17-hydroxyprogesterone Response Research Articles

17-Hydroxyprogesterone Response to Standard Dose Synacthen Stimulation Test in CYP21A2 Heterozygous Carriers and Non-carriers in Symptomatic and Asymptomatic Groups: Meta-analyses

Objective:Standard dose synacthen stimulation test (SDSST) is a gold standard screening test for evaluating adrenal gland function. Despite studies using SDSST to identify heterozygosity in CYP21A2, the reliability of the test for this purpose is still controversial. Therefore, the meta-analyses were performed to determine the differences in 17-hydroxyprogesterone (17-OHP) responses to standard dose (0.25 mg) SDSST in the diagnosis of CYP21A2 heterozygous individuals, with or without clinical signs of androgen excess disorders.Methods:PubMed and MEDLINE databases were searched. A total of 1215 subjects (heterozygous carriers n=669, mutation-free controls n=546) were included in the meta-analyses.Results:Basal 17-OHP median/mean levels were 4.156 (3.05-10.5)/5.241 (±2.59) nmol/L and 3.90 (2.20-9.74)/4.67 (±2.62) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Stimulated 17-OHP median/mean levels were 17.29 (14.22-37.2)/19.51 (±7.63) nmol/L and 9.27 (7.32-15.9)/10.77 (±3.48) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Basal 17-OHP median/mean levels were 3.21 (2.64-4.78)/3.33 (±0.84) nmol/L and 3.12 (1.82-3.6)/2.83 (±0.71) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. Stimulated 17-OHP median/mean levels were 14.16 (12.73-16.37)/14.16 (±1.37) nmol/L and 6.26 (4.9-8.23)/6.48 (±1.2) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. The cut-off levels for stimulated 17-OHP were 10.48 nmol/L and 13.48 nmol/L for asymptomatic heterozygous and symptomatic heterozygous, respectively.Conclusion:The meta-analyses support the idea that stimulated 17-OHP level has potential for use in identifying CYP21A2 carriers. Besides, considering differences in the basal and stimulated 17-OHP levels in symptomatic heterozygous individuals compared to those who were asymptomatic heterozygous could increase the accuracy of the test.

17-Hydroxyprogesterone Response to Standard Dose Synacthene Stımulation Test in CYP21A2 Heterozygous Carriers and Non-Carriers in Symptomatic and Asymptomatic Groups: Meta-Analyses

Objective Standard dose synacthene stimulation test (SDSST) is a gold standard screening test for evaluating adrenal gland functions. Despite the presence of the studies to determine heterozygosity of CYP21A2 by the SDSST, the reliability of the test is still controversial. Therefore, the meta-analyses were performed to determine the differences of the 17-hydroxyprogesterone(17-OHP) response to the standard dose(0.25mg) synacthene stimulation in the diagnosis of CYP21A2 heterozygous individuals with or without a clinical sign of androgen excess disorders. Methods PubMed and MEDLINE databases were searched. A total of 1215 subjects (heterozygous carriers n:669, mutation-free controls n:546) were included in the meta-analyses. Results Basal 17-OHP median-mean levels were determined to be 4.156(3.05-10.5)-5.241(2.59)nmol/L and 3.90(2.20-9.74)-4.67(2.62)nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Stimulated 17-OHP median-mean levels were determined to be 17.29(14.22-37.2)-19.51(7.63)nmol/L and 9.27(7.32-15.9)-10.77(3.48)nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Basal 17-OHP median-mean levels were determined to be 3.21(2.64-4.78)-3.33(±0.84)nmol/L and 3.12(1.82-3.6)-2.83(0.71)nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. Stimulated 17-OHP median-mean levels were found to be 14.16(12.73-16.37)-14.16(1.37) nmol/L and 6.26(4.9-8.23)-6.48(1.2)nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. The cut-off levels for stimulated 17-OHP were 10.48nmol/L and 13.48nmol/L for asymptomatic heterozygous and symptomatic heterozygous, respectively. Conclusion The meta-analyses support the idea that stimulated 17-OHP level has potential to use to determine CYP21A2 carriers. Besides, considering differences of the basal and stimulated 17-OHP levels in symptomatic heterozygous individuals than those who were asymptomatic heterozygous could increase the accuracy of the test.

