Dr. Claudio Parra G.

Med Clin N Am 92 (2008) 11631192

Basic Infertility Including Polycystic Ovary Syndrome

Maryse Brassard, MDa, Youssef AinMelk, MDb, Jean-Patrice Baillargeon, MD, MSca,*
a

Division of Endocrinology, Department of Medicine, Universite de Sherbrooke, 3001, 12th North Avenue, Sherbrooke, QC J1H 5N4, Canada b Department of Obstetrics and Gynecology, Universite de Sherbrooke, 3001, 12th North Avenue, Sherbrooke, QC J1H 5N4, Canada

Infertility is the inability of a couple to conceive after 12 months of unprotected and frequent intercourse. It aects about 10% to 15% of couples [1]. Cycle fecundability is the probability that a single cycle will result in pregnancy and is approximately 20% in normal couples [2]. It typically decreases with age. The fertility rate in developed countries has declined in recent years and can be attributed mainly to delayed childbearing. The eect of aging on female fertility is clear: In women, the fertility peak is between the ages of 20 and 24 years, decreases slightly by age 32, and then declines progressively and more rapidly after age 40 [3,4]. Decreasing fertility is associated with increasing pregnancy wastage. Spontaneous miscarriage increases from 10% in younger women to 40% at age 40, even with assisted reproductive technology. This increase is due to progressive follicular depletion and a high incidence of abnormalities in aging oocytes, mainly aneuploidy. In addition to age, other factors that inuence fertility include lifestyle (smoking, alcohol, caeine, drugs, and body mass index) and the timing and frequency of intercourse. Normal sperm can survive at least 3 days, but an oocyte can be fertilized for only 12 to 24 hours. The major causes of infertility include tubal and peritoneal pathology (30%40%), ovulatory dysfunction (15%), and male factor (30%40%) [5]. Uterine and cervical factors are uncommon. Patients without an

This work was supported by Personal Award #12131 to Jean-Patrice Baillargeon from the Fonds de la recherche en sante du Quebec. * Corresponding author. E-mail address: jp.baillargeon@usherbrooke.ca (J-P. Baillargeon). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.008 medical.theclinics.com

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identiable cause are classied as unexplained infertility (10%). Ovulatory dysfunction and unexplained infertility have the best prognosis. This article reviews the evaluation and treatment of female infertility.

Initial evaluation The evaluation should be initiated after 12 months of unprotected intercourse, at which time 85% of couples attempting conception will have been successful [6]. In women between 35 and 40 years of age, assessment should be considered after 6 months. In such females with oligomenorrhea or amenorrhea, or a history of pelvic infection or chemotherapy [1], assessment should be considered sooner. Initial evaluation includes a complete medical history, physical examination, and screening tests for cervical dysplasia and sexually transmitted infections, including gonorrhea and chlamydia. Basic testing consists of semen analysis, documentation of ovulation (eg, midluteal phase progesterone level above 6.5 ng/mL followed by menstrual bleeding within 2 weeks), and a hysterosalpingogram to assess possible tubal factors. If an obvious cause, such as oligoanovulation, is determined during initial clinical evaluation, semen analysis and hysterosalpingogram can be postponed until after resolution of this condition, assuming that infertility persists. The next steps in the evaluation of female infertility are based on the most probable causes initially identied. These are discussed in this article and summarized in Fig. 1.

Tubal and peritoneal pathology Tubal factors Approximately 20% of female infertility results from tubal disease. This disease can be suspected by a history of pelvic infection disease (PID), tubal or pelvic surgery, or ectopic pregnancy. Infection by Chlamydia trachomatis is one of the main causes of tubal injury, which can ultimately lead to tubal occlusion or adnexal adhesions. Subclinical salpingitis is even more common than symptomatic PID, and can occur despite appropriate antibiotic therapy. The incidence of tubal disease is 10% after one episode of PID and 54% to 75% after three episodes [7]. The mechanism involves anatomic abnormalities in the tubes that prevent the union of sperm and ovum. The classic methods for evaluation of tubal patency are hysterosalpingography (HSG) and laparoscopy with chromotubation. HSG is performed by injecting water-soluble contrast through the cervix into the uterus. HSG images the uterine cavity and reveals the internal architecture and patency of the tubal lumen. Laparoscopy is regarded as the denitive test for the evaluation of tubal factors. It provides more detailed information, such as

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Domapine agonist Lthyroxine Insulin sensitization Ovulation inductors

Prolactin Ovulatory cycles No TSH Androgens Yes

Hyper Hypo PCOS

Not pregnant Male factor Semen analysis Tubal assessment Abnormal Tubal damage Endometriosis Normal

Pregnant

Donor insemination IVF Surgery Medical or surgical treatment

Not pregnant Unexplained infertility

Pregnant

Ovulation inductorsIUI

GonadotropinsIUI

Fig. 1. Algorithm for investigation and treatment of infertile women. IUI, intrauterine insemination; IVF, in vitro fertilization; PCOS, polycystic ovary syndrome; TSH, thyroid-stimulating hormone.

pelvic anatomy, adhesions, and endometriosis. Laparoscopy also oers the opportunity to treat disease at the time of diagnosis. Chlamydia antibody testing has been shown to be as predictive as HSG, or even laparoscopy, for the detection of tubal pathology [8]. The role of chlamydia antibody tests in the evaluation of the infertile women has not yet been dened, but may prove useful as a pretest to select women who warrant earlier or more detailed evaluations [2,9]. The treatment options for tubal factors include reconstructive surgery and in vitro fertilization (IVF). In selected cases, a microsurgical procedure, such as mbriolysis and mbrioplasty, may be used. In most cases, especially in older women, IVF is more ecient and more eective [10]. Uterine factor Abnormalities of the uterine cavity are a relatively uncommon cause of infertility. Abnormalities include congenital malformations, such as a septum or bicornuate uterus, leiomyomas, intrauterine adhesions (Ashermans syndrome), and endometrial polyps. Uterine abnormalities more commonly aect pregnancy outcome than fertility. Assessment of the uterine cavity can be obtained by HSG, transvaginal ultrasound (for uterine malformations

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and myomas), sonohysterography (for submucosal myomas and endometrial polyps), hysteroscopy (the denitive method for diagnosis and treatment of intrauterine pathology), MRI, and laparoscopy. The management of uterine myoma in infertile women must be individualized. The decision for surgical treatment varies depending on age and duration of infertility after excluding other infertility factors [11]. It appears that submucous myomas can lower the rate of pregnancy and implantation [12]. In one study, myomectomy for a submucous myoma increased the pregnancy rate from 27.2% (no treatment) to 43.3% (myomectomy), though there was no improvement in the pregnancy rate following myomectomy in locations outside the uterine cavity. For intrauterine adhesions (ie, synechiae), predisposing events can usually be identied, such as pregnancy termination or postpartum curettage. The presence of adhesions can be conrmed by HSG, though hysteroscopy is considered the preferred technique for diagnosis and treatment [13]. Hysteroscopy is also appropriate for diagnosis and treatment of uterine septum. Cervical factor Cervical mucus is important in the reproductive process. Estrogen stimulates cervical mucus while progesterone inhibits its production and permeability. The traditional postcoital test, the Sims-Huhner test, has a poor predictive value for infertility and its utility has been debated. Routine postcoital testing is not recommended [6]. Because there is no good method for diagnosing infertility due to cervical factor, that diagnosis is usually a one of exclusion when ovulation and semen analyses are normal and the tubes are patent. It is usually included in unexplained infertility (see Fig. 1). Common treatments for cervical factor infertility bypass the cervix and include intrauterine insemination and IVF. Endometriosis There is a higher incidence of endometriosis in infertile women (25% 48%) as compared with all women in the reproductive age group (3%10%) [2]. Despite this association, a causal link between endometriosis and infertility has not been clearly demonstrated and management of infertility associated with endometriosis remains challenging. In severe endometriosis, pelvic adhesions can clearly distort the relationship of the tubal mbria and ovarian follicles with resulting infertility. In minimal and mild endometriosis, mechanisms that cause reproductive failure are subtler and remain controversial. They include alterations in peritoneal uid as a result of inammatory factors (macrophages, cytokines, and growth factors). Such alterations can aect ovum maturation, fertilization, or implantation. Endocrine and ovulatory abnormalities are among other mechanisms that may cause reproductive failure in minimal and mild endometriosis [14,15].

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Fecundity in women with untreated endometriosis is only 2% to 3% per cycle, far below the normal monthly rate of 20%. The medical treatment of endometriosis with a period of ovulation suppression does not improve subsequent fecundity and fertility [2]. Conservative surgical therapy, such as ablation of endometriosis implants, can improve the fecundity in patients with severe disease by up to 50%, but is still controversial in patients with mild endometriosis. A randomized trial of laparoscopic ablation treatment for minimal or mild endometriosis demonstrated a signicant increase in the rate of pregnancy [16]. Thirty-six weeks after surgery, 29% of treated women achieved an ongoing pregnancy compared with 17% of those who were not treated. However, a smaller Italian trial with similar design and laparoscopic ablation therapy showed no eect on live birth rate [17]. Other approaches to consider for treatment of endometriosis are expectant management, superovulation with intrauterine insemination for young patients (!35 years old), or IVF for older women (O35 years old). For more advanced cases, IVF preceded by 3 months of medical treatment for endometriosis is suggested.

