Another cause of ovarian cysts, besides insulin resistance

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Ovarian Hyperstimulation Syndrome Caused by an FSH-Secreting Pituitary
Adenoma

Odelia Cooper; Jordan L Geller; Shlomo Melmed

Nat Clin Pract Endocrinol Metab. 2008;4(4):234-238. ©2008 Nature
Publishing Group
Posted 05/21/2008
Summary

Background: A 40-year-old woman presented with galactorrhea and
oligomenorrhea. She had a history of multiple ovarian cysts and pelvic pain.
Investigations: Laboratory evaluation included measurements of the
levels of estradiol, follicle-stimulating hormone, luteinizing hormone,
prolactin, thyroid-stimulating hormone, free endogenous T4, the
glycoprotein hormone α subunit, cortisol, adrenocorticotropic hormone,
and insulin-like growth factor I. Radiological studies included MRI of
the pituitary.
Diagnosis: Ovarian hyperstimulation syndrome caused by a pituitary
adenoma, secreting follicle-stimulating hormone.
Management: The patient underwent trans-sphenoidal resection of the
adenoma, with subsequent normalization of hormonal values and symptoms.

The Case

A 40-year-old woman presented in 2006 with a 15-year history of
bilateral galactorrhea. She has never been pregnant and had initially
presented at the age of 25 years with menometrorraghia (dysfunctional
uterine bleeding) and bilateral galactorrhea, while being on oral
contraceptives. At that time investigations revealed the presence of
benign luteinized follicular cysts, which were resected
laparoscopically. Her symptoms then temporarily abated, but recurred
with re-growth of ovarian cysts and with features of the ovarian
hyperstimulation syndrome (OHSS) including pelvic pain and enlarged,
multicystic ovaries, which required three separate operations over the
following 5 years.

The patient was referred for endocrinological evaluation in 2006,
because she had persistent galactorrhea. At this time, she reported
having had a normal adrenarche and puberty, and she denied suffering
from headaches, visual disturbances, weight or body habitus changes,
polyuria, hirsutism or acne. Her history revealed that she was receiving
the oral contraceptive pill. On physical examination, she was found to
have bilateral galactorrhea.

Biochemical testing demonstrated a negative pregnancy test, prolactin
levels of 3,000 pmol/l (reference range 165-1,009 pmol/l),
follicle-stimulating hormone (FSH) levels of 19.2 IU/l (reference range
4-13 IU/l), luteinizing hormone (LH) levels of 0.6 IU/l (reference range
1-18 IU/l), estradiol levels of 3,851.0 pmol/l (reference value <1,094.0
pmol/l), adrenocorticotropic hormone levels of 2.9 pmol/l (reference
range 1.1-5.9 pmol/l), 0800 h cortisol levels of 510.4 nmol/l (reference
range 165.5-634.6 nmol/l), glycoprotein hormone α subunit levels of 0.8
µg/l (reference range 0.04-0.38 µg/l), TSH levels of 3.3 mIU/l
(reference range 0.39-4.6 mIU/l), free endogenous T4 levels of 11.6
pmol/l (reference range 10.3-34.7 pmol/l), and insulin-like growth
factor I levels of 33.7 nmol/l (reference range 18.1-53.7 nmol/l). MRI
of the pituitary gland revealed a 16 x 27 x 22 mm pituitary adenoma with
suprasellar extension, elevation and compression of the optic chiasm,
and extension to the right cavernous sinus (Figure 1). The patient
underwent trans-sphenoidal resection of the pituitary mass.



Immunohistochemical staining of the pituitary adenoma specimen was
positive for α subunit, FSHß subunit and LHß subunit; staining was
negative for growth hormone, prolactin, adrenocorticotropic hormone and
for TSH. The Ki-67 proliferative index, measuring the growth fraction of
tumor cells, was low (1%) and almost no cells showing overexpression of
p53 protein were detected. These findings generally suggests a low tumor
grade and a good prognosis.

