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 Table of Contents  
Year : 2018  |  Volume : 2  |  Issue : 4  |  Page : 249-251

Tear up the paper tiger and rediscover fertility and ovarian function

1 Department of Gynecology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai 200011, China
2 Department of Gynecology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China

Date of Submission17-Jul-2018
Date of Web Publication11-Jan-2019

Correspondence Address:
Xiao-Yong Zhu
Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, 419 Fangxie Road, Shanghai 200011
Ying-Li Shi
Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, 419 Fangxie Road, Shanghai 200011
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.249886

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Follicle-stimulating hormone (FSH), as the main indicator of ovarian function, plays an important role in the clinical activities of gynecologic endocrinology. Although anti-Müllerian hormone and antral follicle count are also the indictors evaluating ovarian function, many clinicians are still relentless in their decision to impose the death penalty of ovaries when high FSH levels (especially more than 40 IU/L) are observed. We recently encountered four patients whose FSH levels were inconsistent with actual fertility because all patients had successfully conceived after treatment. In our study, we found the culprit (macro-FSH) of false-positive FSH levels by applying the polyethylene glycol protein precipitation technique. The biological functions of macro-FSH were further evaluated by using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. This study suggests that ovarian reserve function should be comprehensively assessed in clinic, and the causes of serum test indicators inconsistent with clinic should be identified.

Keywords: Fertility; Macro-Follicle-Stimulating Hormone; Ovarian Function; Polyethylene Glycol Precipitation

How to cite this article:
Liu YK, Zhang W, Zhu XY, Shi YL. Tear up the paper tiger and rediscover fertility and ovarian function. Reprod Dev Med 2018;2:249-51

How to cite this URL:
Liu YK, Zhang W, Zhu XY, Shi YL. Tear up the paper tiger and rediscover fertility and ovarian function. Reprod Dev Med [serial online] 2018 [cited 2021 Jun 22];2:249-51. Available from: https://www.repdevmed.org/text.asp?2018/2/4/249/249886

  Introduction Top

Four patients with abnormally high follicle-stimulating hormone (FSH) (>36 IU/L) levels were diagnosed with premature ovarian insufficiency (POI). at their local hospital. We unexpectedly found that their ovarian function did not decrease by detailed examination, leading us to speculating that the abnormal FSH levels were false-positive results due to some unknown causes.

  Case Report Top

The four patients presented to the local hospital for fertility requirements and were diagnosed with POI due to high FSH (>40 IU/L). Cases 1, 2, and 3 showed prolonged menstrual cycle, whereas case 4 was completely normal. Detailed inquiries about medical history, reproductive endocrine examination, and follicle number showed that ovarian reserve function did not decrease. Menstrual disorders in cases 1, 2, and 3 were caused by polycystic ovarian syndrome (PCOS) and they were all pregnant after treatment. By explanation, the case 4 was fully aware of the condition and soon became naturally pregnant. [Table 1] shows the basic information and results of laboratory examination of the four patients.
Table 1: The basic information of the four patients

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  Discussion Top

Although we had resolved the infertility concern, we still did not know the cause for unusually elevated FSH levels. To date, the limit value of FSH is 20 IU/L, below which the presence of a certain proportion of ovarian reserve is still possible; nevertheless, there is a low chance of pregnancy.[1],[2] We were reminded of the presence of macro-prolactin, which leads to an unusually high prolactin (PRL) level.[3],[4],[5] Could a high FSH level be caused by the presence of macro-FSH?

With the approval of the Ethics Committee and with the consent of the patients, we obtained peripheral blood samples from patients 2, 3, and 4, as well as 1 healthy volunteer and 1 patient with POI. We conducted a PEG precipitation assay[3],[4],[5] to deposit macromolecular protein and were then able to determine the actual serum monomeric FSH level. The FSH and luteinizing hormone (LH) levels before and after PEG treatment and the recovery rate are compared in [Table 2]. Compared with the normal and POI groups, the recovery of FSH levels in the case group was markedly reduced [Table 2] and [Figure 1], which is defined as <40%,[3],[4] indicating the presence of macro-molecules. Simultaneously, the recovery of LH levels in all patients but patient 4 was more than 40%. By analyzing the FSH and LH levels after PEG pretreatment, we found that the result of laboratory test in the three cases was completely different, but consistent with their respective clinical manifestations. After PEG pretreatment, the FSH and LH levels of patient 2 were 6.92 and 12.10 IU/L, respectively, which were consistent with PCOS, and they responded to treatment with ethinyl estradiol and cyproterone acetate tablets (Diane-35). Similarly, the FSH and LH levels after PEG pretreatment in patient 3 were 5.18 and 5.88 IU/L, respectively, and PCOS was confirmed according to the medical history, clinical symptoms, and ultrasound findings. However, in patient 4, the levels of FSH and LH were completely normal at 9.06 and 6.4 IU/L, respectively, accounting for the absence of clinical abnormalities.
Table 2: Comparison of FSH and LH levels before and after PEG treatment, as well as the recovery in different groups

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Figure 1: Recovery of FSH and LH in different groups. Compared with the normal and POI groups, the level of FSH in case group was markedly reduced. FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; POI: Primary ovarian insufficiency.

