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Y H M Krul-Poel, C Snackey, Y Louwers, P Lips, C B Lambalk, J S E Laven and S Simsek

Context

Metabolic disturbances, in particular, insulin resistance (IR) and dyslipidemia, are common in women suffering from polycystic ovary syndrome (PCOS). Evidence is accumulating that vitamin D status may contribute to the development of metabolic disturbances in PCOS.

Objective

The aim of this study was to carry out a systematic review addressing the association between vitamin D status, vitamin D receptor polymorphisms, and/or polymorphisms related to vitamin D metabolism and metabolic disturbances in women with PCOS.

Design and methods

A systematic search of electronic databases was carried out up to January 2013 for observational studies and clinical trials in women suffering from PCOS with outcome measures that were related to vitamin D status. We conducted univariate and multivariate regression analyses of the weighted means to gain insights into the association between vitamin D, BMI, and IR based on existing literature.

Results

We found 29 eligible trials with inconsistency in their results. One well-designed randomized controlled trial has been carried out until now. Univariate regression analyses of the weighted means revealed vitamin D to be a significant and independent predictor of IR in both PCOS and control women. The significance disappeared after adjustment for BMI in PCOS women.

Conclusions

Current evidence suggests an inverse association between vitamin D status and metabolic disturbances in PCOS. Owing to the heterogeneity of the studies, it is hard to draw a definite conclusion. The causal relationship between vitamin D status and metabolic disturbances in PCOS remains to be determined in well-designed placebo-controlled randomized clinical trials.

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C. B. Lambalk, J. A. M. J. van Dieten, J. de Koning, J. Schoemaker and G. P. van Rees

Abstract. In the ovariectomized (OVX) rat, the plasma LH response was measured to a pulse of LRH (1.25 or 5 ng/100 g body weight, ia) given before and 1 h after ip administration of phenobarbital (80 mg/kg body weight). The LH response to the LRH pulses was increased 1 h after phenobarbital.

In a second experiment, the pituitary LH content of OVX rats was measured 1 h after administration of phenobarbital or saline. No difference in pituitary LH content was found.

It is concluded that in the OVX rat, phenobarbital increases the response to a pulse of LRH, presumably by suppressing endogenous pulsatile LRH. This, together with results of earlier experiments, further supports the hypothesis that under conditions where endogenous pulsatile LRH is present, there is always a certain degree of pituitary desensitization or refractoriness and that the removal of this endogenous LRH leads to recovery of pituitary sensitivity to LRH.

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C. B. Lambalk, G. P. van Rees, J. Schoemaker, J. de Koning and J. A. M. J. van Dieten

Abstract. Otherwise untreated adult ovariectomized rats were given pulses of GnRH (5 ng/100 g body weight iv) once every 60 or 120 min for 24 or 96 h. On the first and last day of the experiment plasma LH was estimated during the administration of GnRH pulses. Endogenous LH pulses between exogenously generated LH pulses were observed in nearly all animals on both the first and the last day, without any change in nadir and amplitude values. Shortly after an injection of GnRH, the spontaneous LH pulses were fewer than expected. The number of these pulses, however, increased again with time after the injections. The response to exogenous GnRH was reduced on the last day of the experiment. However, not all GnRH injections led to LH pulses. Most injections which did not result in an LH pulse appeared to be given within 15 min after a preceding endogenous LH pulse. The results obtained are in agreement with the hypothesis of an acute short-lasting desensitization of the pituitary gland caused by exogenous as well as endogenous pulses of GnRH.

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C. B. Lambalk, G. P. van Rees, J. Schomaker, J. de Koning and J. A. M. J. van Dieten

Abstract. The effect of pulsatile GnRH administration on the levels of LH and FSH was investigated in rats that had been ovariectomized 2 weeks earlier. Also the asynchronous occurrence of endogenous and GnRH-induced LH and FSH pulses was analysed. A small pulse dose of GnRH (1.25 ng/100 g) was given iv at a frequency of once every 60 min or once every 120 min during 24 h. A larger dose of 5 ng/100 g was given once every 60 or 120 min during either 24 h or 96 h. Blood was sampled arterially every 5 min around the two first and last GnRH injections and LH and FSH were measured. Only the treatment with the larger GnRH pulse dose resulted in a change of LH and FSH plasma levels. LH levels declined under all circumstances, whereas FSH was found to be increased temporarily after 24 h of treatment. The pituitary LH response to pulses of GnRH (5 ng/100 g) decreased irrespective of the frequency or duration with which GnRH was administered. There was a marked asynchronicity between LH and FSH pulses and almost every injection of GnRH (5 ng/100 g) resulted in clear LH pulses but not in FSH pulses.

