Clinical characteristics of functioning gonadotroph adenoma in women presenting with ovarian hyperstimulation: Audit of UK pituitary centres

Functioning gonadotroph adenomas (FGAs) are rare pituitary tumours stimulating ovarian function with potential life‐threatening consequences in women. However, a lack of aggregated clinical experience of FGAs impairs management in affected women. The aim of this study is to present the clinical course of FGA‐induced ovarian hyperstimulation syndrome (OHSS) cases as identified by some of the largest UK pituitary endocrine tertiary centres with a view to increasing awareness and improving diagnosis and management of women with FGA.


| INTRODUCTION
Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to excess gonadotrophin hormones resulting in morbidity and mortality.OHSS is a recognised complication of assisted reproductive technologies (ART).Additional risk factors include age < 35years, low body mass index (BMI), polycystic ovary syndrome (PCOS) and high serum oestradiol (E2). 1 OHSS is categorised into mild, moderate and severe with a prevalence of 15%-33%, 8%-23% and 0.008%-10% in ART cycles, respectively. 2e majority of OHSS cases are associated with ART.
4][5][6] Gonadotroph adenomas represent the most common pituitary adenoma histologically but are usually clinically nonfunctioning, that is, secrete isoforms of gonadotrophins without the clinical syndrome of gonadal hyperstimulation.Rarely, FGAs secrete active gonadotrophins which stimulate the ovaries causing menstrual irregularities and/or subfertility in premenopausal women. 7As are rare; hence data are limited.In this study, we retrospectively reviewed the clinical course of seven women presenting with OHSS with subsequent FGA.This was a UK-wide audit of pituitary centres.We analyse their clinical, biochemical and radiological features with treatment strategies.

| METHODOLOGY
Eight high-volume pituitary/endocrine tertiary units within the United Kingdom were contacted to audit records for cases of FGA-induced OHSS; seven patients were identified to date.In all cases, there was no recent exposure to ART or drugs known to induce OHSS.Given the large number of hormonal values, reference ranges of FSH, luteinising hormone (LH) and E2 for each case are provided in Supplementary Table 1.

| Case 1
A 37-year-old woman presented to her local emergency department (ED) with severe, intermittent lower abdominal pain, nausea and vomiting.Examination revealed a distended abdomen without palpable masses.Initial investigations showed normal full blood count, biochemistry and C reactive protein, a negative pregnancy test and bilateral adnexa masses on computed tomography (CT) scan.Her past medical history included PCOS, with recent combined oral contraceptive pill (COCP) use.Following COCP discontinuation, she had amenorrhoea for several months followed by oligomenorrhoea.
She was referred for a transvaginal ultrasound (TVUS) which showed hyperstimulated ovaries (Figure 1).Hormonal profile revealed FSH: 10.8 U/L, LH: 2.4 U/L and E2: 6992 pmol/L.The case was urgently discussed with the endocrine team requesting a full pituitary profile (Table 1) and subsequently magnetic resonance imaging (MRI) considering elevated E2, unsuppressed FSH, raised prolactin (PRL) and partial hypopituitarism.In the interim, she restarted the COCP for symptom relief without clinical benefit despite E2 reducing to 700 pmol/L, FSH: 6.3 U/L and LH: 1.2 U/L.She self-presented to ED with dyspnoea 1 week later; she was respiratory and haemodynamically stable.A CT-thorax/abdomen revealed a probable haemorrhage on a right adnexal cyst.She was discharged home following analgesia optimisation.The MRI-pituitary revealed a macroadenoma with suprasellar extension and bilateral cavernous sinus involvement (Figure 2).Visual fields assessment showed a left inferior nasal defect.
Lanreotide 60 and 90 mg were prescribed on two occasions off-label.Her vision remains stable.

| Case 3
A 27-year-old woman presented with acute abdominal pain, nausea, vomiting and fevers.She had a distended abdomen with a palpable mass.She had a history of PCOS and menorrhagia for which the COCP was offered but declined.The pregnancy test was negative.She moved out of area and no further follow-up data are available.

