Ted J.M. Korsen

Obese But Not Normal-Weight Women with Polycystic Ovary Syndrome Are Characterized by Metabolic and Microvascular Insulin Resistance

CONTEXT Polycystic ovary syndrome (PCOS) and obesity are associated with diabetes and cardiovascular disease, but it is unclear to what extent PCOS contributes independently of obesity. OBJECTIVE The objective of the study was to investigate whether insulin sensitivity and insulins effects on the microcirculation are impaired in normal-weight and obese women with PCOS. DESIGN AND POPULATION Thirty-five women with PCOS (19 normal weight and 16 obese) and 27 age- and body mass index-matched controls (14 normal weight and 13 obese) were included. Metabolic Insulin sensitivity (isoglycemic-hyperinsulinemic clamp) and microvascular insulin sensitivity [endothelium dependent (acetylcholine [ACh])] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation with laser Doppler flowmetry was assessed at baseline and during hyperinsulinemia. MAIN OUTCOME MEASURES Metabolic insulin sensitivity (M/I value) and the area under the response curves to ACh and SNP curves were measured to assess microcirculatory function at baseline and during insulin infusion (microvascular insulin sensitivity). RESULTS Obese women were more insulin resistant than normal-weight women (P < 0.001), and obese PCOS women were more resistant than obese controls (P = 0.02). In contrast, normal-weight women with PCOS had similar insulin sensitivity, compared with normal-weight women without PCOS. Baseline responses to ACh showed no difference in the four groups. ACh responses during insulin infusion were significantly greater in normal-weight PCOS and controls than in obese PCOS and controls. PCOS per se had no significant influence on ACh responses during insulin infusion. During hyperinsulinemia, SNP-dependent vasodilatation did not significantly increase, compared with baseline in the four groups. CONCLUSION PCOS per se was not associated with impaired metabolic insulin sensitivity in normal-weight women but aggravates impairment of metabolic insulin sensitivity in obese women. In obese but not normal-weight women, microvascular and metabolic insulin sensitivity are decreased, independent of PCOS. Therefore, obese PCOS women in particular may be at increased risk of metabolic and cardiovascular diseases.

Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles

OBJECTIVE To examine whether follicle loss due to ovarian aging is responsible for the occurrence of regular menstrual cycles in aging women with polycystic ovary syndrome (PCOS), the size of the FSH-sensitive follicle cohort was estimated by the exogenous follicle-stimulating hormone ovarian reserve test (EFORT) and related to the follicle count as measured by ultrasound. DESIGN Prospective study. SETTING Reproductive endocrinology unit of an academic medical center. PATIENT(S) Twenty-seven aging women with PCOS (35.8-49.4 years): 20 with regular menstrual cycles and 7 with oligomenorrhea or amenorrhea. INTERVENTION(S) EFORT and transvaginal ultrasound. MAIN OUTCOME MEASURE(S) Baseline (cycle day 2, 3, or 4) FSH, androstenedione (A), T, E(2), and inhibin B levels, the E(2) and inhibin B increment after the EFORT, and the follicle count. RESULT(S) After correction for the body mass index (BMI), the inhibin B increment was higher in the irregular menstrual group, but the E(2) increment did not differ significantly between the two groups. Ultrasound showed a median follicle count of 8.5 (4.0-18.0) in women with regular menstrual cycles (n = 16), compared with 18.0 (8.0-35.0) in irregularly menstruating women (n = 7). The follicle count was significantly correlated to the FSH-induced E(2) increment (r = 0.656) as well as to the inhibin B increment (r = 0.654). The regularly menstruating group was significantly older, had a higher basal FSH concentration, and had lower androgens than the irregularly menstruating group. CONCLUSION(S) The smaller follicle count, the older age, the higher FSH concentration, and the lower FSH-induced inhibin B increment found in women with PCOS and a regular menstrual cycle confirm that a decrease in the size of the follicle cohort due to ovarian aging is largely responsible for the regular menstrual cycles in aging PCOS women.

Obesity, rather than menstrual cycle pattern or follicle cohort size, determines hyperinsulinaemia, dyslipidaemia and hypertension in ageing women with polycystic ovary syndrome.

OBJECTIVE The aim of this study was to investigate if ageing women with polycystic ovary syndrome (PCOS) who gained regular menstrual cycles differed from women who continued to menstruate irregularly with regard to risk factors for developing diabetes mellitus and atherosclerosis.