Individual 17-Hydroxyprogesterone Responses to hCG Are Not Correlated With Follicle Size in Polycystic Ovary Syndrome.

ContextIn women with polycystic ovary syndrome (PCOS), 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation vary from increased to indistinguishable compared with normal controls.ObjectiveTo determine whether 17-OHP responses to recombinant-human chorionic gonadotropin (r-hCG) are individually correlated to the size of antral follicles among women with PCOS.Design, Setting, and ParticipantsA prospective study conducted in 19 women with PCOS and 20 normal controls at an academic medical center.InterventionsBlood samples were obtained before and 24 hours after administration of 25 μg of r-hCG. Ovarian imaging was conducted with three-dimensional pelvic ultrasonography. Each subject underwent a 2-hour oral glucose tolerance test.Main Outcome MeasuresBasal and stimulated levels of 17-OHP, androgens, estradiol, progesterone, anti-Mullerian hormone (AMH), insulin, glucose, follicle number, and size.ResultsIn women with PCOS, mean antral follicle count (AFC) was greater than that of controls, although the size of cohort follicles within individual subjects was not correlated to 17-OHP responses. The numbers of 2- to 3-mm and 3- to 4-mm follicles in PCOS were significantly greater than in controls, whereas differences between larger follicles were not observed. Increased AMH in PCOS was correlated to AFC, but not 17-OHP responses. Insulin sensitivity did not correlate to r-hCG‒stimulated 17-OHP after adjustment for body mass index.Conclusions17-OHP responses to hCG in individuals with PCOS were not correlated to the distribution of antral follicles. Greater numbers of small antral follicles in women with PCOS than in controls suggest an extension of accelerated growth from the preantral stage.

Circulating thyrotropin is upregulated by estradiol

After encountering two women with serum thyrotropin (TSH) levels greater in periovulatory phase than in other days of the menstrual cycle, we hypothesized that TSH levels could be sensitive to changes in circulating estrogens in women.The objective of this study was to evaluate whether serum TSH increases after an induced acute increase of serum estradiol, and compare serum TSH increase with that of prolactin (PRL) which is a classic estradiol-upregulated pituitary hormone.In this retrospective study, we resorted to stored frozen sera from 55 women who had undergone the GnRH agonist (buserelin)-acute stimulation test of ovarian steroidogenesis. This test, that is preceded by dexamethasone administration to suppress adrenal steroidogenesis, had been performed to show an increased buserelin-stimulated response of 17-hydroxyprogesterone, a response that is frequent in polycystic ovary syndrome. Fifty-five women had enough serum volume at pertinent times (first observation early in the follicular phase and all times of the test) to permit assay of serum estradiol, TSH and PRL.Before dexamethasone administration, estradiol averaged 26.4 ± 15.5 pg/ml (reference range 23–139, follicular phase), TSH 1.78 ± 0.86 mU/L (reference range 0.3–4.2) and PRL 409.4 ± 356 mU/L (reference range 70.8–556) (mean ± SD).Serum estradiol, TSH and PRL averaged 47.2 ± 27 pg/ml, 0.77 ± 0.48 mU/L and 246.4 ± 206.8 mU/L just prior to the buserelin injection, but they peaked at 253.4 ± 113.5 pg/ml (nv 83–495, midcycle), 3.30 ± 1.65 mU/L and 540.3 ± 695.2 mU/L after injection. The responses to buserelin of estradiol, TSH and PRL were of wide magnitude. There was a significant correlation between TSH peak and serum estradiol peak, betweeen AUC0-24 h-TSH and AUC0-24 h-estradiol, or between PRL peak and estradiol peak and AUC0-24 h -PRL and AUC0-24 h-estradiol in only a subgroup of women.Therefore, women with estradiol-dependent increase in serum TSH do exist. Reference bands of serum TSH dependent on the phases of the menstrual cycle should be available.

