Functioning Gonadotroph Adenoma
Pituitary gonadotroph adenoma is a type of non-functioning pituitary adenoma that is typically considered clinically silent. However, approximately 35% of these adenomas secrete biologically active luteinizing hormone (LH) or follicle-stimulating hormone (FSH), and these are referred to as functioning gonadotroph adenomas (FGAs). FGAs are rare and often present with unique clinical manifestations depending on the sex of the patient. This article presents three cases of FSH-secreting adenomas treated at Peking Union Medical College Hospital between 2014 and 2016, and provides a comprehensive review of the clinical features, diagnostic challenges, and management strategies for FGAs.
Case Presentations
Case 1
A 37-year-old woman was admitted with a 2-year history of menstrual irregularity and galactorrhea. Laboratory tests revealed significantly elevated estradiol (E2) levels. Transvaginal ultrasonography showed multiple cyst fusions in the ovaries. Pituitary magnetic resonance imaging (MRI) identified a mass measuring approximately 7.5 mm × 10.7 mm in the saddle area, consistent with a pituitary macroadenoma. The patient underwent transsphenoidal microsurgical resection of the adenoma. Pathologic examination confirmed positive staining for FSH, LH, and steroidogenic factor-1 (SF-1), while staining for growth hormone, insulin-like growth factor 1, TPIT, and PIT1 was negative.
Case 2
A 39-year-old woman presented with a 3-year history of menstrual irregularity. She was diagnosed with multiple cervical polyps, and complete curettage of the uterine cavity was performed. Transvaginal ultrasonography revealed cystic lesions in the right ovary (58 mm × 62 mm × 31 mm) and pelvic occupying lesions (109 mm × 90 mm × 70 mm). Laboratory tests showed elevated FSH and E2 levels. MRI identified a 23 mm × 14 mm macroadenoma. Transsphenoidal microsurgical resection was performed, achieving total removal of the tumor. Immunohistochemical staining was positive for FSH, LH, and SF-1, and negative for TPIT and PIT1.
Case 3
A 46-year-old man was admitted with a 3-year history of hypopsia, hemianopsia, and hypogonadism. Hormone measurements revealed elevated prolactin (340.9 ng/mL), FSH (70.6 U/L), and low LH (0.36 U/L). MRI identified a suprasellar lesion measuring 45 mm × 30 mm × 31 mm. The patient underwent transsphenoidal microsurgical resection at a local hospital. Immunohistochemical staining was positive for FSH. Two months later, MRI revealed tumor relapse, and a second transsphenoidal resection was performed. Pathologic examination confirmed positive staining for FSH, LH, and SF-1, and negative staining for TPIT and PIT1.
Clinical Manifestations of FGAs
FGAs can secrete functional FSH or LH, leading to a variety of clinical manifestations. In females, the most common symptoms include menstrual irregularity (15/34 cases), abdominal distension or increasing abdominal girth (13/34), amenorrhea (13/34), galactorrhea (10/34), abdominal or pelvic pain (10/34), hypomenorrhea (5/34), hypermenorrhea (2/34), and infertility (2/34). Elevated E2 levels are often observed in female patients, while FSH levels may be mildly elevated or within the normal range. LH levels are typically decreased.
In males, the most common symptoms include testicular enlargement, hypogonadism, and visual disturbances such as hemianopsia. FGAs in males are often associated with significantly elevated FSH levels, while LH and testosterone levels may be below normal, within normal range, or elevated. Hypogonadism in males with FGAs is thought to result from the mass effect of the adenoma on the normal pituitary, leading to LH and testosterone insufficiency. High FSH levels can also lead to decreased sperm count, although cases of increased sperm count have been reported.
Diagnostic Challenges
FGAs are rare and often misdiagnosed due to their nonspecific clinical manifestations. In females, the symptoms may mimic those of polycystic ovary syndrome (PCOS) or other gynecologic conditions, leading to delayed diagnosis. In males, the symptoms are often less distinctive, and patients may present with larger tumors at the time of diagnosis due to delayed recognition. Hormonal testing and imaging studies, particularly pituitary MRI, are critical for accurate diagnosis. Immunohistochemical staining of resected tumor tissue is essential to confirm the presence of FSH, LH, and SF-1.
Management Strategies
Transsphenoidal microsurgical resection is the most effective treatment for FGAs. In female patients, elevated E2 and FSH levels typically return to normal following complete resection of the tumor. Enlarged ovarian cysts and pelvic cystic lesions may gradually regress after surgery. Early diagnosis is crucial to avoid unnecessary surgical interventions, such as ovary laparotomy, which may be performed in cases of misdiagnosis.
Radiotherapy has been reported as a treatment option for recurrent FGAs, but its effectiveness remains uncertain due to the lack of long-term follow-up data. In the cases presented here, radiotherapy was not administered due to its unknown effects.
Pathophysiology and Hormonal Effects
FGAs secrete biologically active FSH or LH, which can lead to hyperestrogenism in females and hypogonadism or testicular enlargement in males. In Sertoli cells, FSH stimulates the secretion of androgen-binding protein, which provides a high local concentration of testosterone in the seminiferous tubules. In cases of pituitary adenoma with mass effect, LH and testosterone insufficiency may impede the synergistic trophic effects of FSH, leading to hypogonadism. The production of multiple FSH species with variable biologic activity in Sertoli cells is hypothesized to play a role in testicular enlargement.
Conclusion
FGAs are rare but clinically significant pituitary adenomas that can cause a variety of symptoms depending on the sex of the patient. Early diagnosis and appropriate management are essential to prevent unnecessary surgical interventions and improve patient outcomes. Transsphenoidal microsurgical resection remains the most effective treatment, while the role of radiotherapy in recurrent cases requires further investigation. Increased awareness among endocrinologists, gynecologists, and neurosurgeons is critical for the timely diagnosis and management of FGAs.
doi.org/10.1097/CM9.0000000000000184
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