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Which macro-molecules combine with FSH? We reviewed the medical history of patient 1 and found that she had been suffering from Hashimoto's thyroiditis. Tests for thyroglobulin antibody and thyroid peroxidase antibody were positive. These antibodies may combine with FSH and further form IgG-FSH, which leads to high FSH levels in the serum. In addition, because she also had PCOS, which resulted in oligomenorrhea and infertility, we mistook her condition for POI. However, in the other three cases, we did not trace any history of immune-related disease. What caused the formation of macro-FSH? To identify these molecules, we performed co-immunoprecipitation to pull down the molecules that combined with FSH in the serum and further analyzed them with mass spectrometry. Eventually, we found that these molecules contained many immunoglobulins and complement fragments among other molecules. We also found that three proteins (IGHD, WRP73, and FHAD1) were present in the case group only [Table 2] and [Figure 2], but further researches with more patients and experimental data are needed for confirmation of the specific roles of these proteins.
Figure 2: The KEGG pathway analysis and Venn diagram in different groups. (a) The KEGG pathway analysis in different groups. (b) The Venn diagram of different groups. There are three common molecules in case 2 and case 3, which are shown in orange color. KEGG: Kyoto Encyclopedia of Genes and Genomes.

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Based on the above analysis, and after excluding PCOS and other diseases, a false-positive FSH elevation does not harm the patient substantially. If not for the high FSH level, the patient 4 would be normal and healthy. However, when the patient understood the implications of the high FSH levels, we thought that she was afraid and that the fear might affect her health. Therefore, we need to provide patients in such situations a more comprehensive diagnosis. Under special circumstances, high FSH level is a false-positive result and cannot be used as the sole evidence for estimating ovarian function. We should assess the ovarian function by FSH level in combination with the patient history, the number of ovarian follicles, and the serum anti-Müllerian hormone level, and avoid misdiagnosis, adverse psychological effects, and unnecessary treatment.

  Conclusion Top

Similar to the common phenomenon of hyperprolactinemia caused by macro-prolactin, a spurious hyper-FSH due to macro-FSH can lead to diagnostic confusion and unnecessary investigation and treatment if it is not been distinguished by the laboratory test. It is essential that laboratories introduce screening programs to evaluate samples with elevated total immune-reactive FSH levels for the presence of macro-FSH. Studies must be conducted to accumulate additional data on the mechanisms underlying the condition and treatment modalities for patients with macro-FSH.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.


The authors thank the patients and their families for their participation in this study. They also thank Bin Zhang from our hospital for excellent technical support.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (No. 81471438 to Yingli Shi).

Conflicts of interest

There are no conflicts of interest.

  References Top

van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Broekmans FJ, et al. Predictive value and clinical impact of basal follicle-stimulating hormone in subfertile, ovulatory women. J Clin Endocrinol Metab 2007;92:2163-8. doi: 10.1210/jc.2006-2399.  Back to cited text no. 1
Luisi S, Orlandini C, Regini C, Pizzo A, Vellucci F, Petraglia F, et al. Premature ovarian insufficiency: From pathogenesis to clinical management. J Endocrinol Invest 2015;38:597-603. doi: 10.1007/s40618-014-0231-1.  Back to cited text no. 2
Fahie-Wilson MN, John R, Ellis AR. Macroprolactin; high molecular mass forms of circulating prolactin. Ann Clin Biochem 2005;42:175-92. doi: 10.1258/0004563053857969.  Back to cited text no. 3
Fahie-Wilson MN, Soule SG. Macroprolactinaemia: Contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol. Ann Clin Biochem 1997;34(Pt 3):252-8. doi: 10.1177/000456329703400305.  Back to cited text no. 4
Schneider W, Marcovitz S, Al-Shammari S, Yago S, Chevalier S. Reactivity of macroprolactin in common automated immunoassays. Clin Biochem 2001;34:469-73. doi: 10.1016/S0009-9120(01)00256-9.  Back to cited text no. 5


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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