Ovulatory dysfunction Ovulatory dysfunction is associated with infertility and is usually manifested either by oligomenorrhea, dened as eight or fewer menstrual periods per year, or amenorrhea, dened as the absence of menstrual bleeding. This lack of menstrual periods may be classied as primary or secondary. Primary amenorrhea refers to absence of menses by the age of 14 years in the absence of secondary sexual characteristics or by the age of 16 years in the presence of secondary sexual characteristics. Secondary amenorrhea applies to women who have not menstruated for at least 6 months but who have previously menstruated. Furthermore, it is estimated that about 10% of normal menstrual cycles of 35 days or less are actually anovulatory. The causes of ovulatory dysfunction are discussed below. Hypogonadotropic hypogonadism Hypogonadism is dened as an abnormal decrease in the functional capacity of the gonads and is classied as hypergonadotropic or hypogonadotropic, depending on whether the disease is of gonadal or pituitary/ hypothalamic origin. In the presence of abnormal sex hormones and gamete production, low levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are indicative of hypogonadotropic disease, whereas high levels reect a hypergonadotropic hypogonadism. Causes of hypogonadotropic hypogonadism are listed in Box 1. Patients with Kallmann syndrome have hypogonadotropic hypogonadism along with anosmia. The clinical feature of anosmia relates to the embryologic development of gonadotrophin-releasing hormone (GnRH)

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Box 1. Causes of hypogonatotropic hypogonadism Kallmann syndrome Functional hypothalamic amenorrhea, including eating disorders, intense exercise, stress from systemic disease Iatrogenic causes from drugs, pituitary surgery, cranial radiation Tumors of the central nervous system Sheehans syndrome, trauma Inltrative disorders of the pituitary Hyperprolactinemia

neurones. Kallmann syndrome is a genetically heterogeneous condition and aects 1 in 70,000 females [18]. In addition to anosmia, other possible features of Kallmann syndrome include unilateral renal agenesis, synkinesia (mirror movements), hearing loss, midline facial defects, cryptorchidism, and bone abnormalities [1921]. Recently, scientists have isolated the KAL gene as a cause of at least some forms of Kallmann syndrome [2225]. Functional hypothalamic amenorrhea is one of the most frequently encountered forms of ovulation dysfunction. This endocrine disorder is due to a deciency of pulsatile GnRH secretion unrelated to hypothalamicpituitary organic lesions nor endocrine or systemic diseases [26,27]. Based on the degree of GnRH suppression, these women can present with dierent clinical proles that vary from an inadequate luteal phase, to anovulation with menstrual irregularity, to hypothalamic amenorrhea [27]. The incidence of functional hypothalamic amenorrhea ranges from 15% to 48% [28,29] of women with secondary amenorrhea. In clinical practice, functional hypothalamic amenorrhea is often associated with stressors (metabolic, physical, or psychologic), with weight loss due to decreased caloric intake, or with intensive physical exercise [26]. Statistics show that the prevalence of reproductive dysfunction is 6% to 79% in athletic women [30]. Suppression of gonadotrophin release may occur when there is acute [31,32] or chronic [33,34] systemic disease, which can acutely suppress the hypothalamic-pituitary-gonadal (HPG) axis. Chronic systemic illnesses most associated with hypothalamic-pituitary dysfunction include chronic renal failure and AIDS. Acute illnesses, in turn, may lead to transient forms of either hypogonadotropic or hypogonadotropic hypogonadism [35,36]. In fact, suppression of the GnRH pulse generator in response to the physiologic stress of any severe illness inhibits the release of pituitary gonadotropins [31,32] in the same way that excessive exercise does. A few drugs are incriminated in the pathogenesis of hypogonadotrophic hypogonadism. Opioid use is the most common cause of iatrogenic hypogonadism, and it may have a toxic eect on the reproductive axis. The mechanism of amenorrhea in opioid users is probably attributable to

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opioid-induced hypothalamic GnRH suppression [37]. Other drugs causing infertility are certain psychotropic drugs, such as phenothiazines and risperidone, which block prolactin-inhibiting dopamine release [38,39]. Also, anabolic androgenic steroids can cause hyperandrogenism and menstrual irregularity. Most central causes of hypogonadism that are organic in nature can be attributed to pituitary and hypothalamic lesions. Other causes of structural etiology include inltrative diseases, such as sarcoidosis, histiocytosis, and hemochromatosis; head trauma; pituitary apoplexy; and cranial irradiation or surgery. Tumors of the central nervous system, such as craniopharyngiomas, germinomas, and other extrasellar germ cell tumors, may interfere with FSH secretion and lead to ovulatory function failure. Patients who have low levels of other hormones, symptoms of a pituitary tumor (such as frontal headache or reduced visual elds), or increased prolactin levels not due to medication, warrant pituitary MRI. Pituitary imaging is also required when drug-related hyperprolactinemia is associated with one of these factors. The impact of elevated prolactin on the gonads is hypothesized to result from disruption of normal GnRH pulsatility and consequent alterations in the secretion of FSH and LH [40]. The clinical expression is anovulation, with either amenorrhea or oligomenorrhea in most women, as well as galactorrhea and decreased libido. Hyperprolactinemia can be divided into pituitary and nonpituitary causes. Pituitary causes include prolactinsecreting adenomas, nonsecreting pituitary tumors or cysts, and idiopathic hyperprolactinemia. Any disruption of the pituitary stalk, usually by macroadenomas, can lead to failure of the normal hypothalamic suppression of prolactin by dopamine. Nonpituitary causes of hyperprolactinemia are common and include pregnancy, hypothyroidism, and dopamine-antagonist drug therapy (eg, phenothiazines and metoclopramide). Some women with polycystic ovary syndrome (PCOS) have mild hyperprolactinemia [41]. Treating prolactinomas or idiopathic hyperprolactinemia with dopamine agonists reduces tumor size and prolactin levels, normalizes abnormal sexual function, and improves fertility. Hypergonadotropic hypogonadism Premature ovarian failure (POF) is diagnosed when sex steroid deciency, elevated gonadotropins, and amenorrhea are found in women under the age of 40 [4244]. Spontaneous 46,XX POF is not a rare condition. The age-specic incidence is approximately 1 in 250 women by age 35 and 1 in 100 by age 40 [43]. In around 10% of patients, the disorder is familial [45]. POF most commonly presents as secondary amenorrhea, though it may present rarely as primary amenorrhea with variable degree of secondary sexual characteristics. As estrogen deciency progresses, vasomotor symptoms and symptoms of atrophic vaginitis eventually become prominent. Women suering from POF are at increased risk of developing a variety

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of comorbidities [46,47] and nearly double their age-specic mortality risk [48]. They are decient in sex steroids and therefore have a signicantly increased risk of osteoporosis [49,50], particularly in those who have developed POF before achieving peak adult bone mass. The risk of cardiovascular disease in POF suerers is also signicantly increased [51,52], which is probably caused by lower high-density lipoprotein cholesterol and higher insulin resistance than those of age-matched premenopausal women [53]. The most troublesome aspect of the disorder for these young women is infertility [54]. Previously, they were considered as irreversibly sterile. However, accumulating evidence has demonstrated that the infertility associated with POF is not absolute. Up to 50% of young women with 46,XX spontaneous POF have remaining follicles in their ovaries [55,56] and are probably more aected by follicular dysfunction than follicular depletion. Studies in women with POF have demonstrated that up to 20% of patients ovulate spontaneously during 4 months of observation, nearly 50% have intermittent ovarian follicle function (as dened by serum estradiol O50 pg/mL) [56], and 5% to 10% unexpectedly became pregnant some time after diagnosis [57,58]. But ovulations are unpredictable, making appropriate timing of intercourse or insemination impossible. There is no evidence that such treatments enhance the pregnancy rate in patients with POF [57]. There are a variety of causes of POF: chromosomal and genetic abnormalities, autoimmune disease, viral infections, and iatrogenic therapies, such as pelvic surgery, chemotherapy, and radiotherapy. In the majority of cases, however, no etiologic factor can be identied [59]. In fetuses with 45,XO karyotype (Turners syndrome), ovaries develop normally in utero. Due to the absence of the second X chromosome, accelerated follicle atresia occurs from week 18 of pregnancy onwards or over the rst few postnatal months and years, leading to POF [60,61]. Mosaicism, typically 45,XO/46,XX or 46,XX/47,XXX, is more common and characterized by a milder clinical phenotype [62]. Other genetic mutations have also been associated with POF [63,64]. However, in the past 3 decades, much evidence has accumulated to suggest that autoimmune mechanisms are involved in pathogenesis of up to 30% of cases of POF [65,66]. Autoimmune lymphocytic oophoritis is a clearly established mechanism of 46,XX spontaneous POF, which can present in an isolated manner or as part of the autoimmune polyendocrinopathy syndrome, type 1 [67]. Women less than 40 years old with 4 or more months of amenorrhea should have an FSH measured with a repeat in 1 month if it is elevated. If two levels are in the menopausal range (O40 IU/L by radioimmunoassay), POF is diagnosed. These women should have a karyotype [44] and thyroid function studies [68] performed. Hypothyroidism, as well as adrenal insuciency, is associated in 3% of cases [69]. Other invasive procedures do not change management or prognosis.