The patient was diagnosed as harboring a gonadotrope cell adenoma with
secondary ovarian hyperstimulation. Postoperatively, galactorrhea
resolved, and normal menses resumed. Anterior pituitary hormone reserve
was intact.
Discussion of Diagnosis

This case typifies the presentation of OHSS in the face of an
FSH-secreting adenoma. OHSS comprises extravasation of fluid into the
peritoneal cavity, with consequent ascites, hemoconcentration, and
electrolyte abnormalities. When OHSS is caused by an FSH-secreting
adenoma, FSH levels are usually elevated, LH is suppressed, and
estradiol levels are elevated up to 80 times the normal levels. Women
suffering from OHSS usually develop enlarged multicystic ovaries
associated with abdominal pain. The detection of elevated prolactin
levels then triggers the ordering of a pituitary MRI, which will reveal
the presence of a pituitary adenoma. In general, women with
FSH-secreting tumors are asymptomatic, and often FSH levels are only
marginally above the normal range for reproductive-age women.
Gonadotropin-secreting adenomas are more common in postmenopausal women,
who are relatively insensitive to ovarian hyperstimulation.[1]

Gonadotropinomas account for 15-40% of all pituitary tumors. More than
80% of clinically nonfunctioning pituitary adenomas are estimated to be
gonadotrope-derived, accounting for approximately half of all
macroadenomas. These adenomas often arise in middle-aged men, who may
have low testosterone levels with high LH and FSH levels, suggesting a
diagnosis of primary hypogonadism. There are also a few reports of male
gonadotropinomas leading to elevated testosterone levels resulting in an
increased sperm count, and, in addition, there is a case report of a
7-year-old boy who developed precocious puberty as a consequence of a
gonadotropin-secreting adenoma.[2,3] Women with intact gonadotrope
adenomas and supra-normal FSH levels are generally not recognized as
exhibiting a syndrome, because many are over 45 years of age with
ovaries devoid of pre-antral follicles, and are insensitive to the
action of FSH.[4] These gonadotrope adenomas are, therefore, more
difficult to diagnose in women who are perimenopausal or postmenopausal.[5]

In women, gonadotropinomas should also be considered if there is a
history of headaches or visual changes. Measurements of basal FSH, LH,
and α subunit levels may aid the diagnosis, as supra-normal α subunit
levels with intact LH and FSH levels, or with disproportionate FSH and
LH levels, suggest the presence of a gonadotropinoma, especially when
the hormone subunits are induced by a TRH (TSH-releasing hormone)
stimulation test. Administration of TRH rarely enhances gonadotropin or
gonadotropin subunit secretion in healthy individuals, whereas it can
enhance subunit secretion in up to 70% of patients with
gonadotropinomas. Although LHß is the gonadotropin subunit most
sensitive to increase on administration of TRH, there is currently no
standard commercial assay for measuring the LHß subunit, making this
protein impractical for routine use.[5]

Clinical and biological behavior of gonadotropinomas has been gleaned
from in vitro studies and from limited case reports and case series.
Gonadotropinomas exhibit variable degrees of differentiation. Only up to
15% of tumor cells -- grouped in small islets around blood vessels in
the tumor parenchyma -- show immunohistochemical staining (of variable
intensity), which could explain the low levels of circulating hormone
concentrations. Nonfunctioning gonadotropinomas are mainly composed of
tumor cells with negative immunostaining for all pituitary hormone
antibodies, but these tumor cells usually stain positively for the DAX-1
(Nuclear receptor subfamily 0 group B member 1) protein, which regulates
gonadotrope differentiation.[5]