Relationship between 17-hydroxyprogesterone responses to human chorionic gonadotropin and markers of ovarian follicle morphology in women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) have increased 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation although individual variability is substantial, as reflected by exaggerated as well as normal responses. The relationship between 17-OHP responses to gonadotropin stimulation and markers of ovarian function has not been assessed. To determine whether 17-OHP responses are associated with antral follicle count (AFC), anti-Mullerian hormone (AMH), or inhibin B (Inh B) levels in PCOS and normal women. Prospective study. Research center at an academic medical center. Women with PCOS (n = 18) and normal controls (n = 18). Blood samples were obtained before and 24 hours after administration of 25 μg recombinant-human chorionic gonadotropin. Ovarian imaging was conducted with three-dimensional pelvic ultrasound. Basal and stimulated levels of 17-OHP, androgens, estrogen, AMH, Inh B, and AFC. In women with PCOS, 17-OHP responses were heterogeneous and inversely correlated with AMH and Inh B levels, but not AFC. In a subgroup of PCOS women with exaggerated 17-OHP responses, AMH levels were equivalent to that of normal women. In PCOS women with normal 17-OHP responses, AMH levels were markedly elevated. Based on heterogeneous 17-OHP responses to human chorionic gonadotropin in women with PCOS, AMH levels are inversely linked to ovarian androgen production while positively correlated with AFC. These findings suggest that in PCOS, AMH production may reflect redistribution of the follicle population or regulation by intraovarian mechanisms.

Interrelationships Among Cortisol, 17-Hydroxyprogesterone, and Androstenendione Exposures in the Management of Children With Congenital Adrenal Hyperplasia

Hydrocortisone is the standard replacement therapy for children with congenital adrenal hyperplasia (CAH). Relationships between cortisol exposures and pharmacodynamic responses of 17-hydroxyprogesterone and androstenedione exposures have not been systematically evaluated.Objectives(1)...

Characterization of adrenal androgen production in functionally distinct women with polycystic ovary syndrome

Studies have demonstrated differences in ovarian steroid production among women with PCOS when exposed to GnRH agonist (GnRHa) or human chorionic gonadotropin (hCG). Approximately 50% PCOS patients exhibited exaggerated 17-hydroxyprogesterone (17-OHP) responses (hyper-responders, HR-PCOS) while others (normal responders, NR-PCOS) had responses equivalent to normal controls following stimulation. These findings raised the consideration that adrenal androgens may contribute to excess androgen production in NR-PCOS individuals.

HCG-stimulated 17OHP responses and basal serum AMH levels among adolescent women with polycystic ovary syndrome

We have previously shown that some adult women with PCOS have exaggerated 17-hydroxyprogesterone (17-OHP) responses to hCG (HR-PCOS), while the others exhibit responses equivalent to normal women (NR-PCOS)1. Additionally, differences in hormonal profiles were observed among these subgroups. Notably, serum AMH levels were lower in HR-PCOS compared to that of NR-PCOS2. These studies were conducted in adult women. We sought to determine whether disparate responses to hCG exist in adolescents with PCOS.

Determinants of Adrenal Androgen Hypofunction in Premenopausal Females With Rheumatoid Arthritis

The aim of our study was to investigate adrenocortical function in the context of disease activity and inflammatory status in premenopausal RA females. Adrenal glucocorticoid and androgen responses to the 1 microg ACTH 1-24 test were investigated in 23 premenopausal RA and in 15 age- and BMI-matched healthy females. Twelve RA patients were on low-dose prednisone (<8.5 mg/day). Patients with DAS28>3.2 had lower (p<0.05) total plasma cortisol, 17-hydroxyprogesterone, dehydroepiandrosterone and androstenedione responses in the ACTH test compared to healthy controls. Patients with DAS28>3.2 had lower (p<0.05) dehydroepiandrosterone response in the ACTH test compared to patients with DAS28</=3.2. C-reactive protein (CRP), DAS28, and interleukin (IL)-6 negatively correlated with androstenedione response to ACTH 1-24. Responses of all measured adrenal steroids were lower (p<0.05) in patients on low-dose glucocorticoids compared to healthy controls. RA patients not treated with glucocorticoids had lower total cortisol response (p=0.038) but did not differ in free plasma cortisol in the ACTH test. The results indicate an association of increased disease activity with a decrease in adrenal androgen production in RA and normal cortisol bioavailability in patients not treated with glucocorticoids.