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Providing hormone replacement to induce regular menses is probably indicated in these women to normalize symptoms and decrease the risk of osteoporosis associated with estrogen deciency, to reduce the risk of adenocarcinoma with an eective progestin replacement, and possibly to improve chances of spontaneous pregnancy [70]. However, the eectiveness of this strategy to improve fertility has not been conrmed [71]. Ovulatory dysfunction without hypogonadism Polycystic ovary syndrome Introduction. Dened by Stein and Leventhal [72] in 1935, PCOS is now thought to be the most prevalent endocrine disorder in young women, aecting 6% to 10% [7377] of women of childbearing age and accounting for 70% of anovulatory subfertility [78]. In a British population study, 37% of amenorrheic and 90% of oligomenorrheic women treated for infertility had PCOS [79]. Also, PCOS is one of the major causes of infertility overall, aecting up to 20% of infertile couples in some studies [80,81]. Its diagnosis is important not only for the short-term fertility issue, but also for long-term considerations, such as metabolic or insulin resistance syndrome and its associated consequences. Diagnosis and clinical presentation. Based on criteria established during the European Society of Human Reproduction & Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) consensus conference in Rotterdam in 2003 [82], PCOS is diagnosed in the presence of two factors among the following: menstrual irregularity, hyperandrogenism (clinical or biochemical), and polycystic ovaries after excluding other secondary causes of hyperandrogenism, such as congenital adrenal hyperplasia (CAH), Cushings syndrome, hyperprolactinemia, or an androgen-secreting tumor. This denition has been revised in a published Androgen Excess Society guideline, which recommends that hyperandrogenism be mandatory for the diagnosis of PCOS [83]. Menstrual irregularity typically manifests at the time of menarche in women with PCOS, and menarche may be delayed. Some may have normal menses at rst and then develop menstrual irregularity later in life, often after weight gain. Aected women are typically anovulatory with resulting oligomenorrhea or amenorrhea. Heavy bleeding in this situation is typical of anovulatory menses. Infertility in PCOS is mostly related to this chronic absence or low rate of ovulation, but also to an increased rate of early pregnancy loss. Hyperandrogenism is usually a presenting feature of the syndrome, manifested clinically by hirsutism (excess pigmented body hair with a male distribution), acne, and male-pattern alopecia. Evidence of virilization, such as clitoromegaly, increased muscle mass, and deepening of the voice should raise concern for androgen-secreting neoplasm of the ovary or

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adrenal gland, but can also be the result of hyperthecosis, a rare and extreme form of PCOS. Circulating androgens, especially testosterone and androstenedione, are found to be elevated in 50% to 90% of patients, depending upon the androgen measured and technique employed [84]. The ultrasound criteria for polycystic ovaries [82] are based on the presence of 12 or more 2- to 9-mm follicles in each ovary, or ovarian volume greater than 10 mL. A recent prospective systematic study screened 400 unselected reproductive-aged women in the United States to determine the prevalence of PCOS and performed a phenotyping of the women involved [77]. The proportion of overweight and obese women with PCOS seems to be the same as in the general population. Though the proportion of women with the syndrome is similar in normal and obese patients, obese women often have more severe hormonal and metabolic abnormalities [85]. Indeed, obesity increases the degree of insulin resistance typically found in PCOS women, which plays a key role in PCOS pathophysiology, as discussed below. Pathogenesis. The pathogenesis of PCOS has been controversial. Most experts agree that hyperandrogenemia is the central feature of PCOS [83]. Studies found that greater than 60% of the circulating levels of androgens were of ovarian origin, and about 40% were of adrenal source [86]. Furthermore, increased adrenal and ovarian androgen responses to stimulation by LH [87,88] or corticotropin [89,90], respectively, were found in vivo in women with PCOS. Insulin resistance is also a common characteristic of PCOS, both in obese and nonobese aected women [91]. Insulin resistance primarily refers to impaired action of insulin on glucose metabolism, in the presence of normal insulin binding [92]. In turn, the resulting compensatory hyperinsulinemia [9199], or increased insulin action, leads to exaggerated eects of insulin on other actions, including stimulation of androgen secretion by ovarian and adrenal cells [88,100104]. Insulin can also directly inhibit sex-hormonebinding globulin (SHBG) production [105], increasing the active testosterone fraction. The ovarian and adrenal androgenic hyperresponsiveness to LH and corticotropin that characterizes PCOS women may result from increased chronic insulin stimulation. Indeed, this androgenic hyperresponsiveness has been shown to persist after prolonged LH or corticotropin suppression [88,106,107], but to improve after insulin sensitization (with weight loss, metformin, or peroxisome proliferator-activated receptor g agonists) [108112]. Moreover, our group found that PCOS women, who were nonobese, normoinsulinemic, and normally insulin-sensitive, normalized their hyperandrogenemia with a pure insulin-lowering agent (diazoxide) [113]. These results demonstrated that even normal insulin levels contribute to PCOS hyperandrogenemia. Altogether, these ndings suggest that women may develop PCOS because of increased sensitivity of their androgenic pathway to insulin,

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and not just hyperinsulinemia. This increased sensitivity might be improved with insulin sensitization or reduction [114]. It is probable that only a minority of women with PCOS have a defect severe enough to cause a typical syndrome without insulin resistance. Most women with PCOS must develop insulin resistance with compensatory hyperinsulinemia to further aggravate insulin stimulation of androgen production and express the syndrome. Thus, classical insulin resistance and compensatory hyperinsulinemia are not necessary to develop PCOS, but they favor the clinical expression of PCOS and may result from the same factors as for the general population, which are obesity and a genetic predisposition to insulin resistance. As shown in Fig. 2, the combination of elevated levels of androgens and obesity is thought to lead to increased formation of extraglandular estrogen, termed estrone. This hormone exerts a positive feedback on LH secretion and negative feedback on FSH secretion. Studies have provided conicting results on the ability of insulin to increase the pulsatory rate of GnRH [115121]. It is possible that PCOS women have a higher sensitivity to insulin-stimulated LH production, but that this defect is attenuated in obese women because of other factors, such as leptin resistance, other adipokynes, and higher testosterone levels. In some studies, circulating concentrations of FSH are within the normal range in women with PCOS [122124], but the normal intercycle rise in serum FSH levels is lacking. The increased level

Hypothalamus-Pituitary LH secretion FSH secretion Plasma FSH level Adipose tissue Extraglandular aromatisation Chronic anovulation Follicle maturation

Acyclicestrogen (estrone)

Plasma LH level

Stimulation of stroma Ovary and theca

Obesity Androgen excess

Cyclicestrogen (estradiol)

Adrenal androgen

Fig. 2. Proposed mechanism for the initiation and perpetuation of chronic anovulation in the PCOS. (Adapted from Mishell Jr DR, Davajan V, editors. Reproductive endocrinology, infertility, and contraception. 2nd edition. Philadelphia: Davis; 1986; with permission of Blackwell Publishing; and from Yen SCC, Jae RB, Barbieri RL, et al, editors. Reproductive endocrinology. 4th edition. Philadelphia: Saunders; 1999; with permission of Elsevier Health.)

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of LH can lead to hyperplasia of the ovarian stroma and theca cells and increased ovarian androgen production, which in turn provides more substrate for peripheral aromatization and perpetuates the chronic anovulation. Deregulation of local follicle regulatory systems by androgens and other factors impedes normal follicular growth, resulting in follicular arrest at the 4- to 8-mm diameter size [125]. A dominant follicle (ie, 1825 mm in diameter) does not develop, and therefore ovulation does not occur. Complications. In addition to infertility, patients with PCOS are at risk for many other complications. The overall risk of type 2 diabetes mellitus (T2D) is increased in PCOS, particularly in women with a rst-degree relative with T2D [126129]. In a study of 122 obese women with PCOS, 45% had either impaired glucose tolerance (35%) or T2D (10%) [130]. All obese women with PCOS should have frequent assessment of glucose tolerance. This association is less clear in lean women. Fasting plasma glucose for detecting abnormal glucose tolerance was shown to be insensitive in women with PCOS as compared with oral glucose tolerance test (OGTT) [131]. Thus, we recommend performing an OGTT to screen this population. This recommendation was recently stated in an Androgen Excess Society position article, which also recommends repeating OGTTs every 2 years [132]. A recent meta-analysis comparing the risk of pregnancy and neonatal complications in women with PCOS to controls found that those with PCOS demonstrated a signicantly higher risk of developing gestational diabetes (odds ratio [OR] 2.94), pregnancy-induced hypertension (OR 3.67), preeclampsia (OR 3.47) and preterm birth (OR 1.75). Their babies have signicantly higher perinatal mortality (OR 3.07), unrelated to multiple births [133]. Most of these complications have been strongly associated with obesity in the general population, as recently demonstrated in large register study [134]. The importance of weight loss before conception should therefore be strongly emphasized, not only to increase pregnancy rates but also to prevent deleterious eects on the pregnancy outcome. Clinical management of PCOS Lifestyle modications. Women with obesity and PCOS demonstrate improved ovulation and menses with weight reduction, which may be considered as primary therapy for infertility before the use of ovulation-inducing agents [135]. In many overweight and obese women with PCOS, weight loss alone is often associated with a reduction in serum-free testosterone concentrations, resumption of ovulation, and pregnancy [136139]. This is likely related to improvement of the hyperinsulinemic state, concomitant with an increase in SHBG levels, as shown in most of the studies that reported these parameters [140143]. Lifestyle modication, including a weight-reducing diet and exercise, is recommended as rst-line therapy for all obese women with PCOS. A small weight loss of 5% to 10% of total body weight was shown to be eective for

