Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease.

Serum steroid, gonadotropin, and alpha-subunit levels were assessed in 35 women with cycle abnormalities [11 with and 24 without polycystic ovarian disease (PCOD) according to strict clinical and biochemical criteria] and 8 regularly cycling women in the early (cycle day 3 or 4) and mid (cycle day 7 or 8) follicular phase. LH and FSH levels were estimated using two immunological techniques [RIA and immunoradiometric assay (IRMA)] and in vitro bioassays (BIO), using mouse Leydig cells and rat granulosa cells, respectively. In PCOD patients mean alpha-subunit, free androgen index [FAI; testosterone x 100/sex hormone-binding globulin (SHBG)], androstenedione, estrone, and estradiol (E2) were significantly elevated compared to levels in the early follicular phase of control cycles and non-PCOD patients. In addition, in PCOD patients mean IRMA-LH and RIA-LH levels were distinctly increased (2.8- to 3.6 fold, respectively; both comparisons, P less than 0.001) compared to control values, but in the same order of magnitude (1.3- to 1.4-fold increments) as that in non-PCOD patients. However, the median BIO-LH level in PCOD patients was 5.9-fold higher than that in non-PCOD patients and 4.0-fold higher than the BIO-LH in the early follicular phase of control women. Consequently, the median BIO/IRMA-LH ratio was 4.8-fold higher in PCOD patients compared to non-PCOD patients. In women with cycle abnormalities, individual BIO/IRMA-LH ratios correlated with BIO-LH (rs = 0.48), FAI (rs = 0.39), free estrogens (E2/SHBG ratios; rs = 0 0.47), and dehydroepiandrosterone sulfate (rs = 0.60) concentrations. Mean IRMA-, RIA-, and BIO-FSH levels and BIO/IRMA-FSH ratios were not significantly different when various groups were compared. Although RIA- and IRMA-LH levels showed good correlation (rs = 0.88), RIA-LH levels were consistently higher, resulting in distinctly higher RIA-LH/FSH ratios (mean, 4.5) compared to IRMA-LH/FSH ratios (median, 1.8) in PCOD patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen receptor expression in human ovarian and uterine tissue of long-term androgen-treated transsexual women.

Androgen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated transsexual female patients. This was compared with AR expression in the ovaries and uteri of premenopausal and postmenopausal women not receiving treatment and in 10 ovaries of female patients with polycystic ovarian disease (PCOD). In the normal ovaries germinal epithelium, granulosa cells of antral follicles, corpus luteum, and thecal and stromal cells exhibited moderate AR expression. The more intense and uniform staining of ovarian stroma of female transsexual patients and those of patients with PCOD compared with ovarian stroma of normal controls was most remarkable. This similarity in histology and distribution of ARs supports the hypothesis that PCOD is an androgen-mediated disorder. Immunostaining for ARs was only occasionally detectable in the uteri of premenopausal and postmenopausal women. In contrast, myometrial and endometrial stroma of the uteri of female transsexual patients displayed an intense and diffuse nuclear immunostaining, but glandular epithelia remained unstained. Western blot analysis of the ovaries and uterine myometrial tissue samples from transsexual female patients confirmed the presence of the 110-kd AR molecule. Because the androgen treatment of some transsexual female patients was discontinued 6 weeks before they underwent hysterosalpingo-oophorectomy, our data indicate a stable and persistent androgen-induced up-regulation of AR expression in ovaries.

Insulin-like growth factor binding protein-2, 28 kDa and 24 kDa insulin-like growth factor binding protein levels are decreased in fluid of dominant follicles, obtained from normal and polycystic ovaries.

