Polycystic ovary syndrome (PCOS) is the most prevalent endocrine condition in premenopausal women. The syndrome is characterized by hyperandrogenism, irregular menses and polycystic ovaries when other etiologies are excluded. Obesity, insulin resistance and low vitamin D levels are present in more than 50% patients with PCOS, these factors along with hyperandrogenism could have adverse effects on long-term health. Hyperinflammation and impaired epithelial function were reported to a larger extent in women with PCOS and could particularly be associated with hyperandrogenism, obesity and insulin resistance. Available data from register-based and data linkage studies support that metabolic-vascular and thyroid diseases, asthma, migraine, depression and cancer are diagnosed more frequently in PCOS, whereas fracture risk is decreased. Drug prescriptions are significantly more common in PCOS than controls within all diagnose categories including antibiotics. The causal relationship between PCOS and autoimmune disease represents an interesting new area of research. PCOS is a lifelong condition and long-term morbidity could be worsened by obesity, sedentary way of life, Western-style diet and smoking, whereas lifestyle intervention including weight loss may partly or fully resolve the symptoms of PCOS and could improve the long-term prognosis. In this review, the possible implications of increased morbidity for the clinical and biochemical evaluation of patients with PCOS at diagnosis and follow-up is further discussed along with possible modifying effects of medical treatment.
Dorte Glintborg and Marianne Andersen
Marianne Andersen and Dorte Glintborg
Polycystic ovary syndrome (PCOS) is common in premenopausal women. The majority of women with PCOS have insulin resistance and the risk of type 2 diabetes mellitus (T2D) is higher in women with PCOS compared to controls. In non-pregnant women with PCOS, glycemic status may be assessed by oral glucose tolerance test (OGTT), fasting plasma glucose (FPG) or HbA1c. OGTT has been reckoned gold standard test for diagnosing T2D, but OGTT is rarely used for diagnostic purpose in other non-pregnant individuals at risk of T2D, apart from PCOS. OGTT has questionable reproducibility, and high sensitivity of the 2-h glucose value is at the expense of relatively low specificity, especially regarding impaired glucose tolerance (IGT). Furthermore, lean women with PCOS are rarely diagnosed with T2D and only few percent of normal-weight women have prediabetes. Glycemic status is necessary at diagnosis and during follow-up of PCOS, especially in women with high risk of T2D (obesity, previous gestational diabetes (GDM)). We suggest that OGTT should be used in the same situations in PCOS as in other patient groups at risk of T2D. OGTT is indicated for diagnosing GDM; however, OGTT during pregnancy may not be indicated in lean women with PCOS without other risk factors for GDM.
Dorte Glintborg, Guy T'Sjoen, Pernille Ravn, and Marianne Skovsager Andersen
Transgender women are assigned male at birth, but identify as women. The incidence of gender dysphoria is estimated to be around 1% of the population. Gender dysphoria may be associated with depression and low quality of life, which in most cases improves during gender affirming hormonal treatment (GAHT). Feminizing hormonal treatment for transgender women or gender non-binary people typically includes natural estrogen (estradiol). Additional testosterone-blocking treatment is often needed to ensure suppression of the pituitary gonadal axis and may include cyproterone acetate, a gonadotropin releasing hormone agonist (GnRH-a) or spironolactone. The health risks of cyproterone acetate as anti-androgen treatment are debated and randomized protocols with other anti-androgen treatments are requested. Orchiectomy is performed in some transgender women after various duration of GAHT. Currently, natural progesterone is not recommended as part of GAHT due to limited knowledge on the balance between risks and benefits.
In the present article we discuss evidence regarding established and upcoming feminizing treatment for adult transgender women or for gender non-binary people seeking feminization. Data on study populations with transgender women are put into a wider context of literature regarding effects of sex steroid hormones in cisgender study populations. Relevant follow up and monitoring during feminizing treatment is debated. The review has special focus on the pharmacotherapy of feminizing hormonal therapy.
Dorte Glintborg, Marianne Andersen, Claus Hagen, Jan Frystyk, Veronica Hulstrøm, Allan Flyvbjerg, and Anne Pernille Hermann
Objective: Polycystic ovary syndrome (PCOS) patients are abdominally obese and are at increased risk of developing the metabolic syndrome. Low adiponectin and ghrelin levels in PCOS patients could be caused by insulin resistance as well as high testosterone levels.
Design: Adiponectin and ghrelin levels were evaluated in 51 hirsute PCOS patients referred to the outpatient clinic of an academic, tertiary care medical centre and in 63 weight-matched female controls. Relationships between adiponectin, ghrelin, leptin, body composition, testosterone and insulin were examined.
Methods: Measurements of body composition including waist-hip-ratio (WHR), body mass index (BMI) and whole body dual-energy X-ray absorptiometry scan measures of body fat mass. Measurements of fasting levels of adiponectin, ghrelin, leptin, androgen status, oestradiol, lipid variables and insulin during follicular phase.
Results: Adiponectin levels were significantly decreased in obese PCOS patients compared with weight-matched controls (geometric mean (−2 to 2 s.d.) 5.3 (2.5–11.1) vs 7.3 (3.0–17.4) mg/l, P<0.05). Mean ghrelin was significantly lower in hirsute PCOS patients than in controls (0.6 (0.3 to 1.4) vs 0.8 (0.4 to 1.7) μg/l, P<0.001) and this remained significant after subdividing subjects according to waist circumference and BMI. During multiple regression analysis, testosterone correlated positively with adiponectin and negatively with ghrelin independent of BMI, WHR and total fat mass.