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inducing ovulation in many women [139]. Pharmacologic therapy should ideally be considered only if lifestyle modications fail to resolve spontaneous ovulatory cycles after 3 to 6 months [144]. Ovulation-induction agents. Clomiphene citrate (CC) was the rst ovulation inductor and is still the most common one used for ovulation induction. It is a nonsteroidal selective estrogen receptor modulator that releases estrogen inhibition on FSH production at the pituitary level. By increasing FSH levels, it favors follicle recruitment, induction of FSH receptors at the cell surface of granulosa cells, and eventually selection of one or multiple dominant follicles. This drug is taken for 5 days starting on the third or fth day of the menstrual cycle, following either a spontaneous or induced bleeding with progesterone withdrawal. CC is initially begun at a dose of 50 mg daily for 5 days and, if ovulation does not occur in the rst cycle of treatment, the dose is increased to 100 mg and, subsequently, to a maximum of 150 mg. The couple should be advised to have intercourse at least every other day for 1 week beginning the last day of medication. The response to treatment should be monitored. Conversion of a uniphasic to a biphasic basal temperature curve suggests ovulation has occurred, but this should not be used by the couple as an indicator for beginning to have frequent intercourse as the temperature rise occurs up to 4 days after ovulation. The occurrence of ovulation can also be accurately conrmed by a midluteal serum concentration greater than 6.5 ng/mL (ideally greater than 10 ng/mL). Adding transvaginal ultrasonographic monitoring and urinary LH testing is costly and does not appear to improve pregnancy rates signicantly [145]. Transvaginal ultrasound monitoring may be done in the very rst CC cycle to exclude hyperresponse [146]. CC is indicated as rst-line therapy for women with PCOS desiring pregnancy. Based on a meta-analysis in PCOS women, CC doubles the odds of clinical pregnancy as compared with no treatment or placebo [147,148]. Indeed, a cumulative pregnancy rate of up to 73% can be achieved in women with PCOS when CC is repeated for up to nine ovulatory cycles [149]. Side eects are infrequent, dose-dependent, and rarely interfere with therapy. They include hot ashes, blurred vision, exaggerated symptoms of ovulation, and inhibition of estrogen-mediated endometrial growth. The most signicant risk with CC is multiple pregnancy, which occurs in up to 6% of pregnancies [147]. CC has been the preferred fertility treatment in PCOS women for decades because of its low cost, few side eects, and simplicity of administration. The aromatase inhibitor letrozole is another ovulation-inductor drug that is gaining popularity because its side eects appear to be less severe than those of CC. For example, with letrozole, patients experience less of a decrease in cervical mucus, less thinning of the endometrial lining, and less emotional irritability. At the doses usually used for ovulation induction, side eects can include hot ashes, nausea, and vomiting. Insulin-sensitizing agents. Insulin sensitizers, namely metformin and thiazolidinediones, are benecial in controlling both short- and long-term

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issues in PCOS. However, thiazolidinediones are contraindicated during pregnancy because they were found to decrease progesterone levels and impair fetal growth in animal studies. Metformin is a biguanide whose primary mechanism of action is the reduction of hepatic gluconeogenesis, which pathologically increases in insulin-resistant states and thereby produces fasting hyperinsulinemia. Recent studies in women with PCOS have suggested that this may be a safe and eective means of improving the metabolic prole and reproductive function in both lean and obese women with PCOS. The favorable eect of metformin on hyperandrogenemia and ovulation in PCOS may stem from metformin-induced reduction of insulin levels, which reduces ovarian and adrenal secretions of androgens, reduces pituitary secretion of LH, and increases SHBG levels [114]. Accumulating evidence has shown that the rationale for metformin use in PCOS makes sense, and it has been shown to improve ovulation rates in women with PCOS [150,151]. A randomized trial comparing the eectiveness of metformin to CC administration as rst-line treatment in nonobese anovulatory women with PCOS found ovulation rates were not dierent between the groups, whereas the pregnancy rate was signicantly higher in the metformin group (15.1% versus 7.2%) [152]. Ovulation and pregnancy rates with the use of metformin increased steadily during the 6 months of the study with a number needed to treat of three for inducing a pregnancy. In contrast, CC showed higher ecacy initially, but this declined over time [113]. More recently, the same investigators did another head-to-head randomized controlled trial of CC versus metformin as rst-line treatment in infertile anovulatory patients with PCOS. They reported treatment with CC or metformin for 6 months resulted in cumulative pregnancy rates of 49% with CC and 63% with metformin, a dierence that was not signicant [153]. Furthermore, use of metformin during early pregnancy has been shown to reduce rst-trimester pregnancy loss [154,155], which can be as high as 30% to 50% in women with PCOS [156,157]. Finally, metformin induces normal ovulation, such that the risk of multiple gestation is no more than in the general population [147]. Despite such promising initial results, further studies are needed to conrm whether metformin has any benet over CC as an initial treatment in PCOS. The recent Pregnancy in Polycystic Ovarian Syndrome (PPCOS) study [147] brought additional controversy to the subject. In this study, 626 infertile women with PCOS received CC plus placebo, extended-release metformin plus placebo, or a combination of extended-release metformin and CC for up to 6 months. The results suggested that the live birth rate achieved with CC was higher for women who received CC alone (22.5%) or in combination with metformin (26.8%) than for women who received metformin alone (7.2%). Unfortunately, the PPCOS study used an extended-release formulation that demonstrated none of the expected metabolic benets of this insulin sensitizer, especially the absolute change

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in plasmatic insulin concentration and homeostasis model assessment of insulin resistance, both from baseline and compared with CC. The change in body mass index was statistically signicant but minor (0.6 [ 2.2]; 95% CI, 0.90.2 [P!.001]). In the absence of the expected metabolic improvements with metformin, it is not surprising that fertility parameters did not improve. The cumulative rate of ovulation after 6 months in the metformin group was only 29%, as compared with 63% and 55% in the two studies from Palomba and colleagues [152,153] and 58% after 3 to 6 months in a meta-analysis of four randomized controlled trials [150]. Thus, the PPCOS study should probably not be considered the denitive study for the choice of the best pharmacologic rst-line therapy in PCOS anovulatory women. In summary, the rst-line agent for the treatment of PCOS should be chosen by the physician after considering the discussed available data and consulting with the patient. There is no rm recommendation as to which agent should be used for initial therapy. We generally prefer metformin as a rst treatment, as it intervenes at the source of the disease and treats the metabolic abnormalities in PCOS. Even more importantly, metformin acts more slowly and tends to reduce appetite, which allow for lifestyle changes and weight loss before pregnancy. Other endocrine or metabolic disorders Congenital adrenal hyperplasia. CAH is an inherited recessive disorder of adrenal steroidogenesis, usually resulting from deciency of one of the ve enzymes required for synthesis of cortisol in the adrenal cortex. The clinical manifestations reect the severity of the enzymatic defects. The most prevalent disorders are caused by 21-hydroxylase deciency (w90% of cases [158161]), followed by 11b-hydroxylase deciency and 3b-hydroxysteroid dehydrogenase deciency accounting for most of the remaining cases. The adrenal precursors produced proximal to the enzymatic defect accumulate and are converted into androgens, resulting in symptomatic hyperandrogenism. Nonclassical or late-onset 21-hydroxylase deciency is one of the most common autosomal-recessive diseases and is more frequent than cystic brosis. It ranges in prevalence from 1% to 10%, depending on the ethnicity of the patient [162]. Nonclassical forms of CAH have clinical features similar to those of patients diagnosed with PCOS (ie, menstrual irregularity, hyperandrogenism, infertility, and polycystic ovaries). Consequent anovulation, in association with sexual dysfunction [163], is responsible for impaired fertility in these women. Another explanation for their subfertility is high glucocorticoid levels in treated women [164,165]. Finally, CAH women often develop insulin resistance, due to high levels of androgens or exogenous glucocorticoids, with superimposed PCOS. Patients with mild forms of 21-hydroxylase deciency might ovulate with adequate cortisol replacement and conceive spontaneously. Nevertheless, in more severe forms of CAH, fertility and childbirth rates are compromised despite treatment [163,165167].

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In nonclassical CAH women, follicular early-morning measurement of serum 17-hydroxyprogesterone concentration is the most likely to show an elevation. Levels greater than 800 ng/dL (24 nmol/L) are diagnostic of 21-hydroxylase deciency, whereas patients with levels greater than 400 ng/dL (12 nmol/L) and less than 800 ng/dL should be addressed with a provocative test with corticotropin (250 mg intravenously) [65]. A lower cuto 17- hydroxyprogesterone level of 200 ng/dL (6 nmol/L) for CAH screening may be more appropriate if early-morning samples cannot be obtained. The diagnosis of 21-hydroxylase deciency is then made if 17-hydroxyprogesterone levels are greater than 1000 ng/dL (30 nmol/L) 1 hour after administration of corticotropin. The other enzymatic defects that result in nonclassical CAH can be similarly tested with measurements of corticosteroid products proximal to the blockade following provocative testing [168]. The fundamental aim of endocrine therapy for CAH is to provide replacement of the decient hormones, especially in the severe classical forms. Dexamethasone is the corticosteroid of choice for all forms of CAH [169]. CC and other assisted reproduction techniques may be added if glucocorticoid therapy alone is ineective in restoring fertility [170]. Virilizing tumors. Both benign and malignant adrenal tumors can produce androgens, including testosterone, many steroid intermediates, and, rarely, cortisol. Approximately 50% to 60% of adrenal cancers are functional. The most frequent presentation is Cushings syndrome with or without virilization. Androgen-secreting adrenal tumors are more frequently malignant than benign. Nearly all patients have very high serum dehydroepiandrosterone sulphate concentrations and the values do not fall in response to highdose dexamethasone. Ninety-ve percent of adrenal carcinomas are larger than 5 cm in diameter. Androgen-producing carcinomas lead to virilization in women: male-pattern baldness, deepening voice, breast atrophy, clitoral hypertrophy, increased libido, oligomenorrhea or amenorrhea, total testosterone concentrations over 200 ng/dL, and characteristic ultrasound or CT ndings. Ovarian virilizing tumors typically secrete predominantly androstenedione and are thus characterized by a disproportionate elevation of plasma androstenedione relative to testosterone, resulting in anovulation. When a virilizing tumor is suspected, conrmatory imaging is required and the treatment is surgical resection. Adrenal failure and Cushings syndrome. Both adrenal failure and Cushings syndrome may cause infertility. If adrenal insuciency is suspected, the 250-mg corticotropin stimulation test should be performed as a screening measure. The maximal plasma cortisol level following acute corticotropin stimulation should be 20 mg/dL or above [171]. Hormonal supplementation with hydrocortisone generally permits restoration of fertility. Puerperal mortality/morbidity in women with adrenal failure can be prevented by