In order to investigate potential changes in insulin-like growth factor binding proteins (IGFBPs) during human follicle maturation, we examined the IGFBP profiles in follicular fluid from follicles in different stages of maturation. Samples were obtained from ovaries of women with regular menstrual cycles and of subjects with cycle abnormalities and polycystic ovaries (diagnosed as polycystic ovary syndrome (PCOS)) and analyzed by Western ligand blotting. IGFBPs of 43 kDa, 37 kDa, 31 kDa, a doublet around 28 kDa and a minor band of 24 kDa were detected in follicle fluid of normal non-dominant (size < 10 mm) and atretic (androstenedione/estradiol ratio > 4) follicles of both regularly menstruating women and PCOS patients. The 43 and 37 kDa IGFBPs could be identified as IGFBP-3 and the 31 kDa IGFBP as IGFBP-2, whereas the 28 kDa IGFBP could not be identified as IGFBP-1, all by immunoblotting techniques. A dramatic decrease in IGFBP-2, the 28 kDa and 24 kDa IGFBPs was observed in follicular fluid of dominant follicles (size > 10 mm) of both regular menstruating individuals and one PCOS patient as compared with follicular fluid of normal non-dominant or atretic follicles. These observations indicate that the PCOS follicle may not be different from normal with respect to IGFBP profiles. Furthermore, these results suggest that at least one of these IGFBPs might be involved in human folliculogenesis.

Association between ovarian changes assessed by transvaginal sonography and clinical and endocrine signs of the polycystic ovary syndrome.

OBJECTIVE: To determine whether ovarian polycystic changes estimated by transvaginal sonography correlate with clinical and endocrine findings associated with the polycystic ovarian syndrome. DESIGN: Prospective study. SETTING: Reproductive Endocrinology Unit in the Department of Obstetrics and Gynecology at a teaching hospital. PARTICIPANTS: Ninety-five consecutive patients suffering from oligoamenorrhea entering an infertility treatment program. INTERVENTIONS: All women were examined by transvaginal sonography, assessed for body mass index and hirsutism. Blood withdrawal was performed for hormone estimates. MAIN OUTCOME MEASURES: Ovarian follicle number, volume, and stroma echogenicity. Estimates of immunoreactive and bioactive luteinizing hormone (LH), testosterone (T), free T, insulin levels, and insulin resistance index were performed. RESULTS: Hirsutism was present in 63% of the patients and correlated with the number of follicles, ovarian volume, and stroma echogenicity. Follicle number, ovarian volume, and stroma echogenicity values were significantly correlated with immunoreactive LH, bioactive LH, and T levels. Both T and immunoreactive LH were independently correlated with ovarian structure sonography parameters. Insulin and insulin resistance correlated with ovarian volume and stroma echogenicity. Insulin resistance was of significant additional predictive value of ovarian volume and amount of stroma. Evaluating the predictive value of immunoreactive LH and T together in regard to all sonography parameters, only T levels were statistically significant predictors of increase in follicle number, ovarian volume, and stroma amount. CONCLUSIONS: Although immunoreactive LH and bioactive LH correlated with all ovarian parameters, the effect of androgens on ovarian changes appeared to be independent from LH. This further substantiates the apparent cardinal role of androgens in the genesis of polycystic ovaries. Besides, transvaginal sonography assessment of ovaries is a valuable additional tool for the diagnosis of PCOS. In this regard, insulin resistance is of additional predictive value for ovarian volume and stroma echogenicity.

Growth patterns of nondominant ovarian follicles during the normal menstrual cycle.

Transvaginal ultrasound examinations were performed in seven normally cycling women to characterize growth of nondominant follicles in both ovaries. Mean follicle number showed little variation throughout the menstrual cycle with no differences between dominant and nondominant ovaries. Up to 11 follicles (greater than or equal to 2 mm) were observed in any one ovary. From observations of the first appearance of the dominant follicle (mean size 9.9 +/- 3.0 [SD] mm), selection was assumed to take place on cycle day 6.3 +/- 2.3. The diameter of nondominant follicles always remained less than 11 mm. Growth of small follicles was established in both dominant and nondominant ovaries up to the time of selection. The late follicular and luteal phases were characterized by a decrease in mean growth slopes of nondominant follicles in the dominant ovary only. These observations may provide in vivo evidence for the concept of intraovarian paracrine mechanisms and may have implications for the sonographic diagnosis of anovulation and monitoring of ovulation induction.

