Leena Anttila

Expression of insulin-receptor substrate-1 and -2 in ovaries from women with insulin resistance and from controls

OBJECTIVE To evaluate the role of insulin-receptor substrate (IRS)-1 and -2 in ovary dysfunction in women with insulin resistance. DESIGN Immunoblotting and immunohistochemical analyses of the localization and staining intensity of IRS-1 and IRS-2 in the ovaries of women with the polycystic ovary syndrome (PCOS) and gestational diabetes mellitus. SETTING Department of Obstetrics and Gynecology, Turku University Central Hospital. PATIENT(S) Sections of ovary were obtained at the time of cesarean section from five volunteers without medical complications and three patients with gestational diabetes mellitus. Paraffin-embedded ovary sections were selected from those on file from the department of pathology; four were from women with a histologic diagnosis of PCOS and seven were from women with endometriosis (controls). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Protein expression of IRS in human ovary samples. RESULT(S) Immunoblotting with specific monoclonal and polyclonal antibodies showed the presence of 165-kDa and 183-kDa proteins that corresponded to the size of IRS-1 and IRS-2, respectively, in normal pregnant ovaries and human cultured follicles. Immunohistochemical staining showed that positive IRS-2 expression in antral follicles was restricted to theca internal cells in ovulatory ovaries but was distributed widely in all compartments of follicles in different stages in polycystic ovaries. Compared with follicles at a similar stage of development in ovulatory ovaries, follicles in polycystic ovaries showed decreased staining for IRS-1 in granulosa cells but increased staining for IRS-2 in theca internal cells. These features of IRS-1 and -2 expression were also noted in preantral and atretic follicles from patients with gestational diabetes mellitus compared with those who had uncomplicated pregnancy. CONCLUSION(S) This study highlights a shift of the follicular insulin signal protein from IRS-1 to IRS-2 in insulin-resistant states and suggests an association between this change and ovarian abnormality in PCOS and gestational diabetes mellitus.

Optimal use of hormone determinations in the biochemical diagnosis of the polycystic ovary syndrome.

OBJECTIVE To investigate, using logistic regression analysis and receiver operator characteristic analysis, the biochemical diagnosis of polycystic ovary syndrome (PCOS) and if it could be improved by using an array of hormone measurements chosen to yield optimal and cost-effective discrimination between women with PCOS and healthy women. DESIGN Retrospective clinical study. SETTING Outpatient clinic of reproductive endocrinology at Turku University Central Hospital, Turku, Finland. PATIENTS Fifty-four oligomenorrheic women with PCOS diagnosed by ovarian ultrasonography, and 29 healthy regularly menstruating women with normal ovarian morphology. MAIN OUTCOME MEASURES Concentrations of LH, FSH, androstenedione (A), T, and sex hormone-binding globulin in serum. RESULTS Luteinizing hormone, FSH and A, when used in combination, were the hormonal analytes of highest clinical utility. Diagnostic sensitivity, specificity, and overall concordance of 98%, 93%, and 96%, respectively, were attained. Each of the analytes used alone yielded lower degree of discrimination. CONCLUSIONS Simultaneous use of the levels of LH, FSH, and A in serum can be used effectively for classification between women with PCOS and healthy women.

Serum total renin is elevated in women with polycystic ovarian syndrome

OBJECTIVE To examine the serum total renin in women with polycystic ovarian syndrome (PCOS) and in controls. SETTING Outpatient clinic of reproductive endocrinology at Turku University Central Hospital, Turku, Finland. PATIENTS Forty-four oligomenorrheic women with PCOS (body mass index [BMI] 18.0 to 49.0 kg/m2) and 25 control women with regular menstrual cycles (BMI 18.0 to 53.5 kg/m2). MAIN OUTCOME MEASURES The concentrations of total renin, LH, FSH, T, androstenedione (A), sex hormone-binding globulin (SHBG), and insulin in serum. RESULTS The concentration of total renin in serum was higher in PCOS women than in healthy women independently of BMI, age, or serum insulin. The serum total renin measurement discriminated PCOS patients and control women to a similar extent as the previously used hormonal parameters (LH:FSH, T, A, and T:SHBG) as judged by receiver-operating characteristic analysis. Positive correlations were found between the serum total renin level and LH concentration, LH:FSH ratio, T and A levels, and T:SHBG ratio. Analysis of serum total renin in PCOS patients during oligomenorrhea and after menstruation did not reveal any significant changes. CONCLUSIONS The elevated concentration of serum total renin suggests an enhanced activity of ovarian renin-angiotensin system in PCOS. The determination of serum total renin may provide a novel tool in the diagnostics of PCOS, because its serum level is elevated in PCOS women independently of BMI and serum insulin.