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both mineralo- and glucocorticoid replacement with higher doses during stressful periods, such as labor, delivery, and surgery. In Cushings syndrome, the excess cortisol and androgen levels suppress gonadotropin secretion, impair LH response to GnRH [172,173], and, in some cases of Cushings disease due to pituitary tumor, also result in hyperprolactinemia, which suppresses ovulatory LH surge [174176]. The insulin resistance due to cortisol excess may also cause a typical PCOS. Cushings syndrome can be diagnosed, when the clinical suspicion is high, with the administration of 1 mg of dexamethasone at 11 PM and measurement of serum cortisol at 8 AM the next morning [177], which should be less than 2 ug/dL in normal subjects [178]. Twenty-fourhour urinary cortisol excretion also provides a direct and reliable practical measure of cortisol secretion [179,180]. Concern should be raised if the result is a twofold increase compared with normal laboratory values. Cause-specic treatment has a high likelihood of improving fertility, as well as improving maternal and perinatal outcomes in case of Cushings syndrome diagnosed during pregnancy. Other endocrine disorders. Overt hypo- or hyperthyroidism may result in oligomenorrhea, amenorrhea, and anovulatory infertility, whereas subclinical hypothyroidism may result in menorrhagia and luteal phase defect. Subclinical hypothyroidism is dened as thyroxine and tri-iodothyronine levels in the normal range with thyroid-stimulating hormone (TSH) above the upper limit of the reference value, typically greater than 3.5 IU/L. Surprisingly, subclinical or mild hyperthyroidism is rarely associated with infertility [181], but more severe hypothyroidism can cause infertility. According to routine screening studies in infertile populations, 2.3% to 5.1% have abnormal thyroid function tests in this more severe range [182,183]. Thyroid hormones have direct eects on granulosa cells, luteal cells, and oocytes, indicating a direct interference with normal ovarian function [184]. Several studies conrmed that subclinical hypothyroidism or euthyroidism in patients with thyroid antibodies may also adversely aect the mother or fetus [185,186], and substitutive treatment with levothyroxine has been shown to lower the chance of miscarriage and premature delivery in these particular women [187]. Women with subclinical hypothyroidism should then be treated before pregnancy, aiming for a TSH of 2.5 IU/L or less to optimize fertility and ensure normal thyroid hormone levels for the fetus. Diabetic women have a higher incidence of secondary hypogonadotropic amenorrhea, more so if body mass index is low and glycosylated hemoglobin (HbA1c) is higher than normal [188]. In women with diabetes mellitus desiring pregnancy, prepregnancy counseling is essential and adequate glycemic control before conception is critical to diminish the risk of spontaneous abortion [189,190], fetal abnormalities, macrosomia, and other pregnancy complications [191,192]. Thus, diabetic women should aim for an HbA1c below 6%, or below 7% if the risk of hypoglycemic episodes is

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too high, before getting pregnant. The possibility of associated PCOS should also be questioned in this population. General diagnostic approach of anovulatory disorders Anovulatory infertility should be suspected in all women who have oligomenorrhea or amenorrhea and have not been able to conceive despite unprotected and timely intercourse. The use of a questionnaire is a key element of the evaluation (Box 2), in addition to a thorough physical examination, including calculation of the patients body mass index and assessment for signs of potential causes of infertility. Patients should be evaluated for abnormalities of the thyroid gland, galactorrhea, and signs of androgen excess (hirsutism, acne, male-pattern baldness). All women should typically have FSH, LH, prolactin, TSH, and fasting glucose levels checked. Women with signs of androgen excess or menstrual irregularity should be tested with levels of total and calculated free testosterone, as well as 17-hydroxyprogesterone or dehydroepiandrosterone sulphate levels to rule out CAH or androgen-secreting tumors (Fig. 3). Screening tests for Cushings syndrome (24-hour urinary cortisol excretion or 1-mg dexamethasone suppression test) should be reserved for cases with high clinical suspicion. Glycemic control should be assessed in diabetic women with HbA1c.

Box 2. History taking in infertile women Fertility history: duration of infertility, prior pregnancies (including miscarriage), previous infertility testing and/or treatment, frequency of intercourse Gynecologic history: pelvic inammatory disease, broids, endometriosis, cervical dysplasia; surgery of the cervix, ovary, uterus, fallopian tube or abdomen; prior contraceptive use (including intrauterine device); uterine abnormalities Menstrual history: age at menarche, cycle length, regularity and bleeding heaviness; presence of symptoms suggestive of menopause or hyperandrogenism (see text) Change in body weight, galactorrhea, Cushings symptoms, symptoms of dysthyroidism Family diseases: birth defects, reproductive failure, hyperandrogenism Other medical and surgical history: radiation or chemotherapeutic agents Regular medications, drug use (including tobacco, alcohol, other recreational drug use), occupational exposures, exercise, and dietary habits

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Fig. 3. Algorithm for initial evaluation of hyperandrogenic disorders. 17(OH)Pg, 17ahydroxyprogesterone; ACTH, corticotropin; DHEAS, dehydroepiandrosterone sulphate; Stim., stimulation; T testo., total testosterone.

Unexplained infertility Unexplained infertility is dened as the failure to conceive for a couple in whom no denitive cause for infertility can be found. In such cases, basic tests for ovulation, fallopian tube patency, and semen analysis are normal. It is a state of relative inability to conceive. In such cases, the need to include a diagnostic laparoscopy in the basic tests is controversial [2,193]. The incidence of unexplained infertility varies with the population studied and the criteria used. It ranges from 10% to 30% in all infertile couples. The cycle fecundity in unexplained infertility is about 2% to 4%, which is far below the normal rate of 20%. With increasing age of the female partner and increasing duration of infertility (O3 years), conception is even less likely. The proposed treatments of unexplained infertility are empiric. The goal of treatment is to increase monthly fecundity and hasten pregnancy by increasing the gamete density (superovulation). Recommended treatments have included controlled ovarian hyperstimulation with CC (even in ovulatory female) for 3 to 6 months, alone or with intrauterine insemination, or by gonadotropins with or without intrauterine insemination. The cycle fecundability varies from 8.3% with CC plus intrauterine insemination to 17.1% with gonadotropins plus intrauterine insemination [193,194]. IVF can be the last resort of treatment, but caution about the increased risk of multiple births and ovarian hyperstimulation syndrome should be applied with these treatments.

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Assisted reproductive technology Assisted reproductive technology procedures can be divided into several categories, namely IVF, intracytoplasmic sperm injection, gamete intrafallopian transfer, cryopreserved embryo transfer, and donor oocyte or embryo. The indications for IVF are tubal factor infertility, endometriosis, male factor infertility (IVF or intracytoplasmic sperm injection), unexplained infertility, ovarian failure, and diminished ovarian reserve [147]. The main problem with the accessibility of IVF is the high cost with less than 10% of infertile couples undergoing such treatment [195]. The risk of multiple gestation is increased in assisted reproductive technology cycles. In 2006 in the United States, 33% of multiple gestations in women under 35 were a result of IVF. Of these multiple gestations, approximately one third were twins. During the use of assisted reproductive techniques, the risk for spontaneous abortion is about 17% and for ectopic pregnancy 2% [195]. It is recommended that no more than two embryos be transferred in women under 35 and more than two only in older women. In Europe, many in the eld have suggested that multiembryo transfers be discouraged for all women, no matter the age. The success rate of assisted reproductive technology varies with age. In 2003 in the United States, the percentage of cycles resulting in live births were 37% for women younger than 35 years, 30% for women age 35 to 37 years, 20% for women age 38 to 40 years, and 11% for women age 40 to 41 years [195]. In Canada in 2003, the clinical pregnancy rates per cycle started were 31% in IVFintracytoplasmic sperm injection cycles [196]. It was estimated that the number of IVFintracytoplasmic sperm injection cycles cycles per million population per annum is 269 in the United States, 270 in Canada, 784 in France, and 1791 in Denmark [196]. Summary Infertility is a common disorder that has major consequences on womens well-being. Aected women eagerly seek answers and eective therapy. The most common cause of medically treatable infertility is the polycystic ovary syndrome. This syndrome is common in young women and is the cause of anovulatory infertility in 70% of cases. It is therefore an important condition to screen and manage in primary care medical settings. In the past 10 years, insulin sensitization with weight loss or metformin has been shown to be a safe and eective treatment for PCOS infertility that eliminates the risk of multiple pregnancy and may reduce the risk of early pregnancy loss as compared with ovulation-inductor drugs. The authors believe metformin should be considered as rst line therapy because it has the advantage to allow for normal single ovulation, for reduced early pregnancy loss, and, most importantly, lifestyle modications and weight loss before pregnancy. Losing weight not only improves fertility but also reduces adverse pregnancy outcomes associated with obesity.

