Robert P. Kauffman

Detecting Insulin Resistance in Polycystic Ovary Syndrome: Purposes and Pitfalls

Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and “normal” insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to explain the pathophysiology of insulin resistance, to list the factors that affect insulin sensitivity, and to outline the various methods used to assess insulin sensitivity.

Endocrine and metabolic differences among phenotypic expressions of polycystic ovary syndrome according to the 2003 Rotterdam consensus criteria

OBJECTIVE The Rotterdam criteria extend the phenotypic spectrum of polycystic ovary syndrome (PCOS). We characterized endocrine and metabolic differences among women meeting the National Institutes of Health (NIH) definition for PCOS vs two novel phenotypes established by the European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine definition. STUDY DESIGN Endocrine and metabolic data from a retrospective analysis of 160 age- and weight-matched women with PCOS and 23 controls were compared. Insulin sensitivity indices were correlated with androgens, gonadotropins, and lipids within each phenotype. RESULTS Ovarian and adrenal androgens were highest in the NIH-defined PCOS group, lowest in the nonhyperandrogenic PCOS group, and intermediate in the hyperandrogenic ovulatory PCOS population. Insulin sensitivity indices, gonadotropins, and lipids were similar across all PCOS phenotypes. The magnitude of insulin resistance correlated with free testosterone only in the NIH-defined group. CONCLUSION Androgen levels are the major distinguishing endocrine feature differentiating phenotypic expressions of PCOS. Hyperinsulinemia correlates with free testosterone levels only in traditional NIH-defined women with PCOS.

Osteoporosis in children and adolescent girls: case report of idiopathic juvenile osteoporosis and review of the literature.

The diagnosis and treatment of osteoporosis is an important aspect of gynecologic training and practice. Idiopathic juvenile osteoporosis (IJO) is a rare disease of children and adolescents that resolves after the onset of puberty. A case report is presented and current methods of diagnosis and treatment of IJO are discussed as well as the differential diagnosis. A MEDLINE search was performed of the following terms: idiopathic juvenile osteoporosis, pediatric osteoporosis, adolescent osteoporosis, bisphosphonates pediatric adolescent, and pregnancy osteoporosis, and references from bibliographies of selected papers were used as well. All papers in English, French, and German are considered in this review. There were 114 papers selected as relevant to the topic. Data relevant to the diagnosis, pathogenesis, methods of imaging, laboratory evaluation, differential diagnosis, and treatment of IJO are presented. IJO is a diagnosis of exclusion in the pediatric and adolescent patient with osteoporosis. Although bone density gradually improves after the onset of puberty, treatment of currently affected children and adolescents involves activity restriction, calcium, vitamin D, and bisphosphonate therapy. Future reproductive concerns are discussed and areas requiring additional study are reviewed. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to describe the condition idiopathic juvenile osteoporosis, compare the clinical features of this condition to other similar conditions, outline the diagnostic workup of a child with this condition, and list the potential therapeutic options for a patient with idiopathic juvenile osteoporosis.

Impact of the selective serotonin reuptake inhibitor citalopram on insulin sensitivity, leptin and basal cortisol secretion in depressed and non-depressed euglycemic women of reproductive age.

Introduction. Major depression in women of reproductive age may be accompanied by multiple endocrine and metabolic disturbances, which, in turn, may affect reproductive functioning. Enhanced cortisol synthesis, impaired leptin production and diminished insulin sensitivity have been reported in some depressed populations. We sought to determine whether an 8-week administration of citalopram would have an effect on these endocrine factors in a group of euglycemic depressed and non-depressed women of reproductive age. Materials and methods. Fourteen depressed and 18 non-depressed women (diagnosed by structured clinical interview) aged between 18 and 45 years completed an 8-week study. All depressed women were treated with citalopram and non-depressed subjects randomized to citalopram or no treatment in an open label cohort study. An oral glucose tolerance test with insulin levels was performed at baseline and at the end of the 8-week trial. Weight, blood pressure, fasting serum cortisol, fasting serum leptin and Beck Depression Inventory were assessed at baseline, 2, 4 and 8 weeks. Results. Citalopram significantly improved depressive symptoms and Beck Depression Inventory scores in the depressed cohort. Cortisol production was higher in depressed women but did not diminish with citalopram therapy over 8 weeks. Indices of insulin sensitivity and leptin production were similar between depressed and non-depressed women and did not change despite citalopram therapy. Conclusion. Insulin sensitivity in moderately depressed women of reproductive age does not differ from that in a similar group of non-depressed women. Insulin sensitivity, cortisol secretion and leptin production do not change significantly in depressed women following an 8-week course of citalopram despite substantial improvement in depression scores.

