Androstenedione response to recombinant human FSH is the most valid predictor of the number of selected follicles in polycystic ovarian syndrome: (a case-control study)

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Abstract

Background

We aimed to test the hypothesis that the correlation of the changes in the blood Androstenedione (A ₄) levels to the number of selected follicles during ovulation induction with low-dose recombinant human follicle stimulating hormone (rhFSH) is as strong as the correlation to changes in the blood Estradiol (E ₂) levels in polycystic ovary syndrome (PCOS).

Methods

Prospective Case-control study conducted from October 2014 to January 2016. 61 non-PCOS control (Group I) and 46 PCOS (Group II) patients treated with the chronic low-dose step up protocosl with rhFSH. A ₄, E ₂, progesterone blood levels and follicular growth were monitored.. Univariate and hierarchical multivariable analysis were performed for age, BMI, HOMA-IR, A ₄ and E ₂ (with the number of selected follicles as the dependent variable in both groups). ROC analysis was performed to define threshold values for the significant determinants of the number of selected follicles to predict cyle cancellations due to excessive ovarian response.

Results

The control group (Group I) was comprised of 61 cycles from a group of primary infertile non-PCOS patients, and the study group (Group II) of 46 cycles of PCOS patients. The analysis revealed that the strongest independent predictor of the total number of selected follicles in Group I was the E ₂(AUC) (B = 0.0006[0.0003-0.001]; P < 0.001); whereas for Group II, it was the A ₄ (AUC) (B = 0.114[0.04-0.25]; P = 0.01). Optimum thresholds for the A ₄ related parameters were defined to predict excessive response within Group II were 88.7%, 3.1 ng/mL and 5.4 ng*days for the percentage increase in A ₄, the maximum A ₄ value and area under the curve values for A ₄, respectively.

Conclusion

A ₄ response to low-dose rhFSH in PCOS has a stronger association with the number of follicles selected than the E ₂ reponse. A ₄ response preceding the E ₂ response is essential for progressive follicle development. Monitoring A ₄ rather than E ₂ may be more preemptive to define the initial ovarian response and accurate titration of the rhFSH doses.

Trial registration

The study was registered as a prospective case-control study in the ClinicalTrials.gov registry with the identifier NCT02329483.

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Most cited references 24

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Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria.

Zuhal Yapici, Hakan Yarali, Bulent Okan Yildiz … (2012)

What is the prevalence, phenotype and metabolic features of polycystic ovary syndrome (PCOS) in the same population according to three different diagnostic criteria? The prevalence of PCOS under National Institutes of Health (NIH), Rotterdam and Androgen Excess and PCOS (AE-PCOS) Society criteria was 6.1, 19.9 and 15.3%, respectively. PCOS carried a 2-fold increased risk of metabolic syndrome regardless of the diagnostic criteria used. The prevalence rates of PCOS differ depending on the diagnostic criteria used to define the syndrome. The current paper gives the prevalence rates of the component and composite phenotypes of PCOS in the same population and reports similar rates of metabolic syndrome in women with PCOS under contrasting diagnostic criteria. In this cross-sectional study, 392 women between the ages of 18 and 45 years were analyzed. When the prevalence of PCOS according to NIH was set to 8% with a precision of 2.2% and confidence interval of 95%, the sample size required for a prevalence survey was found to be 400 subjects. The study was carried out in the General Directorate of Mineral Research and Exploration, a government-based institute, in which the largest number of female staff (n = 527) are employed within a single institute in Ankara, Turkey. The study was performed between 7 December 2009 and 30 April 2010. All female subjects between the ages of 18 and 45 years were invited to participate. Women older than 45 or younger than 18 years, post-menopausal women, women with a history of hysterectomy or bilateral oopherectomy and pregnant women were excluded. Totally, 392 of the employees were recruited for the final analyses. The prevalence of PCOS under NIH, Rotterdam and AE-PCOS Society criteria were 6.1, 19.9 and 15.3%, respectively. While the prevalence of metabolic syndrome was 6.1% in the whole study group, within the patients diagnosed as PCOS according to NIH, Rotterdam and AE-PCOS Society criteria, it was 12.5, 10.3 and 10.0%, respectively. Even though we have included women working at a single institution with a high response rate for the participation, we cannot exclude potential selection bias due to undetermined differences between our sample and background community. We might have underestimated actual prevalence of metabolic syndrome in PCOS due to lack of oral glucose tolerance test 2 h glucose data. Current results can be generalized to Caucasian populations and may present variations in other populations according to race and ethnicity. This work was, in part, sponsored by Merck Serono. Not applicable.

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Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society.