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References
[1] Medicine PCotASfR. Optimal evaluation of the infertile female. Fertil Steril 2004;82 (Suppl 1):S16972. [2] Spero L, Fritz M. Clinical gynecologic endocrinology and infertility. 7th edition. Philadelphia: Lippincott Williams & Wilkins; 2005. [3] Boivin J, Bunting L, Collins JA, et al. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 2007;22:150612. [4] Dunson D, Colombo B, Baird D. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002;17(5):1399403. [5] Spero L, Glass R, Kase N. Clinical gynecologic endocrinology and infertility. 5th edition. Baltimore (MD): Williams & Wilkins; 1994. [6] Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertility & Sterility 2004;82(Suppl 1):S16972. [7] Westrom L, Joesoef R, Reynolds G, et al. Pelvic inammatory disease and infertility. Sex Transm Dis 1992;19:185. [8] Den Hartog J, Morre S, Land J. Chlamydia trachomatisassociated tubal factor subfertility: immuno genetic aspects and serological screening. Hum Reprod Update 2006;12(6): 71930. [9] Akande V, Hunt L, Cahill D. Tubal damage in infertile women: prediction using chlamydia serology. Hum Reprod 2003;18:18417. [10] Marana R, Quagliarello J. Distal tubal occlusion: microsurgery versus in vitro fertilizationda review. Int J Fertil 1988;33:10715. [11] Griths A, DAngelo A, Amso N. Surgical treatment of broids for subfertility. Cochrane Database Syst Rev Update 2006;3:CD003857. [12] Jun SH, Ginsburg ES, Racowsky C, et al. Uterine leiomyomas and their eect on in vitro fertilization outcome: a retrospective study. J Assist Reprod Genet 2001;18:139. [13] Al-Inany H. Intrauterine adhesions. An update. Acta Obstet Gynecol Scand 2001;80(11): 98693. [14] Medicine PCotASfR. Endometriosis and infertility. Fertil Steril 2006;85(Suppl 5):S15660. [15] Halis G, Arici A. Endometriosis and inammation in infertility. Ann N Y Acad Sci 2004; 1034:30015. [16] Marcoux S, Maheux R, Berube S, et al. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med 1997;337:21722. [17] Parazzini F, dellendometriosi GIPLS. Ablation of lesions or no treatment in minimaldmild endometriosis in infertile women: a randomized trial. Hum Reprod 1999; 14:13324. [18] Seminara S, Hayes F, Crowley WJ. Gonadotropin-releasing hormone deciency in the human (idiopathic hypogonadotropic hypogonadism and Kallmanns syndrome): pathophysiological and genetic considerations. Endocr Rev 1998;19(5):52139. [19] Quinton R, Duke V, de Zoysa P. The neuroradiology of Kallmanns syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 1996;81:30107. [20] Waldstreicher J, Seminara S, Jameson J. The genetic and clinical heterogeneity of gonadotropin-relaeasing hormone deciency in the human. J Clin Endocrinol Metab 1996;81: 438895. [21] Kirk J, Grant D, Besser G. Unilateral renal aplasia in X-linked Kallmanns syndrome. Clin Genet 1994;46:2602. [22] Marshall J, Eagleson C, McCartney C. Hypothalamic dysfunction. Mol Cell Endocrinol 2001;183:2932. [23] Seminara S, Crowley WJ. Perspective: the importance of genetic defects in humans in elucidating the complexities of the hypothalamic-pituitary-gonadal axis. Endocrinology 2001;142(6):21737.

1184

BRASSARD

et al

[24] Hardelin J. Kallmann syndrome: toward molecular pathogenesis. Mol Cell Endocrinol 2001;179(12):7581. [25] MacColl G, Quinton R, Bouloux P. GnRH neuronal development: insights into hypogonatotrophic hypogonadism. Trends Endocrinol Metab 2002;13(3):1128. [26] Genazzani AD, Gastaldi M, Volpe A, et al. Spontaneous episodic release of adenohypophyseal hormones in hypothalamic amenorrhea. Gynecol Endocrinol 1995;9:32534. [27] Spero L, Glass R, Kase N. Clinical gynecologic endocrinology and infertility. 6th edition. Philadelphia: L.W. Wilkins; 1999. [28] Biller BMK, Federo HJ, Koenig JI, et al. Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with hypothalamic amenorrhea. J Clin Endocrinol Metab 1990;70:3117. [29] Perkins R, Hall J, Martin K. Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability and response to neurotrasmitter modulation. J Clin Endocrinol Metab 1999;84:190511. [30] Warren M, Perlroth N. The eects of intense exercise on the female reproductive system. J Endocrinol 2001;170(1):311. [31] Van Steenbergen W, Naert J, Lambrecht S, et al. Suppression of gonadotropin secretion in the hospitalized postmenopausal female as an eect of acute critical illness. Neuroendocrinology 1994;60(2):16572. [32] Woolf PD, Hamill RW, McDonald JV, et al. Transient hypogonadotropic hypogonadism caused by critical illness. J Clin Endocrinol Metab 1985;60(3):44450. [33] Baker H. Reproductive eects of nontesticular illness. Endocrinol Metab Clin North Am 1998;27(4):83150. [34] Traggiai C, Stanhope R. Delayed puberty. Best Pract Res Clin Endocrinol Metab 2002; 16(1):13951. [35] Spratt DI, Bigos ST, Beitins I, et al. Both hyper- and hypogonadotropic hypogonadism occur transiently in acute illness: bio- and immunoactive gonadotropins. J Clin Endocrinol Metab 1992;75(6):15626. [36] Warren M. Clinical reproductive neuroendocrinology. In: Vaitukaitis J, editor. The eects of altered nutritional states, stress, and systemic illness on reproduction in women. New York: Elsevier; 1982. p. 177. [37] Finch PM, Roberts LJ, Price L, et al. Hypogonadism in patients treated with intrathecal morphine. Clin J Pain 2000;16(3):2514. [38] Petty R. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35:S6773. [39] Kleinberg D, et al. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19(1):5761. [40] Gomez F, Reyes F, Faiman C. Nonpuerperal galactorrhea and hyperprolactinemia. Clinical ndings, endocrine features and therapeutic responses in 56 cases. Am J Med 1977;62(5):64860. [41] Luciano A, Chapler F, Sherman B. Hyperprolactinemia in polycystic ovary syndrome. Fertil Steril 1984;41(5):71925. [42] Pitkin J, Rees M, Gray S, et al. Managing the menopause: British Menopause Society Council consensus statement on hormone replacement therapy. Journal of the British Menopause Society 2005;11(4):1526. [43] Coulam C, Adamson S, Annegers J. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:6046. [44] Nelson L, Anasti J, Flack M. Reproductive endocrinology, surgery, and technology Adashi E, Rock J, Rosenwaks Z, editors. Premature ovarian failure. Philadelphia: Lippincott-Raven; 1996. p. 1394410. [45] van Kasteren YM, Hundscheid RD, Smits AP, et al. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum Reprod 1999;14(10): 24559.

INFERTILITY AND THE PCOS

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[46] Jacobsen B, Heuch I, Kvale G. Age at natural menopause and all-cause mortality: a 37-year follow-up of 19,731 Norwegian women. Am J Epidemiol 2003;157:9239. [47] van Der Voort D, van Der Weijer P, Barentsen R. Early menopause: increased fracture risk at older age. Osteoporos Int 2003;14:52530. [48] Snowdon D, Kane R, Beeson W. Is early natural menopause a biologic marker of health and aging? Am J Public Health 1989;79:70914. [49] Anasti J, Kalantaridou S, Kimzey L. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1998;91:125. [50] Ohta H, Sugimoto I, Masuda A. Decreased bone mineral density associated with early menopause progresses for at least ten years: cross-sectional comparisons between early and normal menopausal women. Bone 1996;18:22731. [51] Van Der Schouw Y, Van Der Graaf Y, Steyerberg E. Age at menopause as a risk for cardiovascular mortality. Lancet 1996;347:7148. [52] Cummings S, Black D, Nevitt M. Bone density at various sites for prediction of hip fractures. Lancet 1996;341:725. [53] Senoz S, Direm B, Gulekli B, et al. Estrogen deprivation, rather than age, is responsible for the poor lipid prole and carbohydrate metabolism in women. Maturitas 1996;25(2): 10714. [54] Alzubaidi NH, Chapin HL, Vanderoof VH, et al. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol 2002; 99(5):7205. [55] Rebar R, Erickson G, Yen S. Idiopathic premature ovarian failure: clinical and endocrine characteristics. Fertil Steril 1982;37:3541. [56] Nelson LM, Anasti JN, Kimzey LM, et al. Development of luteinized graaan follicles in patients with karyotypically normal spontaneous premature ovarian failure. J Clin Endocrinol Metab 1994;79:14705. [57] Van Kasteren Y, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 1999;5(5):48392. [58] Kreiner D, Droesch K, Navot D. Spontaneous and pharmacologically induced remissions in patients with premature ovarian failure. Obstet Gynecol 1988;73:9268. [59] Rebar R, Cedars M. Hypergonadotropic forms of amenorrhea in young women. Endocrinol Metab Clin North Am 1992;21:17391. [60] Migeon B, Jelalian K. Evidence for two active X chromosomes in germ cells of female before meiotic entry. Nature 1977;269:2423. [61] Singh R, Carr D. The anatomy and histology of XO human embryos and fetuses. Anat Rec 1966;155:36984. [62] Sarto G. Cytogenetics of fty patients with primary amenorrhea. Am J Obstet Gynecol 1974;119:1423. [63] Kaufman F, Kogut MD, Donnell GN, et al. Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 1981;304:9948. [64] Conte FA, Grumbach MM, Ito Y, et al. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 1994;78(6): 128792. [65] Azziz R, Hincapie LA, Knochenhauer ES, et al. Screening for 21-hydroxylasedecient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil Steril 1999;72:91525. [66] Conway G, Kaltsas G, Patel A. Characterization of idiopathic premature ovarian failure. Fertil Steril 1996;65:33741. [67] Ahonen P, Myllarniemi S, Sipila I, et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:182936.