| Case 4
A 15-year-old girl presented to primary care with abdominal pain and bloating.She denied nausea, vomiting or change in bowel habits, but reported new worsening headaches without visual disturbances.
She had a low BMI (17-18 kg/m 2 ), with restrictive eating behaviours exacerbated by school exams.She was diagnosed with irritable bowel syndrome.Nine months later, she sought medical advice for menstrual irregularities (menorrhagia lasting 5 weeks followed by amenorrhoea) and galactorrhoea.Investigations revealed raised FSH, E2, PRL and suppressed LH (Table 1) prompting gynaecology and endocrinology referrals.
Her menarche was at the age of 14, but menstrual cycles were irregular.
Repeat hormonal profile was similar.TFTs and 9am-cortisol was normal.
Clinical examination revealed a distended abdomen with two palpable

| Case 5
A 47-year-old woman presented with a 3-month history of visual disturbances.Ophthalmological assessment showed bitemporal hemianopia.MRI-pituitary revealed a macroadenoma measuring 27.5 × 24.6 × 25.6 mm compressing the optic chiasm.Hormonal profile is summarised inTable 1.She also reported headaches and lower abdominal pain.Due to depot progestogen injection, her menstrual cycles could not be assessed.
A TVUS revealed hyperstimulated ovaries (right ovary: 27 mL, left ovary: 33 mL) without ascites.She underwent TSS and histology confirmed a gonadotroph adenoma.Three-month postoperative MRI-pituitary was suggestive of a probable small residual tumour, however, the pituitary MDT concluded this may be postoperative changes.She continues clinical follow-up and is no longer on depot progestogen; she had two menstrual periods over the past 5 months.Repeat TVUS showed normal ovaries.

| Case 6
A 43-year-old woman presented to primary care with galactorrhoea and irregular periods.1451 pmol/L, normal TFTs, IGF-1 and optimal SST response (Table 1).She was prescribed clomiphene for fertility, although there is no information on its effectiveness.Twenty months later she developed visual disturbances and headaches prompting an ophthalmological referral; the assessment found bitemporal hemianopia.MRI-pituitary revealed a large pituitary tumour and thus she was referred to endocrinology.On further questioning, she reported postural hypotension and intermittent abdominal pain.Her hormonal profile is shown in Table 1.She was diagnosed with FGA.She underwent TSS and despite a large postoperative residual mass, there was an improvement in her menstrual cycle, vision and hormones (FSH: 5.5 IU/L, LH: 2 IU/L, PRL:

Pituitary-MRI
172 mU/L, E2 not available).While awaiting radiotherapy, she conceived naturally.During her pregnancy, she reported worsening headaches.A small increase of the residual tumour without compromising the optic chiasm was seen on MRI.She continued the pregnancy to term.She underwent a second TSS 4 months postdelivery followed by radiotherapy.Sixteen years after her original surgery, she required a third TSS for FGA enlargement extending into the maxillary sinuses followed by a repeat TSS for significant nasal sinus residuum and plausible trigeminal neuralgia 3 years later.MRI-pituitary demonstrated further tumour growth 2 years later, thus requiring a fifth TSS and radiotherapy.
Histopathological samples stained positive for FSH and LH, with a Ki67 of 3%-5%.
In summary, this patient required five TSSs and two radiotherapy courses over a 25-year period.She remains under clinical follow-up.
The recent MRI-pituitary describes stable residual disease in the cavernous sinuses with extension through the foramen ovale.
Table 1 summarises the clinical characteristics of the seven women included in this study.

