A FSH-secreting pituitary adenoma discovered after ovarian hyperstimulation syndrome: a case report, illustrating pitfalls in the interpretation of serum FSH levels

doi:10.21203/rs.3.rs-4938687/v1

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Case Report

A FSH-secreting pituitary adenoma discovered after ovarian hyperstimulation syndrome: a case report, illustrating pitfalls in the interpretation of serum FSH levels

https://doi.org/10.21203/rs.3.rs-4938687/v1

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Background: Most cases of ovarian hyperstimulation syndrome (OHSS) are caused by infertility treatment using human menopausal gonadotropin (HMG) and human chorionic gonadotropin (hCG). OHSS is widely known to have a “spoke-wheel” appearance on imaging, presenting as bilateral symmetric enlargement of ovaries with multiple cysts of varying sizes. When this spoke-wheel appearance is observed in patients not undergoing infertility treatment, tumor-derived hormones such as follicle-stimulating hormone (FSH) and hCG should be measured. However, pitfalls exist in the interpretation of FSH levels.

Case presentation: A 29-year-old, gravida 0, para 0 woman visited her local doctor for irregular menstruation and to seek fertility treatment. At the first medical examination, bilateral ovarian tumors were found by ultrasonography, and she was referred to our hospital.

Magnetic resonance imaging (MRI) findings of the bilateral ovarian tumors suggested typical OHSS, and thus levels of serum hormones including FSH and hCG were measured to determine whether endogenous follicle-stimulating hormones were the cause. Estradiol was elevated at 737 pg/ml (normal: 28.8-196.8 pg/ml in follicular phase) and luteinizing hormone (LH) was low at < 0.3 mIU/ml (normal: 1.4-15 in follicular phase, 2.1-88 mIU/ml in ovulatory phase). Both FSH and hCG were within normal ranges. Therefore, the ovarian masses seemed to be estrogen-producing neoplasms rather than endogenous OHSS, and surgical resection was scheduled. However, computed tomography of the neck to pelvic region was performed to rule out metastatic ovarian tumors, and indicated a coincidental pituitary lesion, which was pathologically characterized as an FSH-secreting pituitary adenoma. Consequently, the scheduled ovarian surgery was avoided.

Conclusions: Awareness of MRI findings of OHSS is important to avoid unnecessary invasive procedures. When treating patients who have suspected OHSS on imaging but whose serum FSH is in the normal range, it is also important to know that an unsuppressed FSH level despite the negative feedback effect of high estrogen can suggest an FSH-producing tumor.

magnetic resonance imaging

ovarian hyperstimulation syndrome

OHSS

pituitary adenoma

case report

Ovarian hyperstimulation syndrome (OHSS) is known to be caused by endogenous hormones, such as tumor-derived hormones, in the absence of infertility treatment, but most cases of OHSS are caused by infertility treatment using human menopausal gonadotropin (HMG) and human chorionic gonadotropin (hCG) [1]. OHSS is widely known to show a “spoke-wheel” appearance on imaging, presenting as bilateral symmetric enlargement of ovaries with multiple cysts of varying sizes [2]. When this spoke-wheel appearance is observed in patients not undergoing infertility treatment, tumor-derived hormones such as follicle-stimulating hormone (FSH) and hCG should be measured.

Here we report the case of a reproductive-age woman showing OHSS on imaging who was not undergoing fertility treatment. Since serum levels of FSH and hCG were in normal ranges, OHSS due to an FSH-secreting tumor was thought to be unlikely. As a result, it took a long 4 months to discover an FSH-secreting pituitary adenoma. This case illustrates pitfalls in the interpretation of serum FSH level, especially when it is within the normal range. Therefore, we describe the relationship between endogenous OHSS and serum hormone levels, with discussion of previous reports.

A 29-year-old Japanese woman (G0 P0) visited her local doctor with chief concerns of irregular menstruation and seeking fertility treatment. She was suspected of having bilateral ovarian tumors, and was referred to our hospital.

Three years prior, she visited another hospital after feeling a tumor in the right lower abdomen and was diagnosed with large 8-cm cystic masses in both ovaries. Serum LH, FSH, hCG and testosterone levels were measured and were all within normal ranges. The diagnosis was hypothalamic menstrual irregularity due to emaciation, and the patient was treated with Kaufman therapy, but did not visit the gynecologist after that. One and a half years later, left ovarian torsion occurred, and she underwent ovarian de-torsion and ovarian drilling at her local doctor.

Pelvic 1.5-tesla (T) MRI demonstrated bilateral ovarian masses (right 9.2 cm, left 8.7 cm) including multiple large follicle-like cysts showing low signal on T1-weighted (gradient echo [GE]; repetition time [TR]/echo time [TE], 7/4.6 ms) and high signal on T2-weighted images (spin echo; TR/TE, 4500/100 ms) (Fig. 1a, b). The uterine wall showed edematous thickening on T2-weighted images (Fig. 1a). Cyst walls were uniformly enhanced on contrast-enhanced fat-suppressed T1-weighted images (GE; TR/TE, 5.8/1.86 ms) (Fig. 1c), and no solid component was observed in the cysts. No abnormal diffusion restriction was observed in masses in either ovary on diffusion-weighted image (b = 1000 s/mm², TR/TE, 4359/78 ms) (Fig. 1d). Ovarian hyperstimulation syndrome (OHSS) was suspected based on the morphology of the cystic lesions, which is known as the appearance of spokes of a wheel on the bilateral ovaries.