1186

BRASSARD

et al

[68] Kim TJ, Anasti J, Flack MR, et al. Routine endocrine screening for patients with karyotypically normal spontaneous premature ovaian failure. Obstet Gynecol 1997;89(5):7779. [69] Bakalov VK, Venderhoof VH, Bondy CA, et al. Adrenal antibodies detect asymptomatic auto-immune adrenal insuciency in young women with spontaneous premature ovarian failure. Hum Reprod 2002;17(8):2096100. [70] Alper M, Jolly E, Garner P. Pregnancies after premature ovarian failure. Obstet Gynecol 1986;67:59S62S. [71] Taylor AE, Adams JM, Mulder JE, et al. A randomized, controlled trial of estradiol replacement therapy in women with hypergonadotropic amenorrhea. J Clin Endocrinol Metab 1996;81(10):361521. [72] Stein I, Leventhal M. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:18191. [73] Asuncion M, Calvo R, San Millan JL, et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85(7):24348. [74] Knochenhauer E, Key T, Kahsar-Miller M. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998;83:307882. [75] Diamanti-Kandarakis E, Kouli C, Bergiele A. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic prole. J Clin Endocrinol Metab 1999; 84:400611. [76] Michelmore K, Balen A, Dunger D. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol (Oxf) 1999;51:77986. [77] Azziz R, Woods K, Reyna R. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004;89:27459. [78] Hamilton-Fairley D, Taylor A. ABC of subfertility: anovulation. BMJ 2003;327:5469. [79] Hull M. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 1987;1:23545. [80] Hull M, Glazener C, Kelly N. Population study of causes, treatment, and outcome of infertility. BMJ 1985;291:16937. [81] Collins J. Unexplained infertility. In: Keye WR Jr, Chang RJ, Rebar RW, editors. Infertility: evaluation and treatment. 1st edition. Oxford (UK): Saunders WB Co.; 1995. p. 24962. [82] Group REA-SPCW. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81(1):1925. [83] Azziz R. Criteria for dening polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endocrinol Metab 2006; 91(11):423745. [84] DeVane GW, Czekala NM, Judd HL, et al. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 1975;121(4):496500. [85] Apridonidze T, Essah PA, Iuorno MJ, et al. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90: 192935. [86] Cedars M, Steingold KA, de Ziegler D, et al. Long-term administration of gonadotropinreleasing hormone agonist and dexamethasone: assessment of the adrenal role in ovarian dysfunction. Fertil Steril 1992;57(3):495500. [87] Koivunen RM, Morin-Papunen LC, Ruokonen A, et al. Ovarian steroidogenic response to human chorionic gonadotrophin in obese women with polycystic ovary syndrome: eect of metformin. Hum Reprod 2001;16(12):254651. [88] Gilling-Smith C, Story H, Rogers V, et al. Evidence for a primary abnormality of thecal cells steroidogenesis in the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1997;47(1):939. [89] Kamel N, Tonyukuk V, Emral R, et al. Role of ovary and adrenal glands in hyperandrogenemia in patients with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2005; 113(2):11521.

INFERTILITY AND THE PCOS

1187

[90] Azziz R, Black V, Hines GA, et al. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1998;83(7):231723. [91] Dunaif A, Segal K, Futterweit W. Profound peripheral insulin resistance, independent of obesity in polycystic ovary syndrome. Diabetes 1989;38:116574. [92] Ciaraldi TP, el-Roeiy A, Madar Z, et al. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 1992;75:57783. [93] Toprak S, Yonem A, Cakir B, et al. Insulin resistance in nonobese patients with polycystic ovary syndrome. Horm Res 2002;55(2):6570. [94] Ciampelli M, Fulghesu AM, Cucinelli F, et al. Heterogeneity in b cell activity, hepatic insulin clearance and peripheral insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod 1997;12(9):1897901. [95] Singara D, Scarpitta AM, Brigandi M, et al. Feedback inhibition of insulin secretion and insulin resistance in polycystic ovarian syndrome with and without obesity. Eur Rev Med Pharmacol Sci 1997;1(5):16771. [96] Dunaif A, Segal KR, Shelley DR, et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992;41(10):125766. [97] Chang R, Nakamura RM, Judd HL, et al. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 1983;57(2):3569. [98] Holte J, Bergh T, Berne C, et al. Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J Clin Endocrinol Metab 1994;78(5):10528. [99] Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor related serine phosphorylation in cultured broblasts and in skeletal muscles. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96(2):80110. [100] Veldhuis J, Zhang G, Garmey J. Troglitazone, an insulin-sensitizing thiazolidinedione, represses combined stimulation by LH and insulin of de novo androgen biosynthesis by thecal cells in vitro. J Clin Endocrinol Metab 2002;87(3):112933. [101] Sekar N, Lavoie H, Veldhuis J. Concerted regulation of steroidogenic acute regulatory gene expression by luteinizing hormone or insulin (or insulin-like growth factor I) in primary cultures of porcine granulosa-luteal cells. Endocrinology 2000;141(11): 398392. [102] Zhang G, Garmey J, Veldhuis J. Interactive stimulation by luteinizing hormone and insulin of the steroidogenic acute regulatory (StAR) protein and 17a-hydroxylase/17,20-lyase (CYP17) genes in porcine theca cells. Endocrinology 2000;141(8):273542. [103] Barbieri R. Insulin stimulates androgen accumulation in incubations of minced porcine theca. Gynecol Obstet Invest 1994;37(4):2659. [104] Ibanez L, Hall JE, Potau N, et al. Ovarian 17-hydroprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypersecretion: evidence from GnRH agonist and human chorionic gondotropin stimulation testing. J Clin Endocrinol Metab 1996;81(11):41037. [105] Nestler JE, Powers LP, Matt DW, et al. A direct eect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72(1):839. [106] Devesa J, Perez-Fernandez R, Lima L, et al. Adrenal cortex and type II polycystic ovary syndrome. Gynecol Endocrinol 1987;1(3):26977. [107] Chang RJ, Laufer LR, Meldrum DR, et al. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 1983;56(5):897903. [108] Jakubowicz D, Nestler J. 17 alpha-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome oer dietary weight loss. J Clin Endocrinol Metab 1997;82(2):55660.

1188

BRASSARD

et al

[109] Nestler J, Jakubowicz D. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab 1997;82(12):40759. [110] Nestler J, Jakubowicz D. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335(9):6578. [111] Arslanian SA, Lewy V, Danadian K, et al. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab 2002;85(4):15559. [112] Azziz R, Ehrmann DA, Legro RS, et al. Troglitazone decreases adrenal androgen levels in women with polycystic ovary syndrome. Fertil Steril 2003;79(4):9327. [113] Baillargeon J, Carpentier A. Role of insulin in the hyperandrogenemia of lean women with polycystic ovary syndrome and normal insulin sensitivity. Fertil Steril 2007;88(4): 88693. [114] Baillargeon J, Nestler J. Commentary: polycystic ovary syndrome: a syndrome of ovarian hypersensitivity to insulin? J Clin Endocrinol Metab 2006;91(1):224. [115] Eagleson CA, Bellows AB, Hu K, et al. Obese patients with polycystic ovary syndrome: evidence that metformin does not restore sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by ovarian steroids. J Clin Endocrinol Metab 2003;88(11): 515862. [116] Mehta RV, Patel KS, Coer MS, et al. Luteinizing hormone secretion is not inuenced by insulin infusion in women with polycystic ovary syndrome despite improved insulin sensitivity during pioglitazone treatment. J Clin Endocrinol Metab 2005;90(4):213641. [117] Glintborg D, Hermann AP, Andersen M, et al. Eect of pioglitazone on glucose metabolism and luteinizing hormone secretion in women with polycystic ovary syndrome. Fertil Steril 2006;86(2):38597. [118] Yilmaz M, Biri A, Karakoc A, et al. The eects of rosiglitazone and metformin on insulin resistance and serum androgen levels in obese and lean patients with polycystic ovary syndrome. J Endocrinol Invest 2005;28(11):10038. [119] Pagan YL, Srouji SS, Jimenez Y, et al. Inverse relationship between luteinizing hormone and body mass index in polycystic ovarian syndrome: investigation of hypothalamic and pituitary contributions. J Clin Endocrinol Metab 2006;91(4):130916. [120] Dale PO, Tanbo T, Vaaler S, et al. Body weight, hyperinsulinemia, and gonadotropin levels in the polycystic ovarian syndrome: evidence of two distinct populations. Fertil Steril 1992; 58(3):48791. [121] Dunaif A, Mandeli J, Fluhr H, et al. The impact of obesity and chronic hyperinsulinemia on gonadotropin release and gonadal steroid secretion in the polycystic ovary syndrome. J Clin Endocrinol Metab 1988;66(1):1319. [122] Conway G, Honour J, Jacobs H. Heterogeneity of the polycystic ovary syndrome: clinical, endocrine and ultrasound features in 556 patients. Clin Endocrinol (Oxf) 1989;30: 45970. [123] Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:85361. [124] Adams J, Polson D, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. BMJ 1986;293:3559. [125] Fujiwara T, Sidis Y, Welt C, et al. Dynamics of inhibin subunit and follistatin mRNA during development of normal and polycystic ovary syndrome follicles. J Clin Endocrinol Metab 2001;86(9):420615. [126] Lo JC, Feigenbaum SL, Yang J, et al. Epidemiology and adverse cardiovascular risk prole of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91(4):135763. [127] Ehrmann D, Sturis J, Byrne M. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin secretion and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 1995;96(1):5207.