Ovulation induction with pulsatile luteinizing releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: clinical results*†

Eighty-four treatment units were given to 11 women with clomiphene citrate-resistant polycystic ovarian disease (PCOD). PCOD was defined as oligomenorrhea elevated luteinizing hormone (LH), normal follicle-stimulating hormone (FSH), and preference-elevated androgens. Luteinizing-releasing hormone (LRH) was administered intravenously via a portable infusion pump. Doses varied between 5 and 40 micrograms/pulse given at 60-, 90-, or 120-minute intervals. In 11 women, 85 treatment units (TUs) were completed, of which 74 were ovulatory, showing no specific advantage of any particular pulse dose or pulse interval. Five pregnancies occurred in three women. Two women did not ovulate during 52 and 284 consecutive days of therapy, respectively. Oligomenorrheic patients with PCOD can be made more regular by means of LRH, not necessarily leading to a regular menstrual cycle. In general, LRH is sufficient for luteal support. No signs of hyperstimulation were observed, although two patients incidently developed unilocular cysts with a maximum diameter of 8 cm. Ovulation induction with LRH in PCOD is possible, although the disease itself does not change during therapy. This may be further evidence that altered hypothalamic LRH secretion is more the result, rather than the cause, of the phenomenon of PCOD.

Insulin-induced capillary recruitment is impaired in both lean and obese women with PCOS

BACKGROUND Insulin resistance, i.e. impaired insulin-mediated glucose uptake (IMGU), is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). Insulin-induced capillary recruitment (IICR) is considered a significant determinant of IMGU. We investigated whether IICR is a determinant IMGU in obese and lean women with and without PCOS. METHODS The study included 36 women with PCOS (20 lean, BMI 21.9 ± 2.3 kg/m(2) and 16 obese, BMI 35.9 ± 6.0 kg/m(2)) and 27 age-matched healthy controls (14 lean, BMI 22.2 ± 1.8 kg/m(2) and 13 obese, BMI 40.5 ± 7.0 kg/m(2)). IICR was evaluated by capillary microscopy during an isoglycemic-hyperinsulinemic clamp. IMGU was expressed as M/I value. RESULTS The M/I value was significantly lower in obese PCOS women compared with obese controls [0.5 (0.2-1.1) versus 0.8 (0.3-1.4) (mg kg(-1) min(-1) pmol l(-1)) × 100, P < 0.01], whereas the small difference between lean PCOS and lean control women was non-significant [1.5 (0.5-2.6) versus 1.7 (1.0-3.7) (mg kg(-1) min(-1) pmol l(-1)) × 100, P = 0.17]. Hyperinsulinemia increased capillary recruitment in lean controls (53.5 ± 20.3 versus 64.9 ± 27.4 n/mm(2), P < 0.05), but not in either PCOS group nor in obese controls. IICR and androgens were a determinant of M/I value only in lean women with or without PCOS. CONCLUSIONS PCOS per se is associated with impaired IICR. Obese women with PCOS, in part independent of obesity, demonstrated a profound insulin resistance, whereas the difference between lean PCOS women and healthy controls was small and statistically non-significant. IICR was a determinant of IMGU in lean, but not in obese, women regardless of the presence of PCOS.

Induction of first cycles in primary hypothalamic amenorrhea with pulsatile luteinizing hormone-releasing hormone: a mirror of female pubertal development *

During pubertal development in girls, the attainment of regular ovulatory menstrual cycles usually is preceded by cycles that are either anovulatory or show a defective luteal phase. It is not known whether these defective cycles are caused by inadequate luteinizing hormone-releasing hormone (LH-RH) secretion or by an inadequate response of the pituitary-ovarian axis to LH-RH stimulation. To shed new light on this matter, the authors analyzed endocrine data from 12 menstrual cycles induced by pulsatile LH-RH therapy in five women with primary amenorrhea of hypothalamic origin. Anovulatory cycles occurred with and without an increase in estrogen excretion and with and without a luteinizing hormone surge. In addition, ovulatory cycles with and without deficient corpus luteum function were observed. Most of these types of anovulatory and ovulatory menstrual cycles also have been described during normal puberty. Therefore, these observations suggest that, during normal pubertal development, maturation of the pituitary gonadotropes and of the ovary occurs, as well as the increased secretion of LH-RH from the hypothalamus, which the overall process depends upon.

Ovulation induction with pulsatile luteinizing hormone-releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: endocrine results *

The pituitary and gonadal response to pulsatile luteinizing hormone-releasing hormone (LH-RH) administration during the first and consecutive second treatment unit (TU) was studied in nine women with clomiphene citrate-resistant polycystic ovary-like disease (PCOD). The control group consisted of eight eumenorrheic women. Luteinizing hormone levels, LH amplitudes, and total urinary excretion/24 hours did not differ between ovulatory and anovulatory TUs, but were significantly higher compared with the control group. Follicle-stimulating hormone (FSH) in PCOD did not differ from normal cycles. Androgen values in the anovulatory TUs were significantly higher compared with the ovulatory TUs (P = 0.001). We conclude that LH-RH therapy may result in ovulation; however, it does not redress the intrinsic abnormality in PCOD and FSH, and androgen levels do not seem to be critical in ovulation induction.

