Irvin F Stein & Michael L Leventhal : American Gyn 1935 Associted the presence of ovary cysts with anovulation and used as a criteria of Synd.
Opening to lecture . Polycystic Ovarian Syndrome was first recognized by Stein and Leventhal who observed the relationship between obesity and reproductive disorder, what is now known as the “syndrome O” (over-nourishment, overproduction of insulin, ovarian confusion, and ovulation disruption). Since then, this condition is considered to be the most common endocrine disorder of pre-menopausal women, affecting an estimated 5% of the population. Current literature has suggested a higher frequency range (5-10%) through investigations into ethnicity including Hispanic/Latino females who are at an increased risk of diabetes.
Lecture Synopsis. The objective of this review is to briefly address the current knowledge of diagnosis, cause, complications, and infertility treatment.
Review Symptoms and Signs. PCOS is heterogeneous endocrine disorder, a syndrome not a disease, in which no single criterion is sufficient for diagnosis due to the multiple etiologies and presentations. Defining characteristics include menstrual dysfunction, hyperandrogenism, ovarian morphology on U/S, with the exclusions of other endocrine abnormalities (Cushing’s syndrome, thyroid abnormality, hyperprolactinemia, etc.).
Addition of PCO. As implicated through the addition of the PCO criteria, the ultrasound has provided a large contribution to diagnosis, monitoring and management of PCOS.
Insulin Effects . Looking at the effects of insulin in a larger scheme, this table adapted from Cristello and colleagues portrays the cascading consequence of life choices, aging and genetics leading to insulin resistance which progresses into other complications including PCOS. For examples, intrauterine environment may influence expression of PCOS resulting in prenatal exposure to androgens in offspring of PCOS mothers causing a stimulus for low birth weight (LBW) and development of PCOS. Insulin Resistance: Central Role, tissues do not respond to Insulin ( skeletal muscles) ^ insulin secretion ^ androgen production
Heritability. Due to the observable trends within families concerning insulin resistance, the question remains whether PCOS has a genetic connection. For instance, first degree relatives inherit B-cell dysfunction (secretory deficits). Franks and colleagues offered the following hypothesis: Linage analysis-syndrome inherited in autosomal recessive fashion; heterogeneous disorder-need to focus on hyperandrogenism to assign phenotype.
Other Complications. As insinuated by the insulin resistance, PCOS is not just a reproductive disorder but a multifaceted metabolic disorder.. Obesity is also a feature observed, estimated to effect 50% of PCOS women, classically presented in patients with upper body obesity which has been associated to menstrual disturbances (Hartz et al. Int J Obes. 3:57; 1979). It should also be pointed out that obesity is also considered in some literature to be an environmental factor, i.e. lifestyle.; it is now understood that obesity is a modifier of the condition . Obesity in US higher than Europe: Central obesity-waist circumference >35 inches (88 cm).
Other Complications . Endometrial cancer (EC): Due to the high estrogen levels and lack of normal ovulation cycles, there is a risk for endometrial cancer in PCOS women. Endometrial cancer-described as early as 1949 by Speer-cystic ovaries and EC-persistent estrogen stimulation; hyperplasia-lack of differentiation to secretory endometrium. Prolonged stimulatory effect of estrogen with unopposed inhibition by progesterone. Cardiovascular disease (CVD): Putting into consideration the rates of insulin resistance and obesity together plus the complications of high blood pressure and increased lipids values, PCOS patients are also at risk for CVD. CVD-associated with both increase in androgen and IR-increase in levels of inflammatory cytokines-IL6, TNF alpha-increased lipids, BP, obesity, IR-associate with CVD. Higher BMI-greater risk for both conditions.
Other Complications . Two other areas that have been associated to PCOS patients includes sleep apnea and depression effecting a woman’s productivity and quality of life. Apnea: Sleep apnea-greater in PCOS – greater than obesity alone, not correlate with BMI. Gender difference of sleep-disordered breathing (SDB). Found more common in middle age obese men and infrequently in premenopausal, yet prevalent in PCOS even non-obese-related to IR measures-30-40X age & weight-matched controls. PCOS women-glucose tolerance is directly related to severity of SDB. SDB shown to exacerbate metabolic consequence of IR-accelerate conversion to IGT (Ehrmann 2006). Insulin levels and measures of glucose tolerance are correlated with risk and severity of obstructive sleep apnea which confirms a direct relationship between insulin levels and sleep apnea. Androgen not related. Emotional stress : PCOS can influence feminine identity-less satisfied with sex life despite same frequency of intercourse-50 PCOS, 50 control women-loss self worth-feel less feminine, different than other women even when control for BMI.
Reproductive Complications. PCOS not only affects women pre-pregnancy but also post-pregnancy. Several studies have suggested various complications as listed here. Gestational Diabetes(GDM): Lo et al. examined 90,000 births with >5000 cases GDM. PCOS women had a 2.4 fold increased odds of GDM independent of age, race/ethnicity or multiple gestation (Diabetes Care, 2006). Small for Gestational Age (SGA): Polygenic genetically determined factors increase IR-impaired insulin-mediated growth. Environmental-metabolic programming-fetal exposure to sex steroids-maternal intrauterine environment. Although there is some literature that contradicts a few of these claims such as Haakova et al. Hum Reprod. 18:1438; 2003. May ask for audience feedback.