Free access

M L Hendriks, T König, R S Soleman, T Korsen, R Schats, P G A Hompes, R Homburg and C B Lambalk

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.

Free access

Iris J G Ketel, Mariken N M Volman, Jacob C Seidell, Coen D A Stehouwer, Jos W Twisk and Cornelis B Lambalk

Objective: To determine which anthropometric measurement is the most reliable alternative for fat distribution as measured by dual-energy X-ray absorptiometry (DXA).

Design: Population-based survey carried out in Amsterdam, The Netherlands.

Subjects and methods: A total of 376 individuals (200 women) with a mean age of 36.5 years and mean body mass index (BMI) of 24.0 (±3.1) kg/m2 underwent various anthropometric and DXA measurements of central (CFM) and peripheral fat mass (PFM). Furthermore, for the assessment of apple-shaped body composition, CFM-to-PFM ratio was calculated. Anthropometric measurements were waist and hip circumference, waist-to-hip ratio (WHR), BMI, waist/length and the skinfold thickness of biceps, triceps, suprailiacal (SI), subscapular (SS) and upper leg. We determined whether equations of combined anthropometrics were even more reliable for the assessment of fat mass.

Results: In both women and men, reliable alternatives for CFM are central skinfolds and waist (Pearson’s correlation (r) ≥ 0.8). Peripheral skinfolds are the best predictors of PFM (r ≥ 0.8). In contrast, WHR correlated only marginally with any of the DXA measurements. Equations based on several anthropometric variables correlate with CFM even better (R2 ≥ 0.8). CFM-to-PFM ratio has the highest correlation with the ratio (SS+SI)/BMI in women (r = 0.66) and waist/length in men (r = 0.71). Equations are reasonable alternatives of CFM-to-PFM ratio (R2 ≥ 0.5).

Conclusion: Waist and skinfolds are reliable alternatives for the measurement of body fat mass in a cohort of Caucasian adults. WHR is not appropriate for the measurement of fat distribution.

Free access

Femi Janse, Martinus J C Eijkemans, Angelique J Goverde, Eef G W M Lentjes, Annemieke Hoek, Cornelius B Lambalk, Theresa E Hickey, Bart C J M Fauser and Robert J Norman

Objective

The measurement of serum testosterone in women is challenging due to lack of trueness, precision, and sensitivity of various available testosterone assays. Accurate assessment of testosterone in women is crucial especially in conditions associated with alleged over- or under-production of testosterone, such as in polycystic ovary syndrome (PCOS) or primary ovarian insufficiency (POI). The aim of this study was to measure and compare androgen concentrations in women with PCOS, POI, and female controls and to evaluate the performance of extraction RIA and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in these women.

Design

Cross-sectional study.

Methods

Carefully phenotyped women with POI (n=208) or PCOS (n=200) and 45 healthy, regularly cyclic female controls were included. Method comparison analyses were performed for total testosterone, androstenedione (AD), and DHEA, as measured by LC–MS/MS and extraction RIA.

Results

All androgen levels were significantly elevated in women with PCOS compared with POI patients (P<0.05) and controls (P<0.05). Women with POI presented with similar androgen concentrations as controls, except for AD. Compared with measurements by extraction RIA, testosterone, DHEA, and AD concentrations measured by LC–MS/MS were systematically lower. However, using extraction RIA and LC–MS/MS, testosterone, DHEA, and AD measurements were shown to have good agreement as assessed by Bland–Altman analysis and intraclass correlation coefficient: 0.95 (95% confidence interval 0.94–0.91), 0.83 (0.79–0.86), and 0.96 (0.95–0.97) respectively.

Conclusions

LC–MS/MS, compared with a labor-intensive extraction RIA, shows good precision, sensitivity, and high accuracy for measuring female testosterone, DHEA, and AD concentrations under various clinical conditions. LC–MS/MS, therefore, represents a convenient and reliable assay for both clinical and research purposes, where androgen measurement in women is required.