Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features.

STUDY QUESTION: Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER: Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were associated with impaired cardiometabolic features in all women irrespective of their clinical condition. WHAT IS KNOWN ALREADY: Sex steroid hormones play important roles in the development of cardiovascular diseases (CVD). Extremes of low as well as high androgen levels have been associated with increased CVD risk in both men and women. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 680 women with polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), natural post-menopausal women (NM), or regular menstrual cycles (RC) (170 women per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: Measurements of serum testosterone, androstenedione and dehydroepiandrosterone sulfate were performed using liquid chromatography-tandem mass spectrometry. Assessments were taken of body mass index (BMI), blood pressure, lipid profiles, glucose, insulin and SHBG, and the bioactive fraction of circulating testosterone was calculated using the free androgen index (FAI). MAIN RESULTS AND THE ROLE OF CHANCE: PCOS women were hyperandrogenic [median FAI = 4.9 (IQR 3.6-7.4)], and POI women were hypoandrogenic [FAI = 1.2 (0.8-1.7)], compared with RC women [FAI = 1.7 (1.1-2.8)], after adjustment for age, ethnicity, smoking and BMI (P < 0.001). After adjustment for age, there were no significant differences in androgens between POI and NM (P = 0.15) women and between NM and RC (P = 0.27) women, the latter indicating that chronological aging rather than ovarian aging influences the differences between pre- and post-menopausal women. A high FAI was associated with elevated triglycerides (ß log FAI for PCOS: 0.45, P < 0.001, POI: 0.25, P < 0.001, NM: 0.20, P = 0.002), insulin (ß log FAI for PCOS: 0.77, POI: 0.44, NM: 0.40, all P < 0.001), HOMA-IR (ß log FAI for PCOS: 0.82, POI: 0.46, NM: 0.47, all P < 0.001) and mean arterial pressure (ß log FAI for PCOS: 0.05, P = 0.002, POI: 0.07, P < 0.001, NM: 0.04, P = 0.04) in all women; with increased glucose (ß log FAI for PCOS: 0.05, P = 0.003, NM: 0.07, P < 0.001) and decreased high-density lipoprotein (ß log FAI for PCOS: -0.23, P < 0.001, NM: -0.09, P = 0.03) in PCOS and NM women; and with increased low-density lipoprotein (ß log FAI for POI: 0.083, P = 0.041) in POI women. Adjustment for BMI attenuated the observed associations. Associations between FAI and cardiometabolic features were the strongest in PCOS women, even after adjustment for BMI. LIMITATIONS, REASONS FOR CAUTION: Associations between androgen levels and cardiometabolic features were assessed in PCOS, POI and NM women only, due to a lack of available data in RC women. Due to the cross-sectional design of the current study, the potential associations between androgen levels and actual future cardiovascular events could not be assessed. WIDER IMPLICATIONS OF THE FINDINGS: This study affirms the potent effect of androgens on cardiometabolic features, indicating that androgens should indeed be regarded as important denominators of women's health. Future research regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required. STUDY FUNDING/COMPETING INTERESTS: N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose.

Changes in androgens during treatment with four low-dose contraceptives.

The aim of the present study was to compare changes in the endogenous androgen environment in healthy women while on low-dose oral contraceptives (OCs). One-hundred healthy women were randomized to receive one of four OCs during six months: 21 tablets of Cilest, Femodeen, Marvelon, or Mercilon. During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded and the following parameters were measured: sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), testosterone (T), free testosterone (FT), 5 alpha-dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone-sulphate (DHEA-S) and 17 alpha-hydroxyprogesterone (170HP) while also the free androgen index (FAI) was calculated. Measurements were repeated during the 3rd week of pill intake in the 4th and the 6th pill month. There were no differences on body mass and blood pressure with the use of the four OCs. The mean serum DHEA-S decreased significantly in all groups though less in the Mercilon group when compared to Cilest and Marvelon (approximately 20% vs 45%). Mean serum SHBG and CBG increased significantly in all four groups approximately 250% and 100%, respectively. In each group CBG also increased significantly but less in women taking Mercilon (-75%) as compared to the others (-100%). Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S. They may be equally beneficial in women with androgen related syndromes such as acne and hirsutism.