Phenotypically distinct theca cell responses to gonadotropin administration in women with polycystic ovary syndrome

Women with PCOS have heterogeneous ovarian steroid production following GnRH agonist stimulation as 50% demonstrate exaggerated 17-hydroxyprogesterone (17-OHP) responses while the remainder exhibit responses equivalent to normal women. To determine whether this dichotomous 17-OHP response persists following independent administration of LH or FSH, ovarian responses to hCG and FSH were assessed in women with PCOS and normal women.

Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries

To determine the relationship of antimüllerian hormone (AMH) levels to polycystic ovaries and ovarian androgenic function. Prospective case-control study. General clinical research center. Eumenorrheic asymptomatic volunteers without (V-NO; n = 19; reference population) or with (V-PCO; n = 28) a polycystic ovary and hyperandrogenemic anovulatory subjects grouped according to ovarian function into typical PCOS (PCOS-T; n = 37) and atypical PCOS (PCOS-A; n = 18). Pelvic ultrasonography, short dexamethasone androgen-suppression test (SDAST), and GnRH agonist (GnRHag) test. Baseline AMH levels were related to polycystic ovary status, testosterone response to SDAST, and 17-hydroxyprogesterone response to GnRHag test. AMH levels correlated with SDAST and GnRHag test outcomes. AMH was elevated (>6.2 ng/mL) in 32% of V-PCO versus 5% V-NO. The 21% of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyperandrogenism, but AMH levels were similar to nonhyperandrogenic V-PCO. AMH >10.7 ng/mL discriminated V-PCO from PCOS with 96% specificity and 41% sensitivity for PCOS-T, and insignificantly for PCOS-A. AMH levels are independently related to ovarian androgenic function and polycystic ovaries. Very high AMH levels are specific but insensitive for PCOS. In the absence of hyperandrogenism, moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool.

Evaluation of serum concentrations of cortisol and sex hormones of adrenal gland origin after stimulation with two synthetic ACTH preparations in clinically normal dogs

To compare the adrenocortical response of healthy dogs to a commonly used dose of a nonadsorbed tetracosactide product (tetracosactide) with responses to 2 doses of a depot formulation of tetracosactide (depot tetracosactide). 14 dogs. Dogs were randomly assigned to receive tetracosactide (5 mg/kg, IV) or depot tetracosactide (250 μg, IM, or 5 μg/kg, IM). Dogs received each treatment once with a 2-week interval between treatments. Blood samples were assayed for cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, and estradiol concentrations. Serum cortisol concentrations were significantly higher than the preadministration (baseline) concentrations for all treatments 60 minutes after administration of ACTH. Peak cortisol concentration was detected 180 minutes after IM administration of 250 μg of the depot tetracosactide. Serum concentrations of progesterone, 17-hydroxyprogesterone, and androstenedione did not differ significantly from baseline concentrations after stimulation with the 5 μg/kg dose of depot tetracosactide. Adrenal gland progesterone response was significantly higher than baseline concentrations at 60 minutes after administration of the 250-μg dose of depot tetracosactide, and the 17-hydroxyprogesterone and androstenedione responses were significantly higher than baseline concentrations at 120 minutes. Compared with the response to tetracosactide, adrenocortical response was higher and more sustained following administration of the depot tetracosactide, except for androstenedione concentration, which had a nonsignificant response. Except for androstenedione concentrations, a high dose of the depot tetracosactide (250 μg, IM) induced an adrenocortical response similar to that after administration of tetracosactide. Thus, depot tetracosactide may represent an alternative to the nonadsorbed tetracosactide product.

