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. 

In This Article

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.[9,10,11] 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.


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