Endocrine factors associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome: do androgens play a role?

Objective. To characterise the metabolic profile of women with polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD) and to determine whether circulating androgens differ in PCOS women with NAFLD compared to PCOS subjects without NAFLD. Methods. Retrospective study of 21 women with PCOS, elevated liver enzymes and ultrasound evidence of hepatic steatosis matched with 32 PCOS women with normal liver enzymes. Extensive demographic, endocrine and metabolic data were compared. Pearsons correlation coefficients were calculated to assess for potential relationships between the free androgen index (FAI) and other dependent variables. Results. PCOS subjects with NAFLD demonstrate greater insulin resistance but have similar circulating androgen levels. Conclusion. In this pilot study, insulin resistance was the most prominent feature characterising NAFLD complicating PCOS. Total testosterone, FAI, DHEAS and 17-hydroxyprogesterone levels were similar between patients with PCOS and without NAFLD.

Premature Ovarian Failure Associated with Autoimmune Polyglandular Syndrome: Pathophysiological Mechanisms and Future Fertility

BACKGROUND Autoimmune polyglandular syndromes (APS) are a series of disorders characterized by autoimmunity against two or more endocrine organs. Premature ovarian failure (POF) may also have an autoimmune origin and, when accompanied by other autoimmune endocrinopathies, may be part of the APSs. Onset of autoimmune ovarian failure usually occurs in childhood, adolescence, or adulthood, and as a result, fertility may be severely compromised. CASE REPORT A 26-year-old women with secondary amenorrhea, Addisons disease, and autoimmune hypothyroidism requested infertility evaluation. Examination, transvaginal ultrasonography, endocrine evaluation, and ovarian biopsy were performed. 21-Hydroxylase and antithyroid antibodies were demonstrated, but ovarian steroid cell antibodies (StCA) were absent at the time of her infertility evaluation. Transvaginal sonography demonstrated only a few ovarian follicles. An ovarian biopsy revealed lymphocytic infiltration of the ovary. This presentation is consistent with APS type II accompanied by autoimmune POF. DISCUSSION Unlike APS types I and III, autoimmune POF is more commonly encountered with APS types I and III than with APS type II. An autoimmune response to steroidogenic enzymes and ovarian steroid cells appears to mediate destruction of ovarian function. Although immunotherapy with corticosteroids (with or without in vitro fertilization [IVF]) may be successful in limited cases where several follicles are present, oocyte donation with IVF may be the best option for the patient seeking fertility, particularly in the absence of ovarian follicles. CONCLUSIONS Advances in molecular genetics may be valuable in predicting and counseling women at risk for APS and POF, and cryopreservation of ovarian tissue may offer hope to affected unmarried young women. It is reasonable to suggest that children and reproductive aged women with one autoimmune disorder should be periodically screened for other autoimmune disorders.

Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction Following Discontinuation of Citalopram and the Atypical Antidepressant Nefazodone

SSRI therapy is commonly associated with sexual side effects, but it is assumed that these distressing symp- toms resolve with termination of therapy. The atypical antidepressant nefazodone is infrequently associated with sexual dysfunction and may be substituted for SSRIs when sexual symptoms are intolerable. Recently, scattered case reports of persistent sexual dysfunction and genital anesthesia persisting well after termination of SSRI antidepressant therapy have surfaced. In each case, the underlying depressive disorder was in remission. Case: A 32-year old women with major depression was treated with citalopram but switched to nefazodone after 4 weeks of therapy due to genital anesthesia and orgasmic dysfunction. These symptoms continued following institution of nefa- zodone therapy and have persisted for over a year since termination of antidepressant treatment. Her depression remains in full remission. Discussion: It is likely that persistent post-treatment genital anesthesia and other sexual side effects are underreported, and physicians should be aware of this bothersome phenomenon. Formal post-treatment surveillance for this condition is war- ranted. Pharmacogenomic research may ultimately allow physicians to predict who is at risk for antidepressant induced sexual side effects.

Serum magnesium concentrations and metabolic variables in polycystic ovary syndrome.

