Welcome to our webinar on Clinical Pearls from JCEM Case Reports. My name is Bill Young. I'm the Editor-in-Chief of JCEM Case Reports. Our co-host for this webinar is Dr. Adina Turcu, who is the Deputy Editor of the journal. In this webinar, we will be highlighting three case reports that have been published in the journal this year. For each case, we'll have a presenter and a content expert. Our expert for this case is Dr. Niki Karavitaki. She is a Senior Clinical Lecturer in Endocrinology and an Honorary Consultant Endocrinologist at Queen Elizabeth Hospital in Birmingham, UK. Our presenting author is Dr. Ryo Tsukaguchi from Katano Hospital in Osaka, Japan. This case report is entitled, Ovarian Hyperstimulation Syndrome Caused by a Functional Gonadotroph Pituitary Adenoma. Ryo, welcome, and we're looking forward to hearing about your case. Okay, thank you for this great opportunity to present my case report. My name is Ryo Tsukaguchi, Medical Doctor at Medical Research Institute Katano Hospital in Japan. I will describe a recently published case report of Ovarian Hyperstimulation Syndrome Caused by a Functional Gonadotroph Adenoma. First of all, most immunohistochemically gonadotroph-positive pituitary adenomas are clinically diagnosed as non-functioning. Therefore, functional gonadotroph adenomas, FGAs, are rare, which present menstrual irregularities or Ovarian Hyperstimulation Syndrome, OHSS, and so on. OHSS is generally a complication of assisted reproductive technology using human chorionic gonadotropin, HCG. This is characterized by enlarged ovaries and acute fluid shift from the intravascular space to the third space. However, there are limited reports of OHSS caused by FGAs. Now I describe such a patient who developed during the follow-up of a pituitary tumor that was initially considered non-functioning. A 28-year-old woman presented to our hospital with lower abdominal pain, abdominal swelling, and dyspnea. She had no internal medical history, no family history of endocrine disorders, and no history of pregnancy or miscarriage. However, she experienced first menstruation at age 17, and her menstrual cycle was irregular three or four times per year. 11 months prior, a pituitary tumor of 19 mm had been discovered during an examination for a headache. At that time, it was considered non-functioning because of no apparent pituitary hormone disorders. On physical examination, abdominal swelling and a mass from the lower abdomen to the navel level were observed. She did not exhibit symptoms of hypoandrogenism or mass effects from the pituitary tumor, such as visual disturbances or headaches. Then, MRI revealed markedly enlarged multiple ovarian cysts of 15 cm. Additionally, chest X-ray demonstrated bilateral right dominant pleural effusion. On the other hand, pituitary tumor did not change on MRI for the past 11 months. Laboratory investigations showed a markedly elevated estradiol, suppressed luteinizing hormone, LH, and non-suppressed follicle-stimulating hormone, FSH. Considering the absence of exogenous HCG, we suspected OHSS caused by an FGA. Cabergoline was administered, which can improve the condition of OHSS. Started at 0.25 mg and then increased to 0.5 mg per week. Estradiol gradually reduced to 50.1 pg per ml. Pleural effusion also improved three days after Cabergoline administration. However, ovarian cysts continued to enlarge. Therefore, we conducted endoscopic transsphenoidal surgery. Immunohistochemical statin confirmed FSH positive, and other anterior pituitary hormones were negative. MIB1 index was 5%. In postoperative hormonal assessment one week after surgery, estradiol and FSH decreased, and LH increased. Other anterior pituitary hormones, including loading test, were almost normal. In follow-up MRI scans one month after surgery, ovarian cysts significantly reduced. Here is the clinical course. Within three months after surgery, estradiol, LH, and FSH almost normalized. Based on the history and findings, it is suspected that the patient had the background of polycystic ovary syndrome, PCOS. First, irregular menstrual cycle since the first menstruation. Second, relatively high LH level after surgery. These are features of PCOS. And FGA produces FSH, which stimulates ovaries to enlarge. Enlarged ovaries induce OHSS. As for treatment, primary treatment is pituitary surgery. Medical therapy is regarded as adjunctive treatment due to its limited efficacy for tumor shrinkage or ovary shrinkage. In our case, Cabergoline was effective for lowering estradiol and improving pleural effusion, but it had limited effect on ovary shrinkage. In conclusion, OHSS is rarely caused by an FSH-producing pituitary adenoma, typically with high estradiol, low LH, and normal to high FSH level. We have to pay attention to the case of OHSS without HCG administration, or during the follow-up of pituitary tumors in premenopausal females. This brings me to the end of my presentation. Thank you for your attention. Dr. Tsukaguchi, thank you very much for that presentation. A fascinating case, wonderful slides, and you've explained it very well. Dr. Turcu, do you have any questions for Dr. Tsukaguchi? Yes, Ryo, I also want to thank you for sharing this interesting case with us. I want to begin by asking you what happened with the patient's periods after she was a little bit away from her pituitary surgery? Did they ever become regular? After surgery, the patient's menstrual cycle remains