Vaginal sonosalpingography in the evaluation of tubal patency

BACKGROUND During the past few years, sonosalpingography has been suggested as the first-line method to study tubal patency. This study was launched in order to study the applicability of this method at our institution. METHODS Thirty-two patients suffering from primary or secondary infertility were evaluated for tubal patency with sonosalpingography using a pediatric Foley urinary catheter and a combination of air and saline solution as a contrast medium. The uterine tubes were evaluated separately and the results were compared to the findings at laparoscopy and chromotubation performed independently. Four patients conceived before their scheduled laparoscopy and were excluded from the study. In addition, the patency of three Fallopian tubes could not be adequately evaluated, leaving altogether 53 uterine tubes that were evaluated by both methods. RESULTS The findings of both methods agreed in 47 out of 53 tubes (concordance, 88.7%). The sensitivity of sonosalpingography in diagnosing tubal patency was 90.2% and the specificity 83.3%. The positive predictive value for tubal patency by sonosalpingography was 94.9% and the negative predictive value 71.4%. Adverse events of sonosalpingography included moderate to severe abdominal pain in three patients, one vasovagal reaction, and one case of shoulder pain. No infectious complications were recorded. CONCLUSIONS The results confirm that sonosalpingography utilizing air and saline as a contrast medium is a reliable, simple and well-tolerated method to assess tubal patency in an outpatient setting. In addition, the procedure can be performed without prophylactic antibiotics using a regular pediatric Foley urinary catheter instead of an expensive hysterosalpingography catheter.

Y-chromosomal microdeletions among infertile Finnish men

Background. Microdeletions in the Y‐chromosome are known to cause a significant proportion of azoo‐ and oligozoospermia in men. The reported frequency of deletions varies greatly between the studies. Probable reasons for this variation are different selection criteria and number of patients included, and possibly also methodological aspects, whereas the contribution of environmental and genetic factors is not known. The aim of this study was to determine the incidence of Y‐chromosome microdeletions among infertile Finnish men.

Effect of naloxone on plasma insulin, insulin-like growth factor I, and its binding protein 1 in patients with polycystic ovarian disease

Insulin and insulin-like growth factors (IGFs) stimulate ovarian steroidogenesis, and hyperinsulinemia is often accompanied by hyperandrogenemia in women with polycystic ovarian disease (PCOD). Because opioid peptides are involved in the regulation of insulin secretion, we studied the effect of naloxone-induced opiate receptor blockade on the circulating levels of insulin, IGF-I, and IGF binding protein 1 (IGFBP-1) in 13 nonobese and 7 obese PCOD patients and in 6 healthy subjects. In obese PCOD patients, the mean basal insulin concentration was significantly higher and the IGFBP-1 concentration lower than in nonobese PCOD patients. Plasma IGF-I levels were elevated both in obese and nonobese PCOD patients. After an intravenous bolus of 10 mg naloxone, no significant changes were found in the circulating insulin or IGF-I levels, whereas IGFBP-1 levels decreased in nonobese PCOD patients and remained low in obese PCOD patients. No significant decrease was found in healthy subjects. These results suggest that, in addition to insulin, endogenous opioids are involved in the regulation of serum IGFBP-1 level.

Obesity regulates bioavailable testosterone levels in women with or without polycystic ovary syndrome

OBJECTIVE To evaluate [1] the effects of levels of sex hormone-binding globulin (SHBG), albumin, and total testosterone on the distribution of testosterone between SHBG-bound and non-SHBG-bound fractions; [2] the independent effects of polycystic ovary syndrome (PCOS) and body mass index on serum levels of total testosterone, non-SHBG-bound testosterone, SHBG, and albumin; and [3] the usefulness of levels of total testosterone and non-SHBG-bound testosterone and of the free androgen index in the diagnosis of PCOS. DESIGN Retrospective clinical study. SETTING An academic research environment. PATIENT(S) Forty-three women with oligomenorrhea and PCOS. Twenty-five women with regular menstrual cycles and without hirsutism served as controls. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Levels of non-SHBG-bound testosterone, total testosterone, SHBG, and albumin in serum. RESULT(S) Levels of total testosterone and non-SHBG-bound testosterone, and the free androgen index were higher in patients with PCOS than in healthy controls. PCOS did not have an effect on the levels of SHBG or albumin, or on the percentage of non-SHBG-bound testosterone. Levels of SHBG and albumin were inversely related to body mass index. The percentage and concentration of non-SHBG-bound testosterone and the free androgen index were directly related to body mass index. Hirsutism did not have an effect on any outcome measure. CONCLUSION(S) The distribution of total testosterone into SHBG-bound and non-SHBG-bound fractions is associated with body mass index, not with PCOS. The high levels of non-SHBG-bound testosterone and the high free androgen index in patients with PCOS reflect mainly high levels of total testosterone. Thus, the measurement of levels of non-SHBG-bound testosterone and the calculation of the free androgen index provide no further information in the diagnosis of PCOS beyond that provided by the measurement of levels of total testosterone.