Infertility . Franks and colleagues suggested that over 75% of the patients with anovulation were PCOS patients. PCOS involves primary ovarian dysfunction. This intrinsic ovarian abnormality caused an increased density of small preantral follicles, primordial not different, same for ovulatory and anovulatory. Early follicular growth is excessive since the selection of 1 single follicle from the follicular pool to mature to the dominant one not occur.
Weight Loss. Tie in similarity of first line of treatment from previous slide. The most effective benefits are from the calorie-restricted diets which limiting “carbohydrates” rather than fats-reduction of insulin levels. In the Clark study, BMI was still >30, so still obese with weight loss, yet a 5% reduction in body mass was still able to restore ovulation. It is important to offer a program of exercise and sensible eating, plus educate women about long term adverse effects. Infertile women are usually highly motivated since they are also seeking a pregnancy.
Infertility Treatments. Another complicating feature of PCOS is the effects it has on ovulation and fertility. Since there are so many facets to PCOS, there are also multiple options for treating infertility based upon the patient’s characteristics. First line of treatment in overweight patients is weight loss through lifestyle modification. Another cautious approach is administering CC as first line then insulin sensitizer if REGNANCY desired outcome. However, only short-term treatment with sensitizer and although CC has demonstrated benefit it should be limited to three cycles (Gysler et al. Fert Ster 37:161; 1982). The infertility industry has developed multiple treatment protocols to offer women with PCOS. The following slides review two studies demonstrating the published success.
OHSS. Follicular arrest can be reversed by pharmacological manipulations with FSH. However the rescue may lead to OHSS, thus caution must be used. Although proper monitoring is key for preventing OHSS, other steps as listed here are also an option.
Questions and Thank-you.
Q’s• 28 y/o, F, see you c/o irregular menses, she has no had menstrual period for 6 months, also is concerned about weight gain, worsening acne and dark hair on her upper lip, chin and periareolar region, she is interested in becoming pregnant soon. The patient tells you she has started and exercise program which has helped with weight loss but continues to have amenorrhea. Labs:- urine B hCG: negative - serum free testosterone: mild elevate - glucose intolerance
Polycystic Ovarian Syndrome• 1st described by Irving Stein and Michael Leventhal as a triad of amenorrhea, obesity and hirsutism (1935)• The most common endocrine disorder in women of reproductive age ~ 2%-8% of women• Current suggested prevalence in the U.S. – Caucasian: 4.8% – African American: 8.0% . – Hispanic or Latino: 13% – 5%-10% of women
PCOS Presentation• Two of the following symptoms: –Polycystic ovaries (PCO) –Hyperandrogenism –Anovulation No single criteria is sufficient for clinical diagnosis.• Additional features may include: Excessive hair growth Abnormal bleeding Obesity Hair loss Acne Infertility
Genetic Link• Familial clustering of PCOS common – 1st degree relatives of patients with PCOS may be at high risk for diabetes and glucose intolerance – Mothers and sisters of PCOS patients have higher androgen levels than control subjects
PCOS: Metabolic Disorder• Insulin Resistance – High association with PCOS – 10% have Type 2 Diabetes – 30%-35% have Impaired Glucose Tolerance (IGT)• Obesity – 50% of PCOD patients are obese – Amplifies biochemical and clinical abnormalities of PCOS
PCOS: Metabolic Disorder• Endometrial Cancer – Long-term follow-up of 786 PCOS women found an increased risk of endometrial cancer – Women >50 yrs of age with endometrial cancer, PCOS (62.5%) more prevalent than not (27.3%; P=0.033)• Cardiovascular Disease – PCOS is characterized by endothelial dysfunction and resistance to vasodilating action of insulin – Increased risk of myocardial infarction in PCOS women than age-matched controls
PCOS: Metabolic Disorder• Sleep Apnea – Increased Sleep Disordered Breathing (SDB) and daytime sleepiness in PCOS vs. controls• Depression – Higher prevalence in PCOS patients, associated with higher body mass index (BMI, P=0.05) and greater insulin resistance (P=0.02)
PCOS: Weight Loss• Frequency of obesity in women with anovulation and PCO: 30%-75%• Six month weight-loss program for overweight anovulatory women – Lost an average of 6.3 kg (13.9 lbs) – Decreased fasting insulin and testosterone levels – 92% resumed ovulation – 85% became pregnant
Infertility Treatments• Step-by-step. . . . – If BMI elevated, loss of at least 5% body weight – Ovulation induction (OI) with clomiphene citrate – Insulin sensitizer as single agent – Insulin sensitizer + clomiphene – Gonadotropin therapy, FSH hormone – Gonadotropins + insulin sensitizer – In vitro fertilization (IVF)
PCOS: Stimulated Cycles• PCOS patients are often high responders to medications, .• Clomid and FSH . – High risk of multiple pregnancy – Ovarian hyperstimulation syndrome (OHSS) – IVF…single embryo transfer
Conclusions• PCOS is a multifaceted condition – Varying presentations – Begins in adolescence – Long-term consequences – Genetic and pre-natal implications – Metabolic Disorder – Cosmetic issues – Reproductive complications. cycle irregularity / bleeding / endometrial cancer• Infertility – Common endocrinopathy in pre-menopausal women, causing menstrual irregularities and hirsutism – Multiple treatments available with potentially successful outcomes