irregular, but the cycle was one to two months. That is shorter than before. I was curious if possibly this tumor could have contributed to her irregular periods, or if you still thought after surgery that she had PCOS. For example, other than the high LH, did she have any other features of PCOS, such as a little bit overweight, maybe some metabolic syndrome features? No features as I presented. Her BMI was almost 20, not obesity. And her testosterone level was not high. Okay, and this is more of a sensitive aspect, so maybe she didn't report to you, but I was wondering if she complained of, say, breast tenderness that was unusual. And no breast tenderness she complained. Ryo, I have a question for you. So this patient, her tumor was initially detected about a year before she presented to your hospital, and it was about two centimeters at that time at age 28. Was there a discussion when it was first discovered on proceeding to a pituitary operation at that time? The pituitary tumor, 11-months prior, was initially considered non-functioning and no mass effect and other symptoms, such as abdomen swelling. So I was not aware of that at that time. Non-functioning and asymptomatic, so pituitary surgery is not conducted at that time. Okay. And Ryo, even her prolactin was normal on presentation? Her prolactin level was always normal? Prolactin level was, 11 months prior, it is almost normal. But at presentation with lower abdominal pain, a slightly high prolactin level was observed, 65, almost 65 nanogram per milliliter. And I have one more question about the pathology after removing the tumor. Was there staining for alpha subunit along with FSH? No, other staining was conducted due to limitation of my institution. I understand. So I would love to invite our expert on this topic, Dr. Niki Karavitaki, to share her thoughts on this case. Thank you very much, Adina. Thank you, Bill, for kindly inviting me to this wonderful session and discuss a fascinating case, no doubt that it is a fascinating case, which actually brings together reproductive endocrinology and pituitary endocrinology. So we are dealing with a young woman who had a pituitary MRI. It showed a lesion, which seems to be an adenoma. Hormonal investigations at that time were consistent with a non-functioning pituitary adenoma. Later, she has her estrogens checked and they come up high. So the penny drops. Could this be a clinically functioning gonadotroph adenoma, which actually proved to be during her investigations and management? So I would like to take us through the clinically functioning gonadotroph adenomas and obviously take the opportunity and relate what I'm going to say with some aspects of the case that is presented. So these tumours express and secrete biologically active gonadotrophins, which cause distinct clinical manifestations in contrast to the clinically non-functioning gonadotroph adenomas, which do not cause clinical manifestations related with hormonal hypersecretion. They are rare and that's why I think they can be overlooked. We don't know their prevalence, though, because I think we don't look for them sometimes. In terms of pathology, morphologically, they are identical to non-functioning gonadotroph tumours. We discuss staining immunohistochemistry. What we can see when we stain these tumours, there is obviously a nuclear staining for the steroidogenic factor 1 and there is variable intensity staining for alpha subunit, for beta FSH, for beta LH and actually there are cases where we have staining only for FSH or only for LH. What causes them? We still don't know. They definitely produce FSH with high ratio of bioactivity to immune reactivity. It may be that we have more basic isoforms of gonadotrophins which are considered to be more active than the acidic ones, at least in vitro, and there may be a secretion of glycosylated variants which have increased biological activity. This cannot be excluded. Now, let's go to our case. I would like to make some key points for the diagnosis of functioning gonadotropha adenomas. Obviously, we are focusing on females now. I think what probably led to the diagnosis in this case were the clinical manifestations this lady had in her second presentation and obviously the high estrogens and the imaging appearances of the ovaries. these cases can present in premenopausal women with menstrual irregularities, which have a wide spectrum. They can be from oligomenorrhea to spotting, up to menorrhagia. They can present with infertility. Women who cannot conceive, they go to a gynaecologist, they have an ultrasound, enlarged ovaries are found and it is thought that this is PCOS and no further investigations are taken. Galactorrhea we can see. Obviously, mass effects like headaches, visual deterioration and the ovarian hyperstimulation syndrome, which we saw so much being nicely presented by Ryo today. Another point I would like to draw the attention to is that patients may be diagnosed at the end after long standing investigation of recurrent ovarian cysts. And sometimes these patients have undergone surgery for this cyst, so removal of the ovaries, or they may have undergone surgery because of acute abdomen attributed to adnexal torsion. So the true pathology has been missed and the ovaries have been removed, the ovary or the ovaries. I said before that we don't know how common these are, and I will expand that with a comment on post-menopausal women. How do we know if a lady who