Conclusion: Obese hirsute PCOS patients demonstrated significantly lower adiponectin levels than weight-matched controls suggesting a very high risk for the metabolic syndrome. Furthermore, ghrelin levels were decreased in hirsute PCOS patients and showed a significant, negative correlation with testosterone independent of body composition.
Dorte Glintborg, Katrine Hass Rubin, Mads Nybo, Bo Abrahamsen, and Marianne Andersen
The prevalence of type 2 diabetes is increased in polycystic ovary syndrome (PCOS), but the prevalence of other diseases is not clarified. We aimed to investigate morbidity and medicine prescriptions in PCOS.
A National Register-based study.
Patients with PCOS (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital (OUH)) and one control population. Premenopausal women with PCOS underwent clinical and biochemical examination (PCOS OUH, n=1217). PCOS Denmark (n=19 199) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (n=57 483).
Main outcome measures
Diagnosis codes and filled prescriptions.
The mean (range) age of the PCOS Denmark group and controls was 30.6 (12–60) years. Patients in PCOS Denmark had higher Charlson index, higher prevalence of diabetes, dyslipidemia, and hypertension than controls. PCOS was associated with a two times increased risk of stroke and thrombosis, whereas the risk of other cardiovascular diseases was not increased. Thyroid disease, asthma, migraine, and depression were more prevalent in PCOS Denmark vs controls, whereas fractures were rarer. Infertility was increased in patients compared with controls, but the mean number of births was higher in PCOS. Medicine prescriptions within all diagnosis areas were significantly higher in PCOS patients than in controls.
In PCOS OUH, polycystic ovaries (PCO) and irregular menses were associated with a more adverse metabolic risk profile, but individual Rotterdam criteria were not associated with cardiometabolic diagnoses.
Cardiometabolic and psychiatric morbidity were significantly increased in a Danish population with PCOS. Medical diseases are frequent also in young patients with PCOS.
Martin Overgaard, Dorte Glintborg, Henrik Thybo Christesen, Tina Kold Jensen, and Marianne Skovsager Andersen
Low circulating prolactin is a potential marker of metabolic risk during pregnancy. We aimed to investigate associations between prolactin and glucose status in pregnant women with and without gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS).
Prospective observational cohort study. From the Odense Child Cohort, 1497 pregnant women were included.
Blood samples were assessed during first, second (prolactin, hemoglobin A1c (HbA1c)) and third trimester (fasting prolactin, testosterone, HbA1c, insulin, glucose). Oral glucose tolerance test (OGTT) was performed around gestation week 28 in 350 women with risk factors for GDM and in 272 randomly included women. GDM was defined by 2-h plasma glucose ≥9.0 mmol/L.
The median (IQR) prolactin increased from 633 (451–829) mIU/L in first–second trimester to 5223 (4151–6127) mIU/L at third trimester. Prolactin was inversely associated with HbA1c in first (r = −0.19, P < 0.001) and third trimester (r = −0.07, P = 0.014). In third trimester, women with GDM (n = 37; 6.0%) had lower prolactin compared to women without GDM (4269 vs 5072 mIU/L, P = 0.004). Third trimester prolactin multiple of the median (MoM) was inversely associated with risk of GDM in multivariate regression analysis (OR 0.30, P = 0.034). PCOS was diagnosed in 10.0% (n = 146). Early pregnancy prolactin MoM was positively associated to PCOS diagnosis (OR 1.38, P = 0.051).
Low prolactin levels during pregnancy were associated with higher HbA1c and risk of GDM. A diagnosis of PCOS was associated with higher early pregnancy prolactin levels.
Dorte Glintborg, Henrik Bjarke Vaegter, Louise Lehmann Christensen, Emma Bendix, Thomas Graven-Nielsen, Per Grünwald Andersen, and Marianne Andersen
Hypogonadism is prevalent during opioid treatment, but the effect of testosterone replacement treatment (TRT) on body composition, pain perception, and adrenal function is unclear.
To measure changes in body composition, pain perception, quality of life, and adrenal function after TRT or placebo in opioid-treated men with chronic non-malignant pain.
Double-blind, placebo-controlled study in 41 men (>18 years) with total testosterone <12 nmol/L were randomized to 24 weeks TRT (Testosterone undecanoate injection three times/6 months, n = 20) or placebo (placebo-injections, n = 21).
Body composition (lean body mass and fat mass assessed by DXA), clinical pain intensity (numerical rating scale), and experimental pain perception (quantitative sensory assessment), quality of life (SF36), and adrenocorticotrophic hormone (ACTH) test. Data were presented as median (quartiles). Mann–Whitney tests were performed on delta values (24–0 weeks) between TRT and placebo.
The median age was 55 years (46; 59) and total testosterone before intervention was 6.8 (5.0; 9.3) nmol/L. TRT was associated with change of testosterone levels: 12.3 (7.0; 19.9) nmol/L (P < 0.001 vs placebo), increased lean body mass: 3.6 (2.3; 5.0) kg vs 0.1 kg (−2.1; 1.5) during TRT vs placebo and decreased total fat mass: −1.2 (−3.1; 0.7) kg vs 1.2 kg (−0.9; 2.5) kg, both P < 0.003. Changed pain perception, SF36, and ACTH-stimulated cortisol levels were non-significantly changed during TRT compared with placebo.
Six months of TRT improved body composition in men with opioid-induced hypogonadism without significant changes in outcomes of pain perception, quality of life, or adrenal function.