Growth patterns of ovarian follicles during induction of ovulation with decreasing doses of human menopausal gonadotropin following presumed selection in polycystic ovary syndrome.

Data presented in this study indicate that ovulation can be induced in patients with PCOS using a GnRH analogue combined with hMG in a decreasing dose regimen. Based on the observed decline in functional, medium sized follicles in the late follicular phase, it may be speculated that the risk of ovarian hyperstimulation during gonadotropin induction of ovulation in patients with PCOS can be reduced.

Transvaginal sonography and abnormal ovarian appearance in menstrual cycle disturbances.

Transvaginal ultrasound examinations were performed in 37 oligo- or a-menorrheic women to describe ovarian changes and potential correlations with clinical and some biochemical features of polycystic ovarian syndrome (PCOS). Findings were compared between the right and left ovary and between each of three subsequent examinations of the same ovary. In any one ovary, no significant difference was found between mean ovarian volume, stroma echogenicity, mean follicle number and size. Correlation between ovarian volume and follicle number was strong in all examinations. Follicle number in both ovaries correlated significantly with ovarian stroma echogenicity and some biochemical markers of PCOS. These observations validate the usefulness of transvaginal sonography in demonstrating numerous correlations in menstrual cycle disturbances. The strong necessity to reevaluate sonographic criteria of PCOS is highlighted.

[Include teaching of health economics in the medical curriculum--a way of containing cost increases?]. / Inclure l'enseignement de l'économie de la santé dans le curriculum des médecins--une façon de contenir l'augmentation des coûts?

The amount of money spent on health care and related services is expanding exponentially, and today's health bill represents an increasing share of gross national product. An understanding of economic and technical dynamics, and their impact on the health care decisions of physicians and consequently their institutions, are part of a knowledge base that may be of interest to the present and future health care community. The authors outline the present situation and suggest that a course on the economics of health care systems designed for physicians may be a way of contending with increasing health costs.

How to discriminate between normal and polycystic ovaries: transvaginal US study.

Transvaginal sonography was used in 29 women with regular menstrual cycles and 52 patients with the polycystic ovary syndrome to determine cutoff levels in the size and number of ovarian follicles and ovarian echogenicity and volume for diagnosis of polycystic ovaries. Median values of the mean size and number of follicles and ovarian volume were, respectively, 5.1 mm, 5.0, and 5.9 mL in control subjects and 3.8 mm, 9.8, and 9.8 mL in patients. Ovarian stroma echogenicity was normal in 26 control subjects (90%) and moderately increased in three control subjects (10%), whereas it was markedly increased in 28 patients (54%), moderately increased in 21 patients (40%), and normal in 13 patients (6%). The sensitivity and specificity of moderately or markedly increased echogenicity of ovarian stroma in the diagnosis of polycystic ovaries was 94% and 90%, respectively. The greatest power of discrimination between normal and polycystic ovaries was obtained with combined measurement of follicular size and ovarian volume (sensitivity, 92% [48 of 52 patients]; specificity, 97% [28 of 29 control subjects]).

Growth of the dominant follicle is similar to normal in patients with gonadotrophin-stimulated polycystic ovary syndrome exhibiting monofollicular development during a decremental dose regimen.

The aim of this study was to investigate the late follicular phase of seven gonadotrophin-treated patients with polycystic ovary syndrome (PCOS) exhibiting monofollicular growth and to compare developmental characteristics with the dominant follicle in seven regularly cycling control women. Daily serum follicle-stimulating hormone (FSH) levels in patients with PCOS decreased more rapidly compared to controls (-0.3 +/- 0.2 IU/day in controls versus -0.7 +/- 0.4 IU/day in PCOS; p < 0.02). No statistically significant differences were seen in daily increase (30% in controls and PCOS) and mean peak levels (825 +/- 94 pmol/l in controls versus 937 +/- 231 pmol/l in PCOS) of oestradiol (E2) serum levels when comparing both groups. Mean daily growth of the dominant follicle (1.7 +/- 0.4 mm in controls versus 1.9 +/- 0.6 mm in PCOS) was not significantly different. It is concluded from the present study that in patients with PCOS treated with gonadotrophin plus adjuvant gonadotrophin-releasing hormone agonist, development of a single follicle can occur using a decreasing dose regimen resulting in decreasing serum FSH levels. In addition, growth and oestrogen production by the dominant follicle in PCOS is not significantly different from follicle growth under normal conditions.