presents with what seems to be a non-functioning pituitary adenoma, how do we know that she doesn't have a functioning gonadotroph adenoma? In this case, the interpretation of the gonadotrophins is difficult. Obviously, they increase due to menopause. So we don't know, we can't be certain if this lady had a functioning gonadotroph adenoma, which was missed over the years. Maybe a hint could be if the LH levels are low in a post-menopausal woman. The ovarian hyperstimulation syndrome, I have to admit, I have never seen imaging of ovaries like that related with ovarian hyperstimulation with attributed to a functioning gonadotroph adenoma. It's very, very impressive. And it is not just the imaging of the ovaries that we see in such a case. We can have severe ovarian hyperstimulation syndrome with acute shift of fluids from the intravascular to the third space and obviously very serious complication, ascites and thromboembolism. And this requires multidisciplinary and very, very careful management. So that's about the clinical manifestations that can lead to the suspicion of a lady having a functioning gonadotroph adenoma. And having said that, even micro adenomas have been reported causing functioning gonadotroph adenomas, being a functioning gonadotroph adenoma. Biochemistry. I think biochemistry is of major importance and high estrogens are a predominant biochemical finding. So my suggestion, and that's what we do in our clinical practice here, is that in any woman of the reproductive age, which presents with a pituitary adenoma, of course, we take a detailed menstrual history. But we also need to check estrogens and gonadotrophins, provided, of course, our patient is not on estrogens. And are estrogens always extremely high in functioning gonadotrophs? Well, actually, this is not the case because this diagnosis has been found even with normal, when they were checked, estrogens or even fluctuating levels. And actually, ovarian hyperstimulation syndrome has been reported even with just marginally increased estrogen levels. We usually see the high FSH, like in our case. LH tends to be suppressed or within the reference range. And why is LH suppressed? This could be because of stimulation, but by the high amounts of estrogens. Or it could simply be because the tumour compresses the normal pituitary and it may lead to low LH levels. I think the first explanation, the negative feedback of the estrogens could be the most probable. High prolactin. Adina, you asked about breast tenderness. We talked about the prolactin values. Well, we may see, we can see high prolactin levels in these patients. And it is not only stalk effect, but it may be attributed to the very high estrogen levels which lead to hyperprolactinemia. So that's another point here to remember. Further approach to put the diagnosis. Of course, it's the pelvic imaging where we see these ovaries, which are quite large. They have multiceptated cysts. Often they can be larger than five centimetres. Here, in this case, I'm sure they were much, much larger. We have enlarged follicles, which are arranged peripherally around the ovarian parenchyma. The normal stroma is compressed and we may even see fluctuating appearance of the ovarian cysts. We have a case, for example, a lady in our department who has declined surgery for her own reasons. And we monitor her ovaries by imaging and we see fluctuating size. So that's about the diagnosis. Clinical picture, history, biochemistry, usually high estrogens, high FSH and low LH. And imaging of the ovaries, which will put the idea that we are dealing with a function in gonadotroph adenoma in the setting of a pituitary tumour. Another important point, what's the differential diagnosis? We touched upon polycystic ovarian syndrome. How can we differentiate? Well, there are points which do help us differentiate PCOS from a functioning gonadotroph. Example, in PCOS, the LH tends to be high and the FSH lower in contrast to functioning gonadotrophs. In PCOS, hyperadrogenism is the most prominent feature. And on ultrasound, in the PCOS scenario, we have mildly enlarged polycystic ovaries. The cysts rarely are above 10 millimetres, whereas in the function in gonadotroph adenomas, they tend to be much higher. And in PCOS, we have enlarged central stroma, which is usually much, much less seen in FGAs. And if we want to take things further and we want to do a GnRH test in PCOS, we expect a reduction in the gonadotrophin secretion, whereas occasionally in functioning gonadotroph adenomas, we may see an enhanced response. Not always, though. Obviously, the ovarian hyperstimulation syndrome, its etiology needs to be considered. If we have other causes, iatrogenic in assisted reproduction, for example. And we have to consider ovarian neoplasms as well. If we have an imaging of the ovaries which show enlarged, particularly cystic ovaries. So that's about the differential diagnosis. In management, surgery is the protagonist. It's the first line treatment, which if it is successful and we achieve complete removal or gross total removal, we end up with restoration of the gonadotrophin secretion. Obviously, the ovarian hyperstimulation syndrome resolves, reduction in the ovarian size. If we do an ultrasound a couple of months later, we see this impressive decrease, which we saw in the case presented by Ryo. And why not a treatment of normal periods and fertility? We have cases of pregnancies also following successful