| DISCUSSION
Gonadotroph adenomas comprise 40%-60% of all clinically nonfunctioning pituitary adenomas (NFPA) on immunohistochemistry. 8 FGAs are rare but their incidence remains unknown. 7Their clinical picture is sex-and age-specific due to the effect of biologically active gonadotrophins on the gonads as well as mass effect symptoms of the local tumour.Menstrual dysregulation, infertility and OHSS are recognised in premenopausal women.[11] Compressive symptoms including visual field defects and headaches are seen across all patient groups, presumably due to late presentation and/or diagnostic delay.The pathophysiology of FGAs is not fully understood.FSH drives folliculogenesis and oestrogen production, which suppresses LH and stimulates PRL.Kisspeptin is a hypothalamic neuropeptide required for endogenous pulsatile secretion of gonadotrophin-releasing hormone (GnRH) necessary for gonadotrophin secretion. 12,13There is limited research on the direct pituitary effects of kisspeptin, but it has recently been speculated that kisspeptin produced by pituitary adenomas may stimulate secretion of FSH and LH as evidenced by its messenger RNA (mRNA) expression on FGA tissue. 14However, there are no data on protein expression, therefore this should be interpreted cautiously.
Additionally, the presumed increase in Kiss1-mRNA may be the result of the increased E2 levels rather than the driver of gonadotrophin secretion by the FGA as seen in an animal model where KiSS-1 gene expression in gonadotrophs was upregulated in the presence of oestradiol treatment. 15The GnRH-receptor gene has been reported to be preferentially expressed in women with over non-FGAs. 16Activating mutations in the FSHR have also been associated with OHSS, evidenced in cases with spontaneous OHSS (gestational and nongestational), 5,17-19 but not FGAs.Mutant receptors can have broadened specificity with increased sensitivity to hCG inducing massive luteinisation of the ovaries and over secretion of vasoactive mediators responsible for spontaneous OHSS associated with pregnancy. 20In vitro studies confirmed that FGA cells oversecrete FSH in the presence of oestradiol and inhibin-A, despite maintaining oestrogen receptor-a and activin receptors. 21 this study, women had a mean age of 33.4 years (range: 16-47 years) at diagnosis, similar to previous reports. 14,22The reproductive hormonal profile of FGAs may vary; however, serum FSH is mostly higher than LH.A proposed categorisation for FGAs is according to the dominant secreted gonadotrophin, which correlates with the clinical presentation. 14For example, OHSS is not seen in LHpredominant FGAs, although only five cases have been described.
Despite this, immunohistochemistry of FGAs does not correlate with serum gonadotrophin levels.A literature review of 12 FGA cases observed staining for both LH and FSH, LH only, and FSH only, in seven, four and one women, respectively 14 ; however, this had no significant correlation with serum FSH or E2.In our series, a biochemical signature of elevated FSH, E2 and PRL, but suppressed LH, was observed in most cases.Specifically, preoperative LH was below the detection limit of the assay in five of seven women, and low to normal of the reference range in the remaining two women.
Serum FSH ranged from 8 to 33 IU/L and was higher than LH in all cases.E2 and PRL were above the reference range in all, but one woman studied.Furthermore, most women had other pituitary hormone deficiencies.Rarely, FGAs cosecrete other pituitary hormones such as TSH and PRL. 22Case 2 from our series presented with overt thyrotoxicosis, and subsequent immunohistochemistry was positive for TSH staining.Case 3 had evidence of scattered TSH staining without clinical sequelae.Serum PRL can be elevated but this is likely due to stalk compression and/or hyperestrogenemia.
Thirty-seven percent of 171 NFPA-diagnosed tumours stained for gonadotrophins, but few presented with OHSS. 23milarly, a recent case series of 12 women with FGAs reported that four cases had been initially misdiagnosed as NFPA. 14rthermore, in a systematic review by Hasewaga et al., approximately half of the women had undergone pelvic surgery before resection of the adenoma. 22With the exception of adnexal torsion, ovarian surgery could have been avoided if FGA was promptly diagnosed.5][26] In our series, two women required surgery for ovarian torsion and Mucinous neoplasms that can manifest as large multiloculated cystic masses should be considered in premenopausal women. 27ses 3 and 7 were only reviewed in the endocrine clinic 5 years and 20 months, respectively, following initial presentation, highlighting the delays of women with FGA-induced OHSS in reaching diagnosis and specialist endocrinological review.
The women in our series had differing clinical pictures at diagnosis, with abdominal pain being a common symptom.Two women presented acutely, with the remaining five reported intermittent pain.Our study suggests that other common symptoms of FGA are related to pituitary mass effect (headaches, visual disturbances), menstrual disturbance, OHSS (bloating, nausea, vomiting) and hyperprolactinaemia (galactorrhoea).Wang et al reported similar rates of menstrual dysregulation (86.7%), bloating (46.7%) and galactorrhoea (32.3%) in their case series. 14However, they found fewer women complained of compressive effects of FGAs, namely headaches (23.1%) and visual disturbances (26.2%) compared to our series. 14I-pituitary revealed macroadenomas in all our patients, which corresponds with published data indicating that 89% FGA are macroadenomas. 14Total tumour resection has been reported as 25%-78% cases previously 14,22 ; five of our six cases had partial tumour resection due to local infiltration, whilst one case remains indeterminate at this stage.
Surgical resection is the mainstay of treatment of FGAs, with normalisation of FSH levels and biochemical remission achieved. 22ere are limited published data regarding medical therapies, with disappointing efficacy rates. 22Dopamine agonists, somatostatin analogues and GnRH agonists/antagonists have been trialled with conflicting results. 22Additionally, GnRH agonists may exacerbate the symptoms of OHSS.Increasing levels of E2/FSH and further cyst enlargement has been documented in previous reports. 14,28,29mour size increase has also been reported. 22,30GnRH agonists are known to cause ovarian cysts. 31In our study, two of the seven women were treated with the monthly somatostatin analogue Repeat hormonal profile after 6 weeks showed no change.Following a discussion with the pituitary multidisciplinary team (MDT), she underwent transsphenoidal surgery (TSS).Histology confirmed a gonadotroph adenoma with approximately 20% and 30% of cells expressing LH and FSH, respectively.Postoperative MRI showed residual tissue within the left cavernous sinus, whilst serum FSH, LH and E2 had reduced to 0.5 IU/L, <0.1 IU/L and 180 pmol/L, respectively.On follow-up, she was amenorrhoeic with occasional F I G U R E 1 Ultrasound pelvis showing 'hyperstimulated' ovaries; right ovary measures 442 mL; left ovary measures 128 mL.[Color figure can be viewed at wileyonlinelibrary.com]T A B L E 1 Characteristics of women presenting with ovarian hyperstimulation syndrome due to a functioning gonadotroph adenoma.