PIP: Health researchers randomly assigned 100 healthy women aged 18-38 from the Netherlands and Saudi Arabia to one of four various oral contraceptive (OC) groups to undergo six cycles of OC therapy so they could evaluate changes in plasma concentrations of sex hormone binding globulin (SHBG), corticosteroid-binding globulin (CBG), albumin (Alb), testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), androstenedione (A), dehydro-epiandrosterone-sulphate (DHEA-S), and 17 alpha-hydroxyprogesterone (17OHP). The four monophasic OCs were Cilest (35 mcg ethinyl estradiol [E2] and 250 mcg norgestimate), Femodeen (30 mcg E2 and 75 mcg gestodene), Marvelon (30 mcg E2 and 150 mcg desogestrel), and Mercilon (20 mcg E2 and 150 mcg desogestrel). There were 12 dropouts. Neither body weight nor blood pressure changed significantly during the study. All steroidal serum parameters (T, FT, DHT, A, DHEA-S, 17OHP, Alb) fell significantly during the six cycles of OC treatment (ratio of decrease, 1.3-3), regardless of OC type. These changes had appeared after cycle 4. The only significant difference between the OC groups was that the mean decrease of DHEA-S for Mercilon was lower than that for the other OC groups (21% vs. 43% for Cilest, 44% for Marvelon, and 34% for Femodeen; p 0.05). SHBG and CBG rose greatly during OC use in all four OC groups (mean increase = 263% and 94%, respectively; p 0.05). The increase in CBG was significantly less in the Mercilon group than in the other OC groups (74% vs. 96% for Cilest, 101% for Femodeen, and 102% for Marvelon; p 0.05). These findings show that OC use changed the endogenous androgen environment in the direction of hypoandrogenism. Thus, all four OCs can equally treat androgen-related syndromes (e.g., acne and hirsutism).

A cross-over study of three oral contraceptives containing ethinyloestradiol and either desogestrel or levonorgestrel.

A randomised cross-over trial was performed to compare the pharmacodynamic actions of three low-dose oral contraceptives (OCs): Marvelon (150 micrograms desogestrel (DSG)+ 30 micrograms ethinyloestradiol (EE)), Mercilon (150 micrograms DSG + 20 micrograms EE) and Microgynon (150 micrograms levonorgestrel (LNG) + 30 micrograms EE). None of the OCs produced any significant changes in serum cholesterol, LDL-C and apoprotein B. Triglycerides were increased by the desogestrel OCs but not by Microgynon. The latter however increased the glucose and insulin responses to a glucose tolerance test whereas Marvelon and Mercilon had no effect. HDL-C increased with Marvelon, was unchanged with Mercilon and was decreased with Microgynon. Apoprotein AII was increased by all three OCs but only the DSG OCs increased apoprotein AI. All OCs produced similar increases in caeruloplasmin but the increase in SHBG was much greater with Marvelon and Mercilon than with Microgynon. Testosterone was reduced more with Microgynon than with the DSG OCs. Many of the changes reflect the strong anti-oestrogenic action of LNG on metabolic parameters compared to DSG. Except for the effect on HDL-C, there was little difference between Marvelon and Mercilon on metabolic parameters and this complements the findings from large-scale clinical trials of the two OCs. Mercilon, therefore provides a very satisfactory alternative to Marvelon.

