Bloodletting has no effect on the blood pressure abnormalities of hyperandrogenic women taking oral contraceptives in a randomized clinical trial

Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3–4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4–6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P < 0.001). Office and ambulatory BP did not change throughout the experimental period of the trial, both when considering all women as a whole or as a function of the study arm. The frequency of the non-dipping pattern in BP decreased during the experimental period [OR 0.694 (0.577–0.835), P < 0.001], regardless of the study arm. Decreasing iron stores by scheduled bloodletting does not override the BP abnormalities caused by COC in women with functional hyperandrogenism.

Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes

Context Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. Objectives (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. Design Randomized, parallel, open-label, clinical trial. Setting Academic hospital. Patients Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. Intervention After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. Main outcome measures Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin &lt;120 g/L and/or hematocrit &lt;0.36. Results From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: −1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels &lt;120 g/L and hematocrit (Hct) values &lt;0.36, respectively, but none showed Hb &lt;110 g/L or Hct &lt;0.34. Conclusions Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.

Mechanisms of fertility disorders in obese women

Obesity is a common problem among women of reproductive age. Overweight is known to negatively affect a woman’s fertility. So, women of reproductive age who are obese may experience menstrual irregularities, endometrial pathology and, ultimately, infertility. The pathogenetic mechanisms of reproductive dysfunction in obesity remain actively studied issues. It was established that leptin synthesized by adipose tissue inhibits granulosis, cell steroidogenesis and interferes with the ovulation process, which can directly affect reproductive function. Insulin resistance and compensatory hyperinsulinemia, which accompany obesity in women, can contribute to menstrual irregularities, ovulation and, ultimately, fertility. Obesity is also characterized by a state of «relative functional hyperandrogenism», which can affect ovarian function, contributing to the development of infertility. Moreover, obesity is characterized by a state of hyposomatotropinism, which can affect fertility, through changes in ovarian and endometrial function. Weight loss is most likely able to restore fertility in most cases, but there are no practical guidelines that would help the clinician choose the best method to reduce body weight from increased physical activity, dietary restrictions, drug therapy and bariatric surgery.

Modern treatment of hyperandrogenic conditions in women of reproductive age

The objective: to study the effectiveness and safety of modern antiandrogen therapy in patients with polycystic ovary syndrome (PCOS). Materials and methods. Materials and methods. The first (main) study group included 39 patients with PCOS who received combination nonsteroidal antiandrogen therapy: antiandrogen drug containing flutamide (125 mg 3 times a day) and phyto drug Ovarimedin 1 capsule 2 times a day after meals for 6 months . The II (control) group included 37 patients who received a combination drug containing 35 μg of ethinylestradiol and 2 mg of cyproterone acetate for 6 months. Results. After the course of treatment, biphasic MC was preserved in 25 (64.1%) patients of group I, and in 14 (37.8%) of group II. In group I, before the treatment of stage III hirsutism was in 23 patients (58.9%), after treatment – in 6 patients (15.3%); II stage in 10 patients (25.6%) before treatment, after treatment – in 18 patients (46.1%); I stage was found in 6 patients before treatment (15.5%) and in 15 patients (38.6%) after treatment. In group II patients, stage ІІІ hirsutism was detected in 21 patients (56.7%) before treatment, and in 7 patients (18.9%) after treatment; II stage in 9 patients (24.3%) before treatment, after treatment – in 13 patients (35.1%); I stage was found in 7 patients before treatment (19.0%) and in 17 patients (45.9%) after treatment. Conclusions. Antiandrogenic nonsteroidal therapy with multicomponent herbal drug (Ovaremidine) and nonsteroidal antiandrogens may be recommended for the treatment of women with functional hyperandrogenism accompanied by hirsut syndrome, menstrual irregularities and / or infertility. Our study confirmed that the use of this therapy contributes to the effective treatment of hirsutism, the restoration of menstrual disorders and fertility in women. Differential algorithm for the treatment of hyperandrogenism of various etiologies, which can be recommended in the clinical practice of obstetricians and gynecologists. Keywords: hyperandrogenism, polycystic ovary syndrome (PCOS), menstrual cycle, infertility, hirsutism, phytotherapy.

Developmental Programming: Sheep Granulosa and Theca Cell–Specific Transcriptional Regulation by Prenatal Testosterone

Prenatal testosterone (T)–treated sheep, similar to polycystic ovarian syndrome women, manifest reduced cyclicity, functional hyperandrogenism, and polycystic ovary (PCO) morphology. The PCO morphology results from increased follicular recruitment and persistence of antral follicles, a consequence of reduced follicular growth and atresia, and is driven by cell-specific gene expression changes that are poorly understood. Therefore, using RNA sequencing, cell-specific transcriptional changes were assessed in laser capture microdissection isolated antral follicular granulosa and theca cells from age 21 months control and prenatal T–treated (100 mg intramuscular twice weekly from gestational day 30 to 90; term: 147 days) sheep. In controls, 3494 genes were differentially expressed between cell types with cell signaling, proliferation, extracellular matrix, immune, and tissue development genes enriched in theca; and mitochondrial, chromosomal, RNA, fatty acid, and cell cycle process genes enriched in granulosa cells. Prenatal T treatment 1) increased gene expression of transforming growth factor β receptor 1 and exosome component 9, and decreased BCL6 corepressor like 1, BCL9 like, and MAPK interacting serine/threonine kinase 2 in both cells, 2) induced differential expression of 92 genes that included increased mitochondrial, ribosome biogenesis, ribonucleoprotein, and ubiquitin, and decreased cell development and extracellular matrix-related pathways in granulosa cells, and 3) induced differential expression of 56 genes that included increased noncoding RNA processing, ribosome biogenesis, and mitochondrial matrix, and decreased transcription factor pathways in theca cells. These data indicate that follicular function is affected by genes involved in transforming growth factor signaling, extracellular matrix, mitochondria, epigenetics, and apoptosis both in a common as well as a cell-specific manner and suggest possible mechanistic pathways for prenatal T treatment–induced PCO morphology in sheep.