Influence of ovarian manipulation on reproductive endocrinology in polycystic ovarian syndrome and regularly cycling women

OBJECTIVE Little is known about the function of the ovarian neuronal network in humans. In many species, copulation influences endocrinology through this network. As a first step, the possible influence of ovarian mechanical manipulation on pituitary and ovarian hormones was evaluated in polycystic ovarian syndrome (PCOS) and regularly cycling women. DESIGN Prospective case-control study (2008-2010). METHODS Ten PCOS women (Rotterdam criteria) undergoing ovulation induction with recombinant-FSH and ten normal ovulatory controls were included in an academic fertility clinic. In the late follicular phase blood was drawn every 10 min for 6 h. After 3 h the ovaries were mechanically manipulated by moving a transvaginal ultrasound probe firmly over each ovary ten times. Main outcome measures were LH and FSH pulsatility and ovarian hormones before and after ovarian manipulation. RESULTS All PCOS patients showed an LH decline after the ovarian manipulation (before 13.0 U/l and after 10.4 U/l, P<0.01), probably based on a combination of a longer LH pulse interval and smaller amplitude (P=0.07). The controls showed no LH change (before 9.6 U/l and after 9.3 U/l, P=0.67). None of the ovarian hormones (estradiol, progesterone, anti-Müllerian hormone, inhibin B, androstenedione and testosterone) changed in either group. CONCLUSIONS Ovarian mechanical manipulation lowers LH secretion immediately and typically only in preovulatory PCOS patients. The immediate LH change after the ovarian manipulation without any accompanying ovarian hormonal changes point to nonhormonal communication from the ovaries to the pituitary. A neuronal pathway from the ovaries communicating to the hypothalamic-pituitary system is the most reasonable explanation.

Pituitary sensitizing effect of GnRH antagonists: a mechanism explaining LH escape during IVF?

BACKGROUND GnRH antagonists have been introduced to induce persistent LH suppression. Many studies show a gradual increase of LH levels after several days of GnRH antagonist administration, the so-called escape or rebound effect. We hypothesize that, under chronic GnRH antagonist administration, a higher pituitary response to GnRH could be an underlying mechanism explaining the escape phenomenon. METHODS In a prospective study, pituitary response to a supramaximal test dose of GnRH was tested in 12 post-menopausal women before and 8 days after daily treatment with 0.5 mg GnRH antagonist (ganirelix). The same strategy was applied, after a wash-out period, in 11 of the same women using daily 0.5 mg GnRH antagonist in combination with daily estradiol (E(2), 50 microg) administration. The main outcome measure was the LH response 30 min after GnRH administration (Delta LH 30) after the various GnRH tests. RESULTS The Delta LH 30 increased significantly after antagonist administration [Median (range): from 65.5 (32-85) to 77.5 (47-122) IU/l; P = 0.002]. During E(2) administration, the LH response to the GnRH test did not change significantly. CONCLUSIONS Pituitary response increases after 8 days of GnRH antagonist administration. An escape/rebound phenomenon may result from increased pituitary response to endogenous GnRH.

Pituitary response during pulsatile luteinizing hormone-releasing hormone ovulation - induction in patients with clomiphene citrate-resistant polycystic ovary-like disease

The pituitary response to pulsatile luteinizing hormone-releasing hormone (LRH) was studied in 6 women with clomiphene-resistant polycystic ovary-like disease (PCOD). PCOD was defined as oligomenorrhea, elevated luteinizing hormone (LH), normal follicle-stimulating hormone (FSH), and, in general, elevated androgens. LRH was administered in a pulsatile way, chronically, with a pulse dose of 20 micrograms and a pulse interval of 60, 90 and 120 minutes. Blood was drawn every 10 minutes for 6 hours, at the start of therapy (pulse study 1) and 9-15 days after the start of therapy (pulse study 2). Five patients ovulated within 10 days of therapy, which meant that pulse study 2 was performed during the luteal phase. One patient remained anovulatory. The follicular and luteal response during LRH therapy was comparable to that of normal cycles, although the pituitary response was enhanced in PCOD at the start of therapy, which might be related to the state in which the ovary finds itself with respect to follicular development. Desensitization for LH to LRH occurred only incidentally during pulse study 1. Desensitization for FSH to LRH already developed during pulse study 1 and continued to existed during therapy. The 60, 90 and 120 minute LRH pulse interval regimes resulted in LH nadir intervals with wide ranges, although the medians were 60, 90 and 120 minutes respectively.