had a suboptimal response to short synacthen test (SST) and initiated hydrocortisone therapy.TVUS reported an irregular mass of multiple cysts (168 × 146 × 94 mm) superiorly to the uterus.She had undergone bilateral ovarian surgery for ovarian cysts 10 years prior; we cannot exclude ovarian hyperstimulation as a cause.MRI-pituitary revealed a large pituitary macroadenoma with suprasellar extension infiltrating the right cavernous sinus and foramen ovale.Visual field examination revealed left inferior homonymous quadrantanopia.The clinical features were suggestive for a TSH-and FSH-secreting pituitary adenoma.Debulking TSS followed by radiotherapy was proposed by the MDT with carbimazole, monthly lanreotide and progestogen contraceptive pill in the interim.However, surgery was delayed due to challenges including difficulty controlling her thyrotoxicosis, long waiting lists, and the patient being abroad.During the 6-month preoperative period, she developed nausea, worsening visual disturbances and headaches.Three months after lanreotide 90 mg treatment, repeat MRI-pituitary showed no adenoma size change, but evidence of new small foci of haemorrhage within the lesion.FT4 had normalised with TSH remaining elevated.TVUS showed stable appearances.TSS was performed but with incomplete tumour resection.Histology confirmed the high clinical suspicion of a cosecreting adenoma.Postoperatively, she continued the same agents; serum FSH ranged 10-20 IU/L, E2: 700-1100 pmol/L and TSH/FT4 normalised.Her headaches and vision improved.She received 28 fractions of intensity-modulatedradiotherapy (50.4 Gy).Overall, there was a reduction in serum FSH and E2 (mid 40 s to 8 IU/mL and 5000-404 pmol/L, respectively).On the progesterone-only pill, she reported spotting.Ovarian size mildly reduced compared to initial TVUS, yet the 'hyperstimulated' appearance persisted.She developed hypothyroidism requiring carbimazole cessation and levothyroxine replacement therapy, but subsequently developed thyrotoxicosis.The latter coincided with lanreotide treatment cessation for almost a year due to the SARS-CoV-2 pandemic's impact on clinics.FSH and E2 increased (FSH: 15-22 IU/L, E2: 1200-1800 pmol/L).She has recommenced lanreotide 90 mg monthly with regular thyroid and gonadal axis monitoring.It has proven difficult to normalise her thyroid function tests (TFTs) ranging from hyper-to hypothyroidism, and either treated with carbimazole or levothyroxine, respectively, along with monthly lanreotide.She is due to start a 'block and replace' regimen.
Blood results showed neutrophilia, mild anaemia (11.1 g/L) and hypoalbuminaemia (34 g/L).US-abdomen showed a large semisolid/ cystic mass extending from the uterine fundus to the xiphisternum measuring 14 cm transversely.She underwent a right oophorectomy for a twisted gangrenous ovarian cyst (18 × 12 cm) and left ovarian cystectomy for a cyst (10 × 9 cm).Histology showed multiple simple cysts without a residual cyst lining and extensive haemorrhagic infarction on the right ovary.The specimen from the left ovary contained multiple, benign, follicular cysts with oedematous intervening stroma.A year later, she was re-referred to gynaecology services with menorrhagia.TVUS showed a multicystic left ovary.She was prescribed the COCP and tranexamic acid and discharged from the clinic following symptomatic control.Four years later, she presented with acute abdominal pain and was found to have a multicystic left ovary on US (largest cyst measuring 4 cm).Endocrine investigations undertaken for the first time demonstrated FSH: 32 IU/L, LH < 0.2 IU/L, E2: 3551 pmol/L, PRL: 1070 mIU/L, normal TFTs/9am-cortisol, and low insulin-like growth factor (IGF)-1.MRIpituitary revealed a macroadenoma (Figure3).On further questioning, she reported headaches and restricted vision; visual fields assessment showed bitemporal hemianopia.She underwent TSS.An immediate improvement in her headaches, vision and endocrine profile (FSH: 6.8 IU/L, LH: 4.5 IU/L, E2: 48 pmol/L, normal PRL, TFTs, IGF-1) occurred postoperatively but she developed oligomenorrhoea.Postoperative MRI-pituitary showed residual tumour measuring F I G U R E 2 Magnetic resonance imaging pituitary, coronal view, pre-contrast.A 41 × 41 × 24 mm macroadenoma with suprasellar extension, bilateral cavernous sinus involvement and compression of the optic chiasm.14 × 18 mm.Histology confirmed a pituitary adenoma staining positive for FSH, and occasional LH and TSH cells with Ki67 < 3%.She continued radiological surveillance with consideration of transcranial surgery or stereotactic radiosurgery in the event of regrowth.The residual tumour did not change over the following 6 years.Her last endocrine assessment showed FSH: 8.3 IU/L, LH < 0.5 IU/L, E2: 1535 pmol/L with remaining pituitary hormones within range.No data on menstrual history or endometrial thickness were available.
Investigations showed raised PRL (1353 mU/L) prompting an endocrinology referral.Her remaining pituitary profile F I G U R E 3 Magnetic resonance imaging pituitary coronal and sagittal planes: a 48 mm × 27 mm × 21 mm lobulated, well-circumscribed, heterogeneously enhancing extra-axial mass centred on the pituitary fossa with significant extension into the suprasellar cistern and interhemispheric fissure closely applied to the adjacent Circle of Willis vessels and bowing the chiasm significantly.demonstrated FSH: 26 IU/L, LH < 0.5 IU/L and slightly raised E2: revealed a sellar mass lesion without optic chiasm compression.Ophthalmological assessment was normal.TVUS showed enlarged ovaries (right: 43 mL, left: 60 mL) with multiple large follicles and no ascites.A clinical diagnosis of FGA was made.TSS was discussed but she declined, opting for monitoring.A 10-week follow-up TVUS showed a normal-sized right ovary and reduction of left ovarian size, although still enlarged.During her follow-up, her menstrual cycle changed from frequent periods to oligomenorrhoea, and eventually amenorrhoea.She reported hot flushes and intermittent abdominal pain.Repeat TVUS demonstrated a markedly enlarged left ovary (110 mL), a smaller right ovary (25 mL) both containing multiple follicles.The pituitary macroadenoma was stable on repeat imaging.Surgery was offered again in view of her symptoms, and she accepted.