Referral bias in female functional hyperandrogenism and polycystic ovary syndrome

ObjectiveWomen with polycystic ovary syndrome (PCOS) seeking health care in the United States may be more obese and hyperandrogenic than those present in the general population. We aimed to assess the impact of referral bias on European women with functional androgen excess disorders.DesignCross-sectional study.MethodsWe studied two groups of patients: i) 368 consecutive patients referred to our clinic for the study of functional hyperandrogenism (FH) (referral patients); ii) 57 consecutive premenopausal patients identified by screening during blood donation (unselected patients). We compared the anthropometric data from the groups of patients with those of two control populations: iii) a group of unselected premenopausal healthy female blood donors (unselected controls); and iv) data available from the local general premenopausal female population.ResultsReferral patients with FH were more hirsute, had a higher percentage of hyperandrogenemia, and fulfilled PCOS criteria more frequently than unselected patients. The prevalence of obesity in unselected controls was similar to that observed in the general population, whereas referral patients and unselected patients were more frequently obese. The prevalence of obesity was also higher among referral patients compared to unselected patients.ConclusionReferral bias influences the phenotype of patients with FH. Patients studied at the clinical setting may show more severe hyperandrogenic and obese phenotypes than patients from the general population, even though PCOS appears to be associated with weight excess also in the general European population. This fact should be considered when establishing reference values and control populations for clinical and research purposes.

Developmental Programming: Excess Weight Gain Amplifies the Effects of Prenatal Testosterone Excess On Reproductive Cyclicity—Implication for Polycystic Ovary Syndrome

Sheep exposed to testosterone (T) during early to midgestation exhibit reproductive defects that include hypergonadotropism, functional hyperandrogenism, polycystic ovaries, and anovulatory infertility, perturbations similar to those observed in women with polycystic ovary syndrome. Obesity increases the severity of the phenotype in women with polycystic ovary syndrome. To determine whether prepubertal weight gain would exaggerate the reproductive disruptions in prenatal T-treated sheep, pregnant sheep were injected with 100 mg T propionate (∼1.2 mg/kg) im twice weekly, from d 30–90 of gestation. Beginning about 14 wk after birth, a subset of control and prenatal T-treated females were overfed to increase body weight to 25% above that of controls. Twice-weekly progesterone measurements found no differences in timing of puberty, but overfed prenatal T-treated females stopped cycling earlier. Detailed characterization of periovulatory hormonal dynamics after estrous synchronization with prostaglandin F2α found 100% of controls, 71% of overfed controls, 43% of prenatal T-treated, and 14% of overfed prenatal T-treated females had definable LH surges. Only one of seven overfed prenatal T-treated female vs. 100% of control, 100% of overfed control, and seven of eight prenatal T-treated females exhibited a luteal progesterone increase. Assessment of LH pulse characteristics during the anestrous season found both overfeeding and prenatal T excess increased LH pulse frequency without an interaction between these two variables. These findings agree with the increased prevalence of anovulation observed in obese women with polycystic ovary syndrome and indicate that excess postnatal weight gain amplifies reproductive disruptions caused by prenatal T excess. Exposure of sheep to excess testosterone in utero disrupts reproductive cyclicity, with postpubertal excess weight gain amplifying the severity of this adult reproductive phenotype.

Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone

Prenatally testosterone (T)-treated female sheep exhibit ovarian and endocrinological features that resemble those of women with polycystic ovarian syndrome (PCOS), which include luteinizing hormone excess, polyfollicular ovaries, functional hyperandrogenism, and anovulation. In this study, we determined the developmental impact of prenatal T treatment on insulin sensitivity indexes (ISI), a variable that is affected in a majority of PCOS women. Pregnant ewes were treated with 60 mg testosterone propionate intramuscularly in cottonseed oil two times a week or vehicle [control (C)] from days 30 to 90 of gestation. T-females weighed less than C-females or males ( P < 0.05) at birth and at 5 wk of age. T-females had an increased anogenital ratio. An intravenous glucose tolerance test followed by an insulin tolerance test conducted after an overnight fast at 5, 20, and 30 wk of age ( n = 7–8/group) revealed that ISI were higher at 5 than 30 wk of age in C-females, reflective of a developing insulin resistance associated with puberty. T-females had higher basal insulin levels, higher fasting insulin-to-glucose ratio, and higher incremental area under the insulin curve to the glucose challenge. The ISI of T-females was similar to that of males. No differences in ISI were evident between groups at 20 and 30 wk of age. Mean basal plasma glucose concentrations and glucose disappearance and uptake did not differ between groups at any age. Our findings suggest that prenatal T treatment leads to offspring with reduced birth weight and impaired insulin sensitivity in early postnatal life.