PIP: 12 healthy volunteers attending the family planning clinic at Shanghai, First Maternity and Infant China, Hospital, enrolled in the study, Oral contraceptives (OCs) were prescribed: Marvelon (150 mcg of desogestrel--DSG), Mercilon (150 mcg of DSG), and Microgynon (150 mcg of levonorgestrel--LNG). The patients were divided into 6 groups of 2 persons each in a randomized cross-over study. OCs were taken on day 6 of the cycle up to day 21, then stopping for 7 days. Each OC was used for 3 months. During the pretreatment cycle between days 6 and 9 of the follicular phase and 21 and 22 of the luteal phase a blood sample was taken after fasting for determination of lipids, sex hormone binding globulin (SHGB), ceruloplasmin, and testosterone. After glucose loading, significant increases of glucose and insulin occurred at 1, 2, and 3 hours during treatment with Microgynon only. The ratio for total areas of insulin to glucose did not change significantly nor did glycosilated hemoglobin A1 levels. Serum triglyceride concentrations increased significantly for both Marvelon (27%-43%) and Mercilon (29-40%). Serum high density lipoprotein (HDL) cholesterol concentrations were significantly elevated with Marvelon but less so with Mercilon, while HDL-C decreased significantly with Microgynon. The serum low density lipoprotein (LDL) cholesterol changes were not significant, but LDL-C concentrations declined with DSG formulations and increased with Microgynon. Apoprotein A1 and A2 increased significantly for both Marvelon and Mercilon. Apoprotein A2 increased with Microgynon. Serum SHBG increased markedly with Marvelon (335-380%). Serum testosterone concentrations decreased significantly (33.2-40.4% with Microgynon) and so did ceruloplasmin values. The antiestrogenic effect of strong LNG in Microgynon produced significant metabolic changes. The effect of 30 mcg EE in Marvelon and 20 mcg EE of Mercilon was equal.

[Changes in plasma levels of androgens and SHBG in patients with polycystic ovary syndrome (PCOs) treated with oral contraceptives containing desogestrel]. / Modificazione dei livelli plasmatici degli androgeni e della SHBG in pazienti con sindrome dell'ovaio policistico (PCOs) trattate con contraccettivi orali contenenti desogestrel.

PIP: 8 women, aged 17-25, with polycystic ovary syndrome (PCO) were treated with Practil 21 (Organon) containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel, or with Planum (Menarini). Checkups were conducted 3 and 6 months later to measure hormone levels. The average level of testosterone dropped significantly from 121.5 (+ or - 50.9) ng/dl to 23.1 (+ or - 10.6) ng/dl after 3 months. The level of androstenedione also decreased significantly from 265.2 (+ or - 101.4) ng.dl to 96.7 (+ or - 22.5) ng/dl. Similarly, the level of 17-hydroxyprogesterone declined from 120.5 (+ or - 69.8) ng/dl to 24.5 (+ or - 10.7) ng/dl . On the other hand, the level of sex hormone binding globulin rose from 1.3 (+ or - .6) mcg/100 ml to 3.9 (+ or - 1.8) mcg/100 ml. Cortisone level increased significantly from 15 (+ or - 3.2) mcg/100 ml to 30.6 (+ or - 10.4) mcg/100 ml after 3 months, but the normal range (5-20 mcg/100 ml) was attained at the end. Ecographic evaluation of the size of the ovaries indicated a 18.2-66.5% reduction after 3 months. In 3 cases, the number and dimension of follicles also diminished conspicuously. Acne, hirsutism, and other symptoms of hyperandrogenism also declined. Side effects were minor and included slight weight gain, spotting and headache; treatment was suspended in only 1 case because of a grand mal seizure. The administration of this new monophasic OC proved to be a valid alternative therapy for PCO.^ieng

Restovar--new low-dose, combined, oral contraceptive. Effects on serum proteins, free testosterone and clinical efficacy.

PIP: A combined oral contraceptive (OC, Restovar, Organon) containing 0.0375 mg ethinyl estradiol and 0.75 mg lynestrenol was investigated. Various clinical and laboratory variables were studied in 164 women over 1376 treatment cycles. No pregnancies occurred. In common with other low-dose combined preparations, Restovar also caused some intermenstrual bleeding but acceptability was good in the majority of women. The frequency of general complaints was low. The estrogen-sensitive proteins, ceruloplasmin and transcortin, increased in proportion to the estrogen content of the preparation. The estrogen-androgen-sensitive proteins, sex hormone binding globulin, and thyroxin binding globulin, increased to a rather high level. Free testosterone decreased significantly. The elevation of sex hormone binding globulin level was accompanied by a decrease in free testosterone. The strong increases in sex hormone binding globulin and thyroxin binding globulin indicate that the preparation has a very low androgenic activity. The latter was confirmed in 2 women with initially low sex hormone binding globulin levels who showed a marked improvement in hirsutism and acne during treatment; this improvement was correlated with an increase in sex hormone binding globulin and decreased free testosterone levels.^ieng