removal of the tumour. Radiotherapy is in the armamentarium if we have cases of tumour growth and medical treatment. Unfortunately, it plays a much, much more second role here. We don't have enough data to tell us that a particular agent will be helpful. In this case, a dopamine agonist was used. Indeed, there are limited cases reported in which the cabagolin led to reduction in the FSH and improvement of the ovarian hyperstimulation syndrome. But generally, it is thought that it does not provide a benefit in controlling the tumour. Somatostatin analogues, we have some cases with anti-secretory effect, but overall limited efficacy. I want to emphasise on GnRH agonists. Generally, no benefit, but also there is a risk of further stimulation of the gonadotrophin secretion. Possibly, this has been reported increasing tumour size. Whether this was because of the GnRH agonist or the natural history of the tumour, we are not sure. But it has been reported and also increasing the size of the cysts and exacerbation of the ovarian hyperstimulation syndrome. On the plate also are GnRH antagonists, but we have inconsistent results on their secretory effect. In terms of long-term outcomes, if the tumour is completely removed, hopefully and generally, we anticipate good outcomes. There are cases with recurrences and of course, in such cases, surgery plus minus radiotherapy play the protagonist role. So, this is what I wanted to share about functioning gonadotroph adenomas. As I mentioned, I've never seen such imaging of ovaries before related with FGA. And again, this case highlights the importance of detailed biochemical assessment in the setting of pituitary tumour on imaging. Thank you very much for listening and I would be very, very happy to continue the conversation with the panel. Thank you. Well, Niki, thank you very much for sharing those pearls on this fascinating case. And I agree with you, the imaging was remarkable. Adina, do you have any clarifying questions for Niki? Yes. So, we discussed a little bit about the differential diagnosis and the common PCOS is always on the list. But we also have the rare estrogen-producing tumours. And say this woman presented with irregular periods, some signs of hyperestrogenism and infertility, and we didn't yet have any pituitary imaging, but a really high estrogen level. What are the clinical and biochemical features that would distinguish an estrogen-producing tumour? And let's say that the imaging was not quite as impressive as in this case of the ovaries. How would you take the localization of this problem in a patient like this? Yes. Thank you, Adina. That's a very good question. Obviously, we are mainly talking about ovarian neoplasms, I would have thought, like granulosa cell tumours. Yes, we would have elevated estrogens, but we would expect suppressed gonadotrophins in this scenario. Whereas in a functioning gonadotrophin adenoma, this feedback does not exist. So, this would be my first biochemical observation in this type of tumours. And obviously, further imaging could help. Thank you. And a tricky presentation could be during pregnancy. How would you evaluate a case like this occurring during pregnancy? It is very, very difficult. Cases in which the patient had a functioning gonadotroph adenoma and became pregnant have been reported. We had one in Birmingham, I think around 20 years ago, 15 years ago. I wasn't here then and I was looking at the impressive records of this lady who managed to go through pregnancy and deliver. But there have been other cases in which pregnancy was ended up at a very early stage because of severe ovarian hyperstimulation syndrome. Or thrombophlebitis, for example. So, I think it's difficult to diagnose them. But probably the manifestations of the ovarian hyperstimulation syndrome, the clinical manifestations, abdominal pain, as an example, or thrombophlebitis or ascites, would make me think that we are dealing with this, thankfully, very, very rare scenario. Niki, you mentioned that the treatment of choice is pituitary tumor resection. In Ryo's case, though, it really looked like cabergline had a pretty major role to make the patient a better surgical candidate because this patient was quite ill on presentation. What are your comments and thoughts on that? Well, this patient presented, obviously, with ovarian hyperstimulation syndrome. And the priority would be to deal with that and then deal with the tumor. In terms of cabergline, what has been reported is that it may reduce the vascular permeability, the increased vascular permeability, which we see in the ovarian hyperstimulation syndrome, and ameliorate the clinical picture that relates with that. And it may also, obviously, reduce the FSH. So I think I can't say if it was a good or not good approach. What I can see is that it worked. And in cases where we don't have enough evidence on what is best, sometimes we just have to pick up a treatment that we feel is most useful and go with that and individualize our approach. Great. Thanks, Niki. So this concludes our session. I want to thank Ryo for his excellent presentation. I want to thank Dr. Niki Karavitaki for sharing her clinical pearls on this topic. And we'll look forward to our next session where we highlight another case. Thank you all.

Ovarian Hyperstimulation Syndrome

Functional Gonadotroph Pituitary Adenoma

Case Report

Dr. Ryo Tazukaguchi

Lower Abdominal Pain

Abdominal Swelling

Dyspnea