The bioactivity and concentration of baseline serum FSH are higher in
patients with adenomas than in controls. In addition, bioactive and
immunoreactive FSH levels increase in response to the administration of
TRH in patients with adenomas. The cellular machinery for biosynthesis
and processing of FSH is intact, and functional FSH is secreted despite
aberrant tumor growth.[6] It should, however, be mentioned that the
unassociated LHß and FSHß subunits exhibit no intrinsic biological
activity and that formation of a heterodimer with the α subunit is
essential for biological activity. As 70-100% of nonfunctioning adenomas
secrete free subunits, these tumors usually show no biological activity.[7]

In a subject with an intact pituitary gland, one would expect that high
estradiol levels would suppress gonadotropin-releasing hormone (GnRH)
and, therefore, suppress gonadotropin secretion. In gonadotrope
adenomas, however, the normal feedback system is impaired, thereby
permitting the presence of persistently elevated FSH and estradiol
levels, which then leads to the symptoms and signs of OHSS.

Clinical behavior of gonadotropinomas has been described in a number of
case series, including an analysis of 100 patients with
gonadotropin-positive pituitary adenomas reported between 1976 and
1992.[8] In this report, gonadotropin levels were found to be
inappropriately low compared with the expected levels in postmenopausal
women.[8] LH concentrations were elevated in 36% of males, with 9%
showing LH hypersecretion (defined as more than a two-fold increase
above the upper limit of normal). FSH levels were elevated in 42% of
males, with FSH hypersecretion reported in 19%. Levels of α subunit were
high in only 1 of 29 patients. In other case series, however, α subunit
levels were elevated in 15-32% of patients.[9-11] Hypogonadism was
diagnosed biochemically in 78% of males.[8] These patients presented
with mass effect symptoms including loss of vision, symptoms of
hypopituitarism, and headaches.[8]

On electron microscopy, gonadotrope adenomas showed a gender-related
ultrastructural dimorphism. In men, gonadotrope adenomas tend to have
small cells with decreased cytoplasmic volume densities of endoplasmic
reticulum and Golgi membranes, and with variable numbers of secretory
granules. On the other hand, in women gonadotrope adenomas have a
well-developed endoplasmic reticulum, a 'honeycomb' Golgi complex and
sparse, small secretory granules. Using this distinction, 45% of the
adenomas in this series were structurally classified as 'male'
gonadotrope adenomas whereas 9% were 'female' adenomas.[8]

Hypersecretion of gonadotropins and their subunits rarely leads to a
defined clinical syndrome, unlike syndromes associated with prolactin or
growth hormone hypersecretion. Consequently, most gonadotropinomas have,
heretofore, been classified as nonfunctioning or 'null cell' adenomas.
It is known, however, that gonadotropinomas often secrete α subunit, FSH
and FSHß subunit as well as LH and LHß subunit. In fact, the 2004 WHO
classification of pituitary tumors places gonadotrope adenomas in their
own class, as it has now become clear that gonadotrope cells of the
anterior pituitary pursue a pathway of differentiation distinct from
other tropic hormone cells. Unlike 'null cell' adenomas,
gonadotropinomas express the nuclear receptor steroidogenic factor-1
almost exclusively in cells that produce gonadotropin ß subunits;
moreover, this factor has been shown to regulate glycoprotein hormone α
subunit gene expression in pituitary gonadotrope cells.[12]

Patients may present with symptoms of excess gonadotropin secretion
leading to the syndrome of ovarian hyperstimulation. The pathogenesis of
this syndrome has been explored in an animal model in which transgenic
mice with pituitary-directed hypersecretion of LH developed multicystic
ovaries. These mice had an increased pituitary size and showed
proliferation of Pit-1 (pituitary-specific positive transcription factor
1)-positive cells that culminated in the appearance of functional
pituitary adenomas. It is thought that LH could be an extrinsic factor
acting through the ovary leading to the formation of functional
pituitary adenomas.[13]

OHSS has been reported in patients aged 10-39 years, with pituitary
tumors varying in size from 8 mm diameter to huge invasive adenomas. As
in the case presented here, premenopausal women with FSH-secreting
tumors may harbor a clinically functioning adenoma, manifesting with
enlarged multicystic ovaries and with abdominal pain. Similar cases in
the literature are summarized in Supplementary Tables 1, 2, 3.
Differential Diagnosis