The significance of a single serum LH measurement in women with cycle disturbances: discrepancies between immunoreactive and bioactive hormone estimates.

OBJECTIVE: We evaluated the significance of single serum LH estimates (as assessed by radiometric assay (IRMA) and Leydig cell in-vitro bioassay (BIO)) for the diagnosis of polycystic ovary syndrome (PCOS) in women with infertility and cycle abnormalities. DESIGN: Hormonal and clinical comparisons between subgroups were made based on classification according to (a) rigid clinical and endocrine (excluding LH) characteristics of PCOS, (b) elevated IRMA-LH concentrations, (c) BIO-LH levels. In addition, androgen modulation of LH biopotency was studied in these patients. PATIENTS: Ninety-nine women presenting at our infertility Unit with oligo/amenorrhoea. MEASUREMENTS AND RESULTS: Of the total study group, 35 women were diagnosed positive as PCOS and 42 showed elevated IRMA-LH levels. Only 51% (n = 18) of PCOS patients showed elevated IRMA-LH levels, and in PCOS significantly higher levels of BIO-LH, androstenedione, oestrone, and BIO/IRMA-LH ratios were found as compared to non-PCOS patients. In the group with elevated IRMA-LH only 43% (n = 18) of subjects were diagnosed as PCOS, and no difference in BIO/IRMA-LH ratios was found. With increasing BIO-LH levels the probability of PCOS rises sharply (P < 0.001), whereas this probability is of only marginal significance (P < 0.06) for IRMA-LH. In the total study group a correlation is observed between serum testosterone (T) levels and IRMA-LH (r = 0.47), and BIO-LH (r = 0.51) concentrations. This correlation is absent comparing serum T and BIO/IRMA-LH ratios (r = 0.15). CONCLUSIONS: Results presented in this study indicate that (1) women with infertility and oligo/amenorrhoea classified based on signs of PCOS or IRMA-LH levels, exhibit different clinical and endocrine characteristics, (2) only 51% of PCOS women exhibit elevated IRMA-LH concentrations, and only 43% of women with elevated IRMA-LH were diagnosed as PCOS, (3) IRMA-LH levels are a poor predictor of PCOS, whereas the predictive value of BIO-LH is better, (4) elevated BIO/IRMA-LH ratios in PCOS are dependent on alterations in BIO-LH, rather than IRMA-LH concentrations, and (5) no correlation was observed between serum T levels and BIO/IRMA-LH ratios.

Luteal function following ovulation induction in polycystic ovary syndrome patients using exogenous gonadotrophins in combination with a gonadotrophin-releasing hormone agonist.

The luteal phase was studied in 12 polycystic ovary syndrome (PCOS) patients following ovulation induction using exogenous gonadotrophins combined with a gonadotrophin-releasing hormone agonist (GnRH-a). Human menopausal gonadotrophin (HMG) was preceded by 3 weeks of treatment with GnRH-a (buserelin; 1200 micrograms/day intra-nasally) and administered in a step-down dose regimen starting with 225 IU/day i.m. GnRH-a was withheld the day before administration of human chorionic gonadotrophin (HCG; 10,000 IU i.m.). Blood sampling and ultrasound monitoring was performed every 2-3 days until menses. The luteal phase was significantly shorter in PCOS patients as compared to eight regularly cycling controls: 8.8 (3.3-11.4) days [median(range)] versus 12.8 (8.9-15.9) days (P = 0.01). Median peak values for progesterone did not show significant differences comparing both groups: 52.3 (17.1-510.3) nmol/l versus 43.0 (31.2-71.1) nmol/l, respectively (P = 0.8). The interval between the day of the progesterone peak and return to baseline was significantly shorter in the PCOS patients than in controls: 2.5 (0.3-4.9) days versus 4.2 (3.9-10.5) days (P < 0.005). Luteinizing hormone (LH) concentrations during the luteal phase as reflected by area under the curve were significantly lower in PCOS as compared to controls: 4.4 (1.6-21.0) IU/l x days and 49.0 (27.8-79.6) IU/l x days, respectively (P < 0.001). In conclusion, patients with PCOS may suffer from insufficient luteal phases after ovulation induction using HMG/HCG in combination with a GnRH-a. The corpus luteum apparently lacks the support of endogenous LH and may be stimulated only by the pre-ovulatory injection of HCG.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation between clinical manifestations of polycystic ovary syndrome and beta-cell function.