Blood tests showed elevated E2 of 737 pg/ml (normal: 28.8-196.8 pg/ml in follicular phase) and decreased LH < 0.3 mIU/ml (normal: 1.4-15 in follicular phase, 2.1-88 mIU/ml in ovulatory phase). FSH (18.6 mIU/ml; normal: 3.0-14.7 in follicular phase, 4.5-22.5 mIU/ ml), hCG (< 1.0), PRL (30.4 ng/ml; normal: 4.91-29.32 ng/ml) and thyroid-stimulating hormone (TSH) (1.84 mIU/L; normal: 0.4-4.0 mIU/L) were within normal limits. Since FSH and hCG, which can stimulate ovarian follicles and swell bilateral ovaries, were in normal ranges, an endocrinologist interpreted this result as indicating hyperestrogenemia produced by ovarian tumors causing negative feedback effect on LH secretion. Therefore, the possibility of estrogen-producing ovarian neoplasms could not be ruled out, and gynecological surgery was scheduled.

When a whole-body CT was performed to exclude metastatic ovarian tumors before surgery, a tumor was noted in the pituitary gland (Fig. 2a). A pituitary adenoma invading the left cavernous sinus was detected on 1.5-T MRI of the pituitary gland (Fig. 2b), and a transsphenoidal sinus pituitary tumor was resected. Pathologically, the pituitary tumor was FSH-positive and LH-negative on immunostaining and was diagnosed as an FSH-producing pituitary adenoma.

One month after the surgery, serum estrogen was within the normal limit and FSH also decreased to 5.3 mIU/ml. LH started to increase 5 months later (Table 1).

Table 1: Changes in blood hormone levels before and after surgery for FSH-producing pituitary adenoma

In general, OHSS is a complication sometimes seen in patients receiving HMG-hCG therapy for infertility [3]. Other endogenous diseases including hypothyroidism, FSH receptor mutations, polycystic ovary syndrome (PCOS) [4] [5] [6], and FSH-secreting pituitary adenomas can also cause persistent OHSS [7].

Based on MR findings, this case was considered to be OHSS due to an FSH and/or hCG-secreting tumor somewhere else in the body. However, the diagnosis was difficult to reach and it took more than four months to find the FSH-secreting pituitary adenoma because serum levels of FSH and hCG were within the normal range, which seemed to suggest that the bilateral ovarian masses were not associated with hormonal stimulation by tumors elsewhere. The rarity of FSH-producing pituitary adenomas also contributed to the delayed diagnosis. These facts were critical pitfalls in the clinical diagnosis.

Pituitary gonadotrophin-producing tumors account for 40% of macroadenomas. However, most of them are non-functional because they produce only parts of the hormone, either the alpha or beta subunits. In contrast, pituitary adenomas producing a functional, fully circulating protein are rare, accounting for less than 1% of all pituitary adenomas [8]. Thus, most pituitary adenomas do not produce enough hormone to cause menstrual abnormalities or OHSS, and even large pituitary adenomas producing FSH and LH rarely present with such symptoms associated with OHSS [9]. FSH-producing tumors are generally described as having elevated FSH, low LH, and elevated E2, although FSH levels may be elevated to the upper limit of the reference range [7] [10] [11] and E2 may be within the normal range [11] in patients of reproductive age. In an environment of very high estrogen levels, negative feedback suppresses FSH and LH secretion from the normal pituitary tissue. In the presence of an FSH-producing tumor, negative feedback due to elevated E2 from tumor-produced FSH also occurs, resulting in suppression of FSH and LH production by the normal pituitary gland. However, FSH, which is constantly produced by the tumor, is not suppressed. This results in a mismatch where LH falls below the reference value but FSH does not. Consequently, the possibility of an FSH-producing tumor must be considered even when FSH is in the normal range. In this case, LH was suppressed due to the high level of E2 produced by bilateral swollen ovaries, but the fact that FSH was not suppressed to below the reference range should have been considered inconsistent with findings suggestive of an E2-producing ovarian tumor.

In previous reports, some patients underwent surgery based on a mistaken diagnosis of serous cystadenoma or ovarian enlargement refractory to hormone therapy despite having endogenous OHSS [12]. In our case, surgery for ovarian masses was scheduled because the possibility of an ovarian tumor was suspected before the diagnosis of endogenous OHSS was established. Although surgery was not performed because a pituitary lesion was detected on preoperative CT, an invasive procedure might have been performed if the lesion had not been found. As such, a correct diagnosis of OHSS by MRI was important to avoid unnecessary invasive procedures.

Awareness of MRI findings of OHSS is important to avoid unnecessary invasive procedures. When treating patients who have suspected OHSS on imaging but whose serum FSH is in the normal range, it is also important to know that an unsuppressed FSH level despite the negative feedback effect of high estrogen can suggest an FSH-producing tumor.

OHSS: ovarian hyperstimulation syndrome; HMG: human menopausal gonadotropin; hCG: human chorionic gonadotropin; FSH: follicle-stimulating hormone; G: gravida; P: para; LH: luteinizing hormone, E2: estradiol; GE: gradient echo; TR: repetition time; TE: echo time; MRI: magnetic resonance imaging; CT: computed tomography; T: tesla; GE: gradient echo; TSH: thyroid-stimulating hormone

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report.

Availability of data and materials

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding.

Author contributions

KY and GN contributed to writing the manuscript. HM contributed to correcting the patient’s data for the work. MO contributed to the patient’s operation. KY contributed to the acquisition of MRI data. KO contributed to revising the manuscript.

Acknowledgements

Not applicable

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A FSH-secreting pituitary adenoma discovered after ovarian hyperstimulation syndrome: a case report, illustrating pitfalls in the interpretation of serum FSH levels

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