OHSS can occur in association with other disease states. Patients with
polycystic ovary syndrome who become pregnant are at risk of OHSS as
they have multiple partially stimulated antral follicles, which can
over-respond to exogenous gonadotropins as reported during assisted
reproductive treatment. OHSS has also been reported in association with
primary hypothyroidism, possibly caused by TSH-mediated stimulation of
the FSH receptor or by enhanced TRH production stimulating gonadotropin
release. In addition, a single patient with bilateral granulosa cell
tumors has been reported to have developed OHSS.[14]
Treatment and Management

Surgical resection is the definitive and primary therapy for OHSS due to
gonadotropin-secreting adenomas. Surgery results in normalization of
gonadotropin and estradiol levels. Menstrual cycles resume and the
ovaries revert to normal size with cyst remission. In those with
recurrent tumors, radiation therapy may be required.

Medical therapies are generally not effective. In theory, one possible
medical treatment would be the administration of a GnRH analog which
would decrease FSH levels, thereby leading to resolution of OHSS;
however, reports have actually shown a paradoxical increase in
gonadotropin secretion in response to this treatment,[4,15-20] and in
one case OHSS was induced after initiation of GnRH therapy with dramatic
increases in FSH and estradiol levels.[21]

There are three reports of patients with OHSS who were initially treated
medically. These patients presented with oligomenorrhea, abdominal
distension, and enlarged multicystic ovaries. Estradiol levels were as
high as 6,755 pmol/l, with elevated prolactin and FSH levels and
suppressed LH levels. The three patients were treated with a dopamine
agonist and two of the patients also received medroxyprogesterone.
Ovarian volumes and hormonal values normalized. Eventually, however, the
adenomas continued to grow and were resected, showing positive
immunostaining for LH in two cases and for FSH in one case.[15,22]

After resection of a pituitary adenoma, patients are monitored annually
with MRI, looking for evidence of a possible recurrence. Patients should
also undergo hormonal testing 3 months after surgery to assess whether
hypopituitarism is present. If there is evidence of a deficiency of any
of the hormones of the pituitary axis, hormonal replacement therapy is
initiated.
Conclusions

We present a case of a woman who developed OHSS due to an FSH-secreting
pituitary adenoma. This syndrome comprises enlarged, multicystic
ovaries, oligomenorrhea or amenorrhea, elevated estradiol levels and,
usually, elevated serum FSH levels. After resection of the pituitary
adenoma, the endocrine profile and symptoms revert to normal.

Our case brings to light two instructive points. Firstly, contrary to
the assumption that gonadotrope adenomas are clinically nonfunctioning
adenomas, FSH-secreting adenomas may in fact be functional, leading to
hypersecretory symptoms as in the development of OHSS. Secondly, when
clinicians encounter patients presenting with symptoms of abdominal
pain, abnormal menses and multicystic ovaries, they should measure
estradiol and gonadotropin levels to exclude OHSS caused by a pituitary
adenoma. In our case, the patient had a 15-year history of such symptoms
but had not undergone an endocrine work-up, which could have revealed
the presence of a pituitary adenoma during that period. Clinical
awareness and an appropriate endocrine work-up facilitate early
diagnosis and treatment of this syndrome, thereby avoiding multiple
therapeutic procedures for ovarian cysts and ultimately also restoring
fertility.



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Acknowledgements

Consent for the publication of Figure 1 was obtained from the patient.
Funding Information

This work was supported by NIH grants T32 DK007770-06A2 and CA75979.
Reprint Address

Shlomo Melmed, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room
2015, Los Angeles, CA 90048. E-mail: melmed@csmc.edu .

Odelia Cooper, Jordan L Geller, Shlomo Melmed, Cedars-Sinai Medical
Center, Los Angeles, CA