INFERTILITY AND THE PCOS

1189

[128] Colilla S, Cox N, Ehrmann D. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their rst degree relatives. J Clin Endocrinol Metab 2001;86(5):202731. [129] Ehrmann D, Kasza K, Azziz R. Eects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90(1):6671. [130] Ehrmann DA, Barnes RB, Roseneld RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22(1):1416. [131] Gagnon C, Baillargeon J. Suitability of recommended limits for fasting glucose tests in women with polycystic ovary syndrome. CMAJ 2007;176(7):9338. [132] Salley K. Position statement: glucose intolerance in polycystic ovary syndrome a position statement of the Androgen Excess Society. J Clin Endocrinol Metab 2007;92(12): 454656. [133] Boomsma CM, Eijkemans MJ, Hughes EG, et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 2006;12(6):67383. [134] Chu SY, Bachman DJ, Callaghan WM, et al. Association between obesity during pregnancy and increased use of health care. N Engl J Med 2008;358:144453. [135] Balen A, Dresner M, Scott A. Should obese women with polycystic ovary syndrome receive treatment for infertility? BMJ 2006;332:4345. [136] Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989;68(1):1739. [137] Bates G, Whitworth N. Eect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 1982;38(4):4069. [138] Guzick D, Wing R, Smith D, et al. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994;61(4):598604. [139] Huber-Buchholz M, Carey D, Norman R. Restoration of reproductive potential by lifestyle modication in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:14704. [140] Moran L, Noakes M, Clifton P. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:8129. [141] Kiddy D, Hamilton-Fairley D, Seppala M. Diet-induced changes in sex hormone binding globulin and free testosterone in women with normal or polycystic ovaries: correlation with serum insulin and insulin-like growth factor-I. Clin Endocrinol (Oxf) 1989;31:75763. [142] Kiddy D, Hamilton-Fairley D, Bush A. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;36:10511. [143] Hamilton-Fairley D, Kiddy D, Anyaoku V. Response of sex hormone binding globulin and insulin-like growth factor binding protein-1 to an oral glucose tolerance test in obese women with polycystic ovary syndrome before and after calorie restriction. Clin Endocrinol (Oxf) 1993;39:3637. [144] Baillargeon J, Iuorno M, Nestler J. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol 2003;46(2):32540. [145] Smith YR, Randolph JF Jr, Christman GM, et al. Comparison of low-technology and high-technology monitoring of clomiphene citrate ovulation induction. Fertil Steril 1998;70(1):1658. [146] Kousta E, White D, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3(4):35965. [147] Legro R, Barnhart H, Schal W. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:55166. [148] Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. Cochrane Database Syst Rev 2000;(2):CD000056.

1190

BRASSARD

et al

[149] Imani B, Eijkemans MJ, te Velde ER, et al. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1999;84(5):161722. [150] Kashyap S, Wells G, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with ploycystic ovarian syndrome. Hum Reprod 2004;19(11):247483. [151] Lord J, Flight I, Norman R. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327(7421):9513. [152] Palomba S, F.Orio J, Falbo A. Prospective parallel randomized, double-blind, doubledummy controlled clinical trial comparing clomiphene citrate and metformin as the rstline treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:406874. [153] Palomba S, Orio F Jr, Falbo A, et al. Clomiphene citrate versus metformin as rst-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92(9):3498503. [154] Jakubowicz DJ, Iuorno MJ, Jakubowick S, et al. Eects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:5249. [155] Baillargeon JP, Legro RS. Should metformin be used as front-line therapy for fertility in women with PCOS. Sexuality, Reproduction and Menopause 2007;5(2):179. [156] Balen AH, Tan SL, MacDougall J, et al. Miscarriage rates following in vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod 1993;8:95964. [157] Sagle M, Bishop K, Ridley N, et al. Recurrent early miscarriage and polycystic ovaries. BMJ 1988;297:10278. [158] Speiser P, White P. Congenital adrenal hyperplasia. N Engl J Med 2003;349:77688. [159] Merke DP, Bornstein SR, Avila NA, et al. NIH conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deciency. Ann Intern Med 2002;136:32034. [160] Merke D, Cutler GJ. New ideas for medical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:12135. [161] White P, Speiser P. Congenital adrenal hyperplasia due to 21-hydroxylase deciency. Endocr Rev 2000;21:24591. [162] Speiser P, Dupont B, Rubinstein P. High frequency of nonclassical steroid 21-hydroxylase deciency. Am J Genet 1985;37:65067. [163] Mulaikal R, Migeon J, Rock J. Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deciency. N Engl J Med 1987;316:17882. [164] Bradford J. Pharmacological treatment of the paraphilias. American Psychiatric Press Review of Psychiatry 1995;14:75577. [165] Helleday J, Siwers B, Ritzen EM, et al. Subnormal androgen and elevated progesterone levels in women treated for congenital virilizing 21-hydroxylase deciency. J Clin Endocrinol Metab 1993;76:9336. [166] Holmes-Walker DJ, Conway GS, Hoour JW, et al. Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21-hydroxylase deciency. Clin Endocrinol (Oxf) 1995;43:2916. [167] Kuhnle U, Bullinger M, Schwartz H. The quality of life in adult female patients with congenital adrenal hyperplasia: a comprehensive study of genital malformations and chronic disease on female patients life. Eur J Pediatr 1995;154:70816. [168] Greenspan F, Gardner D. Basic & clinical endocrinology. In: Rosen M, Cedars M, editors. Female reproductive endocrinology & infertility. 7th edition. New York: Lange Medical Books/Mc Graw Hill; 2004. [169] Birnbaum M, Rose L. The partial adrenocortical hydroxylase deciency syndrome in infertile women. Fertil Steril 1979;32(5):53641. [170] Lo J, Grumbach M. Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30(1):20729.

INFERTILITY AND THE PCOS

1191

[171] Kehlet H, Binder C. Value of an ACTH test in assessing hypothalamic-pituitaryadrenocortical function in glucocorticoid-treated patients. BMJ 1973;2:14752. [172] Boccuzzi G, Angeli A, Bisbocci D, et al. Eect of synthetic luteinizing hormone releasinghormone (LHRH) on the release of gonadotropins in Cushings disease. J Clin Endocrinol Metab 1975;40:8925. [173] Sakakura M, Takebe K, Nakagawa S. Inhibition of luteinizing hormone secretion induced by synthetic LHRH by long-term treatment with glucocorticoids in human subjects. J Clin Endocrinol Metab 1975;40:7749. [174] Jurney T, deRuyter H, Vigersky R. Cushings disease presenting as amenorrhea with hyperprolactinemiadreport of two cases. Clin Endocrinol (Oxf) 1981;14:53946. [175] Lamberts S, DeLange S, Stefanko S. Adrenocorticotropin-secreting pituitary adenomas originate from the anterior or the intermediate lobe in Cushings disease: dierences in regulation of hormone secretion. J Clin Endocrinol Metab 1982;54:28691. [176] Rodriguez S, Alger M, Forsbach G, et al. Amenorrhea-galactorrhea associated with Cushings disease due to pituitary tumor. J Endocrinol Invest 1981;4:3740. [177] Nugent C, Nichols T, Tyler F. Diagnosis of Cushings syndrome; single dose dexamethasone suppression test. Arch Intern Med 1965;116:1726. [178] Blethen S, Chasalow F. Overnight dexamethasone suppression test: normal responses and the diagnosis of Cushings syndrome. Steroids 1989;54(2):18593. [179] Crapo L. Cushings syndrome: a review of diagnostic tests. Metabolism 1979;28(9):95577. [180] Mengden T, Hubmann P, Muller J, et al. Urinary free cortisol versus 17-hydroxycorticosteroids: a comparative study of their diagnostic value in Cushings syndrome. Clin Investig 1992;70(7):5458. [181] Goldsmith R, Sturgis S, Lerman J. Menstrual pattern in thyroid disease. J Clin Endocrinol Metab 1952;12:846. [182] Stratford G, et al. Value of thyroid function tests in routine screening of women investigated for infertility. Hum Fertil (Camb) 2000;3:2036. [183] Lincoln S, Ke R, Kutteh W. Screening for hypothyroidism in infertile women. J Reprod Med 1999;44:4557. [184] Wakim AN, Polizotto SL, Buo MJ, et al. Thyroid hormones in human follicular uid and thyroid hormone receptors in human granulosa cells. Fertil Steril 1993;59:118790. [185] Davis L, Leveno K, Cunningham F. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988;72:10812. [186] Glinoer D, Riahi M, Grun JP, et al. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994;79: 197204. [187] Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: eects on obstetrical complications. J Clin Endocrinol Metab 2006;91(7):258791. [188] Kjaer K, Hagen C, Sando SH, et al. Epidemiology of menarche and menstrual disturbances in an unselected group of women with insulin-dependent diabetes compared to controls. J Clin Endocrinol Metab 1992;75:5249. [189] Miodovnik M, Lavin J, Knowles H. Spontaneous abortion among insulin dependent diabetic women. American Journal of Obstetrics & Gynecology 1984;150(4):3726. [190] Miodovnik M, Skillman C, Holroyde J. Elevated maternal glycohemoglobin in early pregnancy and spontaneous abortion among insulin dependent diabetic women. Am J Obstet Gynecol 1985;153:43942. [191] Bigazzi M, Ronga R, Lalcrajan I. A pregnancy in an acromegalic woman during bromocriptic treatment: eects on growth hormone and prolactin in the maternal, fetal, and amniotic compartments. J Clin Endocrinol Metab 1979;48:912. [192] Fuhrmann K, Reiher H, Semmler K. The eect of intensied conventional insulin therapy before and during pregnancy on the malformation rate in ospring of diabetic mothers. Exp clin endocrinol 1984;83:1737.

1192

BRASSARD

et al

[193] Guzick D, et al. Ecacy of treatment for unexplained infertility. Fertil Steril 1998;70: 20713. [194] Deaton J, Gibson M, Blackmer K. A randomized controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990;54:10838. [195] CDC, CfDC, ASfR Medicine, et al. Assisted reproductive technology success rates. Atlanta (GA): US Department of Health and Human Services and CDC; 2005. [196] Gunby J, Daya S. Assisted reproductive technologies (ART) in Canada: 2003 results from the Canadian ART register. Fertil Steril 2007;88(3):5509.