Clinical Evidence for Predominance of Delta-5 Steroid Production in Women with Polycystic Ovary Syndrome

In women with polycystic ovary syndrome (PCOS), the basis for ovarian androgen overproduction involves an overall increase of steroidogenesis, notably in the delta-4 pathway. However, in vitro studies have suggested that excessive androgen production occurs predominantly through the delta-5 pathway. This study was performed to assess androgen dose-responses after human chorionic gonadotropin (hCG) stimulation in PCOS and normal women. We conducted a prospective study to compare androgen production after iv hCG in PCOS and normal women. The study was conducted in a General Clinical Research Center in an academic medical center. Women with PCOS (age, 18-37 yr; n = 10) and normal ovulatory controls (age, 18-37 yr; n = 11) were recruited. For dose-response studies, blood samples were obtained before and at 0.5, 24, and 48 h after iv recombinant hCG (1, 10, 25, 100, and 250 μg). A subset of subjects underwent frequent blood sampling over 24 h after iv injection of 25 μg of recombinant hCG. We measured basal and stimulated serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone, estradiol, and progesterone responses after hCG administration. In PCOS women, maximal A and T production was observed at the lowest doses of hCG, whereas responses were minimal in normal women. Incremental responses of 17-OHP, estradiol, and progesterone were greater in PCOS compared to normal women. In PCOS women, maximal A and T responses to hCG relative to those of 17-OHP are consistent with ovarian androgen overproduction via the delta-5 pathway.

Asymptomatic Volunteers with a Polycystic Ovary Are a Functionally Distinct but Heterogeneous Population

Our objective was to determine the ovarian function of asymptomatic volunteers with a polycystic ovary (V-PCO). Non-hirsute eumenorrheic V-PCO (n = 32) and volunteers with ultrasonographically normal ovaries (V-NO) (n = 21) were compared with one another and with polycystic ovary syndrome (PCOS) patients who met National Institute of Health criteria (n = 90). DESIGN/SETTING/INTERVENTIONS: GnRH agonist (GnRHag), ACTH, and oral glucose tolerance tests were prospectively performed in a General Clinical Research Center. The distribution of 17-hydroxyprogesterone (17OHP) responses to GnRHag of V-PCO formed a distinct population intermediate between that of V-NO, the reference population, and PCOS. Nevertheless, the V-PCO population was heterogeneous. There were 53% (seventeen of 32) that were functionally normal, with 17OHP responses and free testosterone levels like V-NO. A total of 25% (eight of 32) had an elevated free testosterone, thus meeting Rotterdam criteria for PCOS; one third of these had 17OHP hyperresponsiveness to GnRHag testing. The remaining 22% (seven of 32) had 17OHP hyperresponsiveness to GnRHag, but normal free testosterone. Of PCOS, 69% had elevated 17OHP hyperresponsiveness to GnRHag. Ovarian volume correlated significantly with 17OHP responses only in PCOS, accounting for just 10% of the variance. Many asymptomatic volunteers have a PCO. They are a distinct, but heterogeneous, population with respect to ovarian function, ranging from normal (53%) to occult PCOS by Rotterdam criteria (25%). Nearly one quarter (22%) had the typical PCOS type of ovarian dysfunction without hyperandrogenemia, termed a "dysregulated PCO"; they or their offspring may be at risk for PCOS. Ovarian ultrasonographic characteristics must be considered when establishing norms for ovarian function.