OBJECTIVE: Hyperandrogenism in patients with polycystic ovary syndrome has been shown to correlate with hyperinsulinaemia of insulin resistance. We have investigated if basal levels of insulin and the response to the intravenous administration of glucagon can reveal insulin resistance in patients with polycystic ovary syndrome. PATIENTS: Nine obese (BMI > 25 kg/m2) and nine non-obese (BMI 19-25 kg/m2) women with PCOS, chosen from a population of 91 women attending the infertility clinic, and 19 normally cycling women (seven obese, 12 non-obese) were studied. Oligo or amenorrhoea, hirsutism, and 12 or more follicles in a given ovary were selection criteria. MEASUREMENTS: Glucagon, 1 mg, was given intravenously to 18 of the 91 women and to the control subjects. Blood was taken at -5, 0, 5, 10 and 15 minutes for measurements of integrated areas under the response curve for insulin, C-peptide and glucose, respectively. Basal blood samples were drawn for fasting insulin, C-peptide, glucose, testosterone, sex hormone-binding globulin (SHBG), free fatty acids and IGF-I measurements. The free androgen index was calculated according to the formula FAI = testosterone x 100/SHBG. RESULTS: There were no significant differences in maximal increment and area under the response curve for glucose, C-peptide and insulin. FAI was significantly higher in all patients with features of polycystic ovary syndrome. However, fasting insulin levels were significantly higher only in obese patients when compared with obese control subjects and lean patients. CONCLUSIONS: The administration of 1 mg glucagon i.v. did not distinguish patients with polycystic ovary syndrome from control subjects. The mild insulin resistance of polycystic ovary syndrome is related only to obesity and is therefore unlikely to play an important role in the hyperandrogenism associated with the syndrome.

Ovarian morphology in long-term androgen-treated female to male transsexuals. A human model for the study of polycystic ovarian syndrome?

Descriptions of the effect of androgens on ovarian human tissues are exceptional. This opportunity was provided for us by 17 women with transsexualism--female to male transsexuals (TSX)--who had been given androgens for a mean period of 21 months before hystero-salpingo-oophorectomy took place. Twenty-nine ovaries from TSX and 14 control ovaries from 13 regularly cycling women were examined. As compared with controls, TSX ovaries were enlarged and displayed a two-fold increase in cystic follicles and a 3.5-fold increase in atretic follicles; the ovarian cortex was collagenized and three-times thicker. Theca interna hyperplasia and luteinization were uniformly observed in TSX cystic follicles. Stromal hyperplasia was a constant finding in TSX ovaries, accompanied by clusters of luteinized stromal cells in 12 cases. Eventually, these findings met the histological criteria for the diagnosis of polycystic ovaries. These observations demonstrate that androgens alone may induce polycystic changes. The assumption that the role of androgens is pivotal at the follicular level--inducing follicle growth arrest and accelerating cystic changes--in the genesis of polycystic ovaries is reinforced.

Normal human follicle development: an evaluation of correlations with oestradiol, androstenedione and progesterone levels in individual follicles.