Didier Dewailly, Marla E Lujan, Enrico Carmina … (2014)

BACKGROUND The diagnosis of polycystic ovary syndrome (PCOS) relies on clinical, biological and morphological criteria. With the advent of ultrasonography, follicle excess has become the main aspect of polycystic ovarian morphology (PCOM). Since 2003, most investigators have used a threshold of 12 follicles (measuring 2-9 mm in diameter) per whole ovary, but that now seems obsolete. An increase in ovarian volume (OV) and/or area may also be considered accurate markers of PCOM, yet their utility compared with follicle excess remains unclear. METHODS Published peer-reviewed medical literature about PCOM was searched using PubMed.gov online facilities and was submitted to critical assessment by a panel of experts. Studies reporting antral follicle counts (AFC) or follicle number per ovary (FNPO) using transvaginal ultrasonography in healthy women of reproductive age were also included. Only studies that reported the mean or median AFC or FNPO of follicles measuring 2-9 mm, 2-10 mm or <10 mm in diameter, or visualized all follicles, were included. RESULTS Studies addressing women recruited from the general population and studies comparing control and PCOS populations with appropriate statistics were convergent towards setting the threshold for increased FNPO at ≥25 follicles, in women aged 18-35 years. These studies suggested maintaining the threshold for increased OV at ≥10 ml. Critical analysis of the literature showed that OV had less diagnostic potential for PCOM compared with FNPO. The review did not identify any additional diagnostic advantage for other ultrasound metrics such as specific measurements of ovarian stroma or blood flow. Even though serum concentrations of anti-Müllerian hormone (AMH) showed a diagnostic performance for PCOM that was equal to or better than that of FNPO in some series, the accuracy and reproducibility issues of currently available AMH assays preclude the establishment of a threshold value for its use as a surrogate marker of PCOM. PCOM does not associate with significant consequences for health in the absence of other symptoms of PCOS but, because of the use of inconsistent definitions of PCOM among studies, this question cannot be answered with absolute certainty. CONCLUSIONS The Task Force recommends using FNPO for the definition of PCOM setting the threshold at ≥25, but only when using newer technology that affords maximal resolution of ovarian follicles (i.e. transducer frequency ≥8 MHz). If such technology is not available, we recommend using OV rather than FNPO for the diagnosis of PCOM for routine daily practice but not for research studies that require the precise full characterization of patients. The Task Force recognizes the still unmet need for standardization of the follicle counting technique and the need for regularly updating the thresholds used to define follicle excess, particularly in diverse populations. Serum AMH concentration generated great expectations as a surrogate marker for the follicle excess of PCOM, but full standardization of AMH assays is needed before they can be routinely used for clinical practice and research. Finally, the finding of PCOM in ovulatory women not showing clinical or biochemical androgen excess may be inconsequential, even though some studies suggest that isolated PCOM may represent the milder end of the PCOS spectrum.

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The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest.

Sophie Jonard, Didier Dewailly (2004)

This review exposes the follicular abnormalities responsible for anovulation in polycystic ovary syndrome (PCOS). The putative pathophysiological explanations involve the principal intra- and extra-ovarian regulators which intervene during normal folliculogenesis to control the initial recruitment and growth and then the cyclic recruitment. We propose the hypothesis that the follicular problem in PCOS is 2-fold, but with the two abnormalities being linked. First, the intra-ovarian hyperandrogenism may promote early follicular growth, leading to a 2-5 mm follicle excess. Second, the ensuing excessive number of selectable follicles would inhibit the selection process, presumably through follicle-follicle interaction involving granulosa cell (GC) products such as the anti-Müllerian hormone (AMH). These factors would induce a reversible refractoriness to the FSH-induced differentiation of GC. This explanation challenges but does not exclude other hypotheses about the follicular arrest, such as the premature LH action on the GC of selectable follicles. Hyperinsulinism or insulin resistance would act as a second hit, worsening the follicular arrest either through amplification of the intra-ovarian hyperandrogenism or through dysregulation of the GC. The loss of cyclic rhythm would prevent the inter-cycle elevation of FSH, thus perpetuating the impairment of the ovulation process.

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Author and article information

Contributors

Eser Sefik Ozyurek: +905309322345 , eozyurek@yahoo.com

Tevfik Yoldemir: tevfik@yoldemir.com

Gokhan Artar: drgokhanartar@hotmail.com

Journal

Journal ID (nlm-ta): J Ovarian Res

Journal ID (iso-abbrev): J Ovarian Res

Title: Journal of Ovarian Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-2215

Publication date (Electronic): 12 May 2017

Publication date PMC-release: 12 May 2017

Publication date Collection: 2017

Volume: 10

Electronic Location Identifier: 34

Affiliations

[1 ]Bagcilar Research and Training Hospital Obgyn Department, Merkez Mh., Mimar Sinan Caddesi, 6. Sokak, 34100 Bagcilar, Istanbul, Turkey

[2 ]ISNI 0000 0001 0668 8422, GRID grid.16477.33, , Marmara University Teaching and Research Hospital Obgyn Department, ; Fevzicakmak District Muhsin Yazicioglu Street 10 Ustkaynarca Pendik, Istanbul, Turkey

Article

Publisher ID: 330

DOI: 10.1186/s13048-017-0330-7

PMC ID: 5427586

PubMed ID: 28494798

SO-VID: ef32b403-ba3f-4b3c-b390-5dc1b6fbac97

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 February 2017

Date accepted : 28 April 2017

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: androgens,androstenedione,polycystic ovary syndrome,ovulation induction,folliculogenesis,human fsh,gonadotropins

Data availability:

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: androgens, androstenedione, polycystic ovary syndrome, ovulation induction, folliculogenesis, human fsh, gonadotropins

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Androstenedione response to recombinant human FSH is the most valid predictor of the number of selected follicles in polycystic ovarian syndrome: (a case-control study)

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Abstract

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Estudio del peso al nacer

Most cited references 24

Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria.

Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society.

The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest.

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