17-Hydroxyprogesterone Responses to Gonadotropin-Releasing Hormone Disclose Distinct Phenotypes of Functional Ovarian Hyperandrogenism and Polycystic Ovary Syndrome

The exaggerated 17-hydroxyprogesterone response to GnRH agonists, which reflects functional ovarian hyperandrogenism (FOH), is believed to be the prominent abnormality in women with polycystic ovary syndrome (PCOS). Our objectives were to quantify the prevalence of PCOS with FOH and to evaluate whether the presence of FOH may distinguish different clinical and biochemical phenotypes. We conducted an observational study at an academic hospital that included 148 PCOS women and 22 healthy age-matched normal-weight control women. A hormone profile was taken at baseline and in response to (1-24)ACTH and to a GnRH agonist, buserelin, administered during dexamethasone suppression. Based on the data obtained in the control subjects, the PCOS patients were divided into two groups, one with a normal (NR-PCOS, n = 78) and one with a high 17-hydroxyprogesterone response (HR-PCOS, n = 70) to buserelin. The two groups of PCOS subjects had similar anthropometric parameters and clinical signs of hyperandrogenism. Age and body weight at menarche were significantly lower and higher, respectively, in the HR-PCOS group than the NR-PCOS group. Moreover, the HR-PCOS group had higher basal testosterone (P < 0.001), free androgen index (P < 0.01), 17-hydroxyprogesterone (P < 0.05), estrogens (P < 0.05), area under the curve for insulin (insulin(AUC)) (P < 0.05), and C-peptide(AUC) (P < 0.01) and lower insulin sensitivity (as composite insulin sensitivity index) (P < 0.05) than the NR-PCOS group. The response of 17-hydroxyprogesterone to (1-24)ACTH (as percent variation) was lower in the HR-PCOS group with respect to the NR-PCOS group (P < 0.05), whereas the response of cortisol, androstenedione, and dehydroepiandrosterone was similar. Finally, the HR-PCOS group had lower percent suppression of androstenedione (P < 0.001) and 17-hydoxyprogesterone (P < 0.05) to dexamethasone. In a multiple regression model applied in all PCOS women, insulin(AUC) but not androgens or markers of insulin resistance predicted the 17-hydroxyprogesterone response to buserelin to a highly significant extent (t = 3.269; P < 0.01). This study indicates that the paradigm that FOH is a specific feature of the PCOS status can no longer be sustained. We have shown that women with an exaggerated 17-hydroxyprogesterone response to a GnRH agonist, buserelin, are characterized by more severe hyperandrogenemia, glucose-stimulated beta-cell insulin secretion, and worse insulin resistance than those without evidence of FOH. Our data may be consistent with the hypothesis that excess insulin may represent a candidate factor responsible for FOH in these women, through the overactivation of the cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17) enzyme pathway.

Functional Significance of Polycystic-Size Ovaries in Healthy Adolescents

The relevance of adult polycystic ovary criteria to adolescence is unclear. The objective was to determine the functional significance of polycystic-size ovaries (PSO) in healthy adolescents. DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS: Healthy 11- to 18-yr-old postmenarcheal volunteers (n = 22) were recruited and divided into groups with normal size ovaries (VNSO; n = 10) or a polycystic-size ovary (VPSO; n = 12). They were secondarily compared with adolescents with polycystic ovary syndrome (PCOS; n = 8) matched for gynecological age and a PSO. All underwent GnRH agonist (GnRHag), oral glucose tolerance, and ACTH1-24 testing in our General Clinical Research Center. VPSO had a higher peak 17-hydroxyprogesterone (17PROG) response to GnRHag than VNSO (146 +/- 14 ng/dl, mean +/- sem, vs. 85 +/- 11; P = 0.008), as well as larger ovaries (13.3 +/- 0.7 cc vs. 8.5 +/- 0.8 cc). VPSO peak 17PROG was elevated (>137 ng/dl) in 42% (5 of 12). However, VPSO and VNSO androgen levels were similar, with the exception of one VPSO subject who had hyperandrogenemia and thus met criteria for PCOS. VPSO were similar to VNSO in LH, FSH, estradiol, and adrenal androgenic function. Although the VPSO group resembled the PCOS group in their 17PROG response to the GnRHag test, they differed in having significantly smaller ovaries and lower body mass index and in lacking evidence of peripheral androgen excess and of insulin resistance. A PSO in asymptomatic adolescents seems typically to be a normal variant. However, about half have a subclinical PCOS type of ovarian dysfunction; it is unknown whether this indicates a genetic carrier state or a risk for anovulation.