OBJECTIVE: The mechanism of dominant follicle selection remains obscure. We have investigated the association between follicle diameter and follicular steroid levels in individual human ovarian follicles throughout the menstrual cycle. DESIGN: Fluid from ovarian follicles (n = 326) was obtained in vivo during surgery from 55 regularly cycling women with proven fertility. Follicles were divided into dominant (diameter >9 mm, n = 45) and non-dominant (diameter < or = 9 mm, n = 281) based on ultrasound measurements. MEASUREMENTS: Fluid was assayed for oestradiol (E2), androstenedione (AD), and progesterone (P). RESULTS: Median P and E2 levels were significantly lower (P < 0.0001) and AD levels significantly higher (P = 0.03) in non-dominant as compared to dominant follicles. In non-dominant follicles AD (r = 0.14, P = 0.02), but not P and E2, levels were correlated to follicular diameter, and significant changes in steroid concentrations across the menstrual cycle were absent. In dominant follicles, diameter was positively correlated with P and E2 (P < 0.001) levels, and inversely correlated with AD concentrations (P = 0.01). CONCLUSIONS: Results indicate that (1) intrafollicular oestradiol concentrations rise only in follicles exceeding 9 mm in diameter and correlate with the diameter of these dominant follicles, suggesting that significant increase in aromatase enzyme activity occurs only in the dominant follicle (2) a cycle-independent accumulation of androstenedione with size occurs in non-dominant follicles, and (3) progesterone production occurs in the largest dominant follicles only, suggesting a limited, if any, role for progesterone during follicle development.

17 beta-Oestradiol, androstenedione and inhibin levels in fluid from individual follicles of normal and polycystic ovaries, and in ovaries from androgen treated female to male transsexuals.

OBJECTIVE: The aim was to monitor carefully follicular growth arrest in polycystic ovaries by assay of hormones in individual follicles. DESIGN AND PATIENTS: Fluid from follicles less than or equal to 10 mm was obtained from ovaries of 16 regularly cycling women between days 1 and 12 of the follicular phase (controls, n = 120 follicles), polycystic ovaries of five women with polycystic ovary syndrome (n = 43), and polycystic ovaries from 14 long-term testosterone treated female to male transsexuals (n = 120). MEASUREMENTS: Fluid was assayed for oestradiol, androstenedione, and immunoactive inhibin. Luteinizing hormone, follicle-stimulating hormone, and testosterone levels were estimated in serum. RESULTS: Median serum LH was lower in transsexuals than in controls (P less than 0.05), and in polycystic ovary syndrome (P less than 0.01). Median serum testosterone was not significantly different between polycystic ovary syndrome and transsexuals, and was elevated in both groups as compared to controls (P less than 0.01). Oestradiol was present in all follicles obtained from polycystic ovaries of polycystic and transsexual patients, in which no follicle greater than 10 mm could be detected. In the three groups, between-patient differences in mean oestradiol, androstenedione, inhibin, and androstenedione/oestradiol ratio were significantly larger than expected in view of the variation between follicles within individuals. Taking into account this between-patient difference, no significant differences could be established between the three groups for all endocrine parameters. The percentage of presumed healthy follicles (androstenedione/oestradiol ratio less than or equal to 4) was 12% in controls, 17% in polycystics, and 14% in transsexuals, and was not significantly different between groups. CONCLUSIONS: The results may indicate that (1) abnormally high circulating androgen concentrations with or without elevated LH levels disturb the process of selection, and could therefore play a role in the pathogenesis of polycystic ovaries; (2) in polycystic ovaries from polycystic ovary syndrome and transsexual patients, aromatase activity is present in vivo in small antral follicles, and the proportion of presumed healthy follicles is not different from that encountered in normal ovaries; (3) oestradiol levels are not different between non-dominant follicles of normal and polycystic ovaries, suggesting that only enhancement of aromatase activity by FSH may be disrupted in polycystic ovaries, (4) because androstenedione levels are not different comparing follicles of normal and polycystic ovaries, hyperandrogenaemia in the syndrome seems to originate from the abnormally high number of cystic atretic follicles generally observed in polycystic ovaries; (5) marked variation in the endocrine follicular microenvironment within and between-women precludes pooling fluid from several follicles.