Serum testosterone, androstenedione and luteinizing hormone levels after short‐term medroxyprogesterone acetate treatment in women with polycystic ovarian disease

Background. Medroxyprogesterone acetate (MPA) ‐treatment suppresses serum gonadotropin and androgen concentrations in women with polycystic ovarian disease (PCOD). This study ws designed to determine serum testosterone (T), androstenedione (A) and luteinizing hormone (LH) patterns in a group of oligomenorrheic PCOD patients after MPA‐treatment.

Total renin after gonadotropin stimulation in polycystic ovarian disease

OBJECTIVE To examine the influence of polycystic ovarian disease (PCOD) on the levels of total renin in plasma and follicular fluid (FF) after stimulation with hMG. DESIGN Comparative study of the plasma and FF concentrations of total renin in women with and without PCOD after stimulation with hMG. SETTING In vitro fertilization-embryo transfer program at the Department of Obstetrics and Gynecology, the University Central Hospital of Turku, Finland. PATIENTS Thirty-six women undergoing IVF-ET for infertility with (n = 10) or without (n = 26) ultrasonographically diagnosed PCOD. Of the latter group, 15 women had tubal infertility, and the rest suffered from an anovulatory infertility and reacted with PCO-like ovarian response to stimulation. MAIN OUTCOME MEASURES The concentrations of total renin in plasma and FF, serum E2, and protein in FF. RESULTS The concentrations of plasma total renin after the gonadotropin stimulation were significantly higher in the PCOD and PCO-like groups when compared with the tubal group. The concentration of total renin in FF and the ratio of total renin per protein in FF were higher in the PCOD and PCO-like groups than in the tubal group, but the differences did not reach statistical significance. Positive correlations were found between the plasma total renin and serum E2 concentrations in the PCO-like and in the tubal group and between plasma total renin concentrations and the number of mature follicles in all groups. Follicular fluid total renin did not correlate with FF protein in any group. All findings were independent of the total hMG dosage used and the body mass index of the patients. CONCLUSIONS In the present study the concentrations of total renin in plasma were enhanced markedly after gonadotropin stimulation in women with PCOD compared with women having tubal infertility. The pattern of the hormonal secretions revealed a group of infertile patients reacting biochemically like women with PCOD.

Serum free testosterone in polycystic ovary syndrome measured with a new reference method

OBJECTIVE To quantify the actual serum free T with a specific new reference method in women with polycystic ovary syndrome (PCOS) and to analyze the effects of serum free T, total T, and the T:sex hormone-binding globulin (SHBG) ratio on the diagnosis of PCOS. SETTING Outpatient clinic of reproductive endocrinology at Turku University Central Hospital, Turku, Finland. PATIENTS Forty-four oligomenorrheic women with PCOS and 26 weight-matched control women with regular menstrual cycles. MAIN OUTCOME MEASURES The concentrations of free T, total T, androstenedione (A), LH, FSH, SHBG, and insulin in serum. RESULTS The mean concentrations of free T, total T, A, and LH as well as the LH:FSH and T:SHBG ratios were higher, whereas the mean concentrations of FSH was lower in the women with PCOS than in healthy women. No differences were found in the free T, total T, or T:SHBG levels or in the body mass indexes (BMIs) between the hirsute (n=26) and nonhirsute (n = 18) women with PCOS. Both elevated free T concentrations and high T:SHBG ratios were associated with obesity, but serum total T was independent of BMI. The serum free T measurement discriminated PCOS women from controls to a similar extent as total T and T:SHBG ratio as judged by a receiver operating characteristics analysis. CONCLUSIONS The present data indicate that determination of free T provides little additional information in the diagnosis of hirsutism or PCOS and does not have to be included to the basic evaluation of these patients. Only half of women with PCOS exhibited elevated serum free T concentrations.