Discontinuous Low-Dose Flutamide???Metformin Plus an Oral or a Transdermal Contraceptive in Patients With Hyperinsulinaemic Hyperandrogenism: Normalizing Effects on CRP, TNF-?? and the Neutrophil/Lymphocyte Ratio

A recent report found that in women with polycystic ovary syndrome (PCOS), adding low-dose flutamide–metformin (Flu-Met) to an oral contraceptive (OC) containing drospirenone reduced excessive fat and the deficit in lean mass, and also countered low-grade inflammation as reflected by levels of interleukin-6 and adiponectin and the neutrophil count. The present study evaluated this approach in 31 young, nonobese women having hyperinsulinemic hyperandrogenism. The participants ranged in age from 13 to 21 years and were 2 to 8 years postmenarche. Criteria for ovarian hyperandrogenism were amenorrhea, oligomenorrhea, or hirsutism accompanied by a high serum level of androstenedione, total testosterone, or free androgen index and, in addition, an exaggerated response of 17-hydroxyprogesterone to a gonadotropin-releasing hormone agonist. All the women received 850 mg metformin daily and 62.5 mg flutamide daily for 21 days in every 28-day cycle for 6 months. In addition, they were randomized to receive either an OC containing ethynylestradiol plus drospirenone or a transdermal contraceptive (TC) containing ethynylestradiol plus norelgestromin. At the outset, the participants had an adipose body composition, high levels of tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP), and elevated leukocyte counts. Only 2 patients in each treatment group had regular menses. Discontinuous Flu-Met treatment combined with either an OC or TC led to appreciable reductions in hirsutism scores and levels of testosterone, CRP, and TNF-α as well as increased levels of high-density lipoprotein cholesterol. Regular menses resumed in all instances, and circulating levels of sex hormone-binding globulin increased. Initially, elevated neutrophil/lymphocyte ratios declined in both treatment groups, primarily because of a decrease in neutrophils. Lean body mass increased by an average of more than 1 kg in both groups, but fat mass did not decrease significantly. Treatment was well tolerated, and there were no changes in indices of liver or kidney function. In treating nonobese women with hyperinsulinemic hyperandrogenism, Flu-Met is equally effective when combined with an OC or a TC. Beneficial endocrine/metabolic, antiinflammatory, and adiposity-reducing effects all may ensue.

Polycystic Ovarian Morphology With Regular Ovulatory Cycles

This study was an attempt to determine whether polycystic ovarian morphology (PCOM) is an important factor in the development of polycystic ovarian syndrome (PCOS). Among the 68 women studied, all of whom had regular ovulatory menstrual cycles and lacked clinical signs of hyperandrogenism, 39 had PCOM and 29 had morphologically normal ovaries. Ovarian morphology was examined by ultrasonography, usually performed transvaginally. Hormone levels were estimated at baseline in the early follicular phase (EFP) of the cycle and, in 36 women, studies were repeated each day during a complete cycle. Body mass index did not differ in women with PCOM and those with normal ovaries. Ovarian volume was twice as great in the PCOM group, and these women had higher numbers of follicles than did those with normal ovaries (8-15 vs. 4-8 per ovary). Baseline EFP levels of testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) were higher in women with PCOM, and levels of sex hormone-binding globulin (SHBG) were lower. Four PCOM women had elevated testosterone levels. The difference in DHEAS levels was independent of age. Sampling across the cycle disclosed no significant group differences in luteinizing hormone, follicle-stimulating hormone, progesterone, or estradiol. In EFP and also at midcycle, women with PCOM had significantly higher testosterone levels compared with those with normal ovaries. SHBG levels tended to be lower in women with PCOM across the cycle, but not significantly so. Levels of free testosterone were higher in women with PCOM, especially in the EFP. Fasting insulin and insulin resistance were higher in women with PCOM; both parameters correlated inversely with SHBG. No group differences were found in blood pressure or serum lipid levels. Women with PCOM had greater androstenedione, testosterone, and 17-hydroxyprogesterone responses to human chorionic gonadotropin compared with women with normal ovaries. These findings indicate that PCOM is the mildest form of ovarian hyperandrogenism. Whether PCOM favors the development of PCOS remains to be determined.

Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhesus monkey.

An association between epilepsy and reproductive disturbances with an apparent increase in a polycystic ovarian syndrome (PCOS) has been reported. Whether this association can be attributed to epilepsy itself or is related to antiepileptic drug therapy, in particular valproate (VPA), remains controversial. We studied effects of a long-term VPA treatment on cycling monkeys, postulating that, if VPA monotherapy were to promote abnormal endocrine and metabolic parameters that are characteristic of PCOS, changes in cyclicity would be readily demonstrated. After a 2-month control, a 12- to 15-month VPA monotherapy was initiated in 7 regularly cycling rhesus monkeys. Overall mean levels of VPA were 88.7 +/- 4.0 (SE) microg/ml. Mean body weight increased progressively during VPA treatment from 8.5 +/- 0.5 kg before treatment to 9.6 +/- 0.7 kg in the last week of treatment (P < 0.05). Monkeys continued to have regular ovulatory menstrual cycles throughout VPA monotherapy. Length of the cycles was 28 +/- 0.58 d in control and 28.4 +/- 1.18 d in the last 3 months of VPA treatment. Follicular and luteal lengths and peak preovulatory estradiol and integrated luteal progesterone levels did not differ between control and treatment. Ovaries from VPA-treated monkeys showed histological evidence of ovulation, and none had characteristic features of PCOS. Endocrine PCOS markers, such as increased early follicular LH/FSH ratio and androgen levels were not different in control and VPA treatment cycles. LH and 17-hydroxyprogesterone responses to GnRH agonist challenges and the insulin response to glucose tolerance tests were similar in control and VPA groups. Lipid profiles were not affected by VPA treatment. The data indicate that a 12- to 15-month therapeutic exposure to VPA does not induce cyclic hormonal or morphological ovarian abnormalities or characteristics of the PCOS when administered to nonepileptic normally cycling nonhuman primates.

Avaliação da utilidade do estímulo agudo das gonadotrofinas e dos esteróides ovarianos com análogo do hormônio liberador de gonadotrofinas no diagnóstico diferencial do hiperandrogenismo ovariano funcional

A resposta da 17-hidroxiprogesterona (17OHP) ao estímulo agudo com um análogo do hormônio liberador de gonadotrofinas (GnRHa) e sua relação com a sensibilidade à insulina (SI) foi avaliada em 8 mulheres voluntárias normais e obesas (grupo N), com idades entre 24 e 40 anos (mediana de 29) e índice de massa corpóreo (IMC) entre 32,0 e 46,5kg/m² (mediana de 35,7) e 8 pacientes portadoras da síndrome dos ovários policísticos (grupo SOP) com idades entre 19 e 28 anos (mediana de 26) e IMC entre 30,1 e 40,1kg/m² (mediana de 35,8), submetidas a estímulo agudo com acetato de leuprolide, 10µg/kg SC e a teste de tolerância oral à glicose (TTOG). Observou-se aumento significativo da concentração de 17OHP, tanto no grupo N (1,5 vs. 2,9ng/mL; p= 0,023) quanto no grupo SOP (0,8 vs. 3,1ng/mL; p= 0,007), não havendo diferença significativa entre os grupos. A SI foi avaliada através da área sob a curva de insulina (ASCI) no TTOG. O grupo N apresentou ASCI significativamente menor que o grupo SOP (14.384 vs. 22.800µUI/mL/min, p= 0,04). Não houve correlação entre a concentração de 17OHP após estímulo e a ASCI.