3. 7 | 7
CaseThis case highlights the course of a 50-year-old woman who first presented to ED aged 25 with acute abdominal pain.She underwent emergency laparotomy; an enlarged (10 × 7cm) right ovary with numerous thick wall cysts and 360°torsion and a 5 cm multicystic left ovary were identified.A right oophorectomy and left cystectomy were performed.A one-week postoperative US showed a normal-sized left ovary.Over subsequent years, she experienced irregular periods and the ovary continued to enlarge on imaging.Her hormonal profile showed FSH: 16.3, LH: 6.8 and E2: 962 (units and reference range not provided).

F
I G U R E 4 (A, B) Magnetic resonance imaging (MRI) pelvis, coronal and axial view: Bilateral circumscribed thin walled multiseptated cystic masses arising from the pelvis and extending into the abdomen.The right measures 13 × 11 × 7.3 cm, the left 13 × 12 × 8 cm.(C) Coronal view MRI pituitary: a 36 × 18 mm mass arising from the pituitary, with significant suprasellar extension.[Color figure can be viewed at wileyonlinelibrary.com] torted gangrenous ovarian cyst.Additionally, one woman had a history of bilateral cystectomies 10 years before diagnosis.Case 3 had evidence of multiple follicular cysts with oedematous stroma and superimposed infarction of the right ovary on histopathology.Other conditions such as PCOS (although smaller follicle size), OHSS of other aetiology and ovarian neoplasms might have a similar clinical picture to FGA-induced OHSS.