Some studies reported that this drug might have favorable effects on visceral fat and on the lipid profile in patients with PCOS (22,23). These effects are of great interest in subjects who frequently show abdominal obesity, insulin resistance, and multiple metabolic abnormalities.

New Developments and Future Trends

Leukotrienes Inflammatory Mediators

Role in the physiopathology of peripheral hyperandro-genism, including acne 117 . Insulin-sensitizing agents have recently been investigated for their role in the short term treatment of insulin resistance in polycystic ovary syndrome. Controlled studies have shown that metformin administration, by promoting body weight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 X daily to decrease insulin secretion and to reduce ovarian production of 17a-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitizing agents as a novel approach in the treatment of ovarian hyperan-drogenism.

Androgens and Sebum Production

Acne Vulgaris

Severe acne is often associated with elevated serum androgens 11 . Conditions of androgen excess or hyper-androgenism are associated with increased sebum production and the development of acne. Hyperplasia or carcinomas that produce excess androgens (e.g. of the ovary or the adrenal) are often associated with the development of acne. Sudden onset of acne or treatment-resistant acne may be associated with hyperandrogenism from causes such as an adrenal or ovarian tumor or from conditions such as congenital adrenal hyperplasia or polycystic ovary disease. Conversely, it has been observed that men with androgen insensitivity (nonfunctional androgen receptors) do not produce adult levels of sebum and they do not develop acne 7 . This clinical observation implies that a Serum androgens are elevated in cases of acne associated with hyperandrogenism and in cases of severe cystic acne. Serum androgens are however within normal limits in the majority of females with acne. For this reason, it...

Screening for an Endocrine Disorder

A medical history and physical examination directed towards eliciting any symptoms or signs of hyperan-drogenism should be performed. Screening tests for hyperandrogenism include serum DHEAS, total testosterone, free testosterone, and luteinizing hormone follicle-stimulating hormone (LH FSH) ratio. In some cases additional information can be gained from a serum level of 17-hydroxypregnenolone. These tests should be obtained in the luteal phase of the menstrual cycle (within 2 weeks prior to the onset of menses). If a patient is taking oral contraceptives, any underlying hyperandrogenism would be masked. Therefore, it is required that the patients dis

Classification and evolution of increased cardiometabolic risk states

Prevalence Metabolic Obesity

Polycystic ovary syndrome AACE these key clinical signs are considered risk factors. Other risk factors include polycystic ovary syndrome sedentary lifestyle age ethnicity (certain groups) and family history of type 2 diabetes, hypertension, or cardiovascular disease AACE these key clinical signs are considered risk factors. Other risk factors include polycystic ovary syndrome sedentary lifestyle age ethnicity (certain groups) and family history of type 2 diabetes, hypertension, or cardiovascular disease

Fetal Nutrition and Timing of Puberty

Over the last decade growing evidence has been documented on the relationship between intrauterine growth retardation (IUGR) and pubertal development indicating changes in timing and progression of puberty. These changes in pubertal development are part of a growing list of IUGR-related diseases, which includes type 2 diabetes mellitus, cardiovascular disease, short stature and polycystic ovary syndrome. The influence of IUGR on the mechanisms behind the onset of puberty is still elusive. In the absence of prospective studies on gonadotropin-releasing hormone pulse patterns in IUGR children, other markers of pubertal development such as age at menarche in girls and progression of puberty have been employed. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) after third trimester growth retardation and children born appropriate for gestational age (AGA). A faster progression of puberty was found in girls but not in boys. DHEAS levels...

Excessive hair

Hirsuties occurs most commonly after the menopause and may be present to some degree in normal women as a result of familial or racial traits. It may arise without any underlying hormonal disorder or as a result of virilising hormones. These causes are listed in the box on the right. In addition to androgens, a number of drugs can cause hirsuties. It is important to remember that hirsuties may be part of a virilising syndrome or polycystic ovaries. It is useful to measure the serum testosterone and oestrogen level, as well as urinary 17 oxosteroid concentrations.


Although hormones influence acne, it is clear that the majority of acne patients do not have an endocrine disorder. Hyperandrogenism should be considered in female patients whose acne is severe, sudden in its onset or is associated with hirsutism, or irregular menstrual periods. Additional clinical signs of hyperandrogenism include Cushinoid features, increased libido, acanthosis nigricans or a deepening of the voice. Women with hyperandrogenism may also have insulin resistance. They are at risk for the development of diabetes and cardiovascular disease. It is therefore important for the long-term health of these patients to identify hyperandrogenism so that they can receive appropriate therapy from an endocrinologist or gynecologist.

Acne Genetics

The genetic influence on pathogenesis of acne is well documented in twins 30 and genealogic studies. In some types of acne, such as acne conglobata, hereditary factors are more apparent, and a correlation has been suggested between neonatal acne and familial hyperandrogenism 4 . Nodulocystic IA is often observed in relatives of patients with extensive steatocystoma, adolescent and postadolescent acne 31 . Fifty percent of postadolescent acne patients have at least one first-degree relative with the condition 32 . 4 Bekaert C, Song M, Delvigne A Acne neonato-rum and familial hyperandrogenism. Dermatology 1998 196 453-454. 9 Rosenfield RL Hyperandrogenism in peripu-bertal girls. Pediatr Clin N Am 1990 37 1333-1358. 12 De Raeva L, De Schepper J, Smitz J Prepuber-tal acne Cutaneous marker of androgen excess J Am Acad Dermatol 1995 32 181-184.

Prepubertal Acne

Adrenarche presents with high levels of DHEA and DHEAS that start rising at 6-7 years in girls and 7-8 years in boys and follow increasing during mid puberty. Excessive androgen production may result due to adrenal hyperandrogenism (exaggerated adrenarche, exuberant production of adrenal androgens relative to cortisol), congenital adrenal hyperplasia, Cushing's disease, 21-hyroxy-lase deficiency, and more rarely androgen producing tumors. Ovarian contribution to androgens can be through tumors (malignant and benign), but most commonly due to polycystic ovarian disease associated very often with obesity, persistent or resistant acne and insulin resistance 3, 12 .

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