Objective. Hypomagnesemia is associated with diabetes mellitus type 2 and other components of the metabolic syndrome in older patients. Whether serum magnesium concentrations correlate with insulin resistance, obesity, hypertension, dyslipidemia, or other components of metabolic syndrome in younger women with polycystic ovary syndrome (PCOS) is currently unknown. Design. Cross‐sectional analysis. Setting. Academic medical center. Population. 100 consecutive women with PCOS by the Rotterdam criteria and 20 age‐ and BMI‐matched normal women. Methods. Statistical analysis of the relationship between magnesium levels and a variety of physical, endocrine, and metabolic variables. The STROBE guidelines for a cross‐sectional analysis were followed. Main outcome measurements. Serum magnesium levels, insulin sensitivity indices, and glucose assessments. BMI, waist circumference, blood pressure, and lipids served as secondary endpoint measurements. Results. No patient demonstrated hypomagnesemia. Magnesium levels did not differ between women with and those without insulin resistance, glucose intolerance, or hypertension. Magnesium levels were similar across PCOS phenotypes and WHO‐defined BMI categories. Multiple regression analysis did not suggest that serum magnesium concentrations correlated with any physical, metabolic, or endocrine variable. Conclusions. Magnesium levels do not correspond with age, BMI, waist circumference, insulin sensitivity, glycemic levels, blood pressure, or lipid levels in reproductive‐age women with PCOS. Magnesium concentrations are similar across PCOS phenotypes and indistinguishable from women without PCOS.

Current Recommendations for Cervical Cancer Screening: Do They Render the Annual Pelvic Examination Obsolete?

The development of a screening test for cervical dysplasia has been a major force in diminishing the worldwide incidence of invasive cervical cancer. Screening intervals recommended by professional organizations have changed over the past half century. Recognition of the human papillomavirus (HPV) as the causative agent and enhanced understanding of the natural history of HPV and cervical dysplasia in different age groups have prompted the American College of Obstetricians and Gynecologists and other professional societies to defer Pap smear screening to intervals no less than 2 years apart in women 21-29, and every 3 years in women 30 and over assuming no prior history of cervical dysplasia. Screening should start no sooner than age 21. These recommendations more closely resemble those currently practiced in Europe and other parts of the developed world. Those who have undergone hysterectomy no longer need screening unless high-grade dysplasia was present. Although the value of pelvic examination is not debated in women with symptoms referable to the female genital tract, the endorsement by several professional societies of less than annual cervical cancer screening in healthy women also begs the question of whether annual pelvic examination (speculum and/or bimanual examination) benefits asymptomatic women. Some sexually transmitted infections are amenable to self-insertion of a vaginal probe or detectable by voided urine specimen. Bimanual examination is insensitive in detecting early ovarian cancer with a high false-positive rate leading to patient anxiety, excessive diagnostic testing, and unnecessary surgical procedures. Future study should focus on the frequency in which healthy asymptomatic women should undergo pelvic examination.

Infant feeding and contraceptive practices among adolescents with a high teen pregnancy rate: a 3-year retrospective study.

BACKGROUND Adolescents consistently demonstrate the lowest rates of breastfeeding among women of reproductive age despite well-documented benefits of breastfeeding. In Amarillo, Texas, a medium-sized community with a perennially high teen pregnancy rate, we sought (1) to determine breastfeedings practices among adolescent females immediately after delivery and again at 6 weeks and (2) to identify contraceptive choices among the same teen population. METHODS This was a retrospective chart review focused on adolescents between the ages of 13 and 18 coming to a university-based obstetrical service between January 1, 2006, and December 31, 2008. Data on breastfeeding and contraceptive practices were analyzed. RESULTS Five hundred forty-three cases were analyzed. At hospital discharge, 59.3% initiated breastfeeding, but this dropped to 22.2% at the 6-week postpartum appointment. Over 27% of all study subjects failed to appear for postpartum evaluation. Multiparity was the only outcome variable associated with failure to initiate breastfeeding. Depot-medroxyprogesterone acetate, the levonorgestrel intrauterine device (IUD), and combination oral contraceptives were the most popular contraceptive choices, but 16% elected to forego any form of contraception at the postpartum visit. CONCLUSIONS Adolescent women living in an area of Texas with a high teen pregnancy rate reported relatively low breastfeeding rates immediately postpartum, with a >50% decrease in breastfeeding in any form by 6 weeks postpartum. A substantial number failed to initiate any form of contraception at the postpartum visit. These findings support the critical need for additional breastfeeding support and contraceptive education in this at-risk adolescent population.