آدنوم نان فانکسیون هیپوفیز
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25 to 30 percent of pituitary adenomas are clinically nonfunctioning or “silent”; 80 to 90 percent of these are gonadotroph adenomas, making them the most common type of pituitary macroadenoma.
OVERVIEW — Most adenomas (65 to 70 percent) secrete an excess amount of hormone including prolactin, growth hormone, ACTH, or TSH.
30 to 35 percent of pituitary adenomas are clinically nonfunctioning or “silent”. Of these, 80 to 90 percent are gonadotroph adenomas .
The majority of gonadotroph adenomas are clinically “silent” .
The hormones secreted by gonadotroph adenomas in order of decreasing frequency include: FSH, FSH-β, alpha subunit, LH, and LH-β .
Gonadotropin subunits are not biologically active .
Gonadotroph adenomas are thought to be most common in men over age 50 years ,and less common in similar aged women.
CLINICAL PRESENTATIONS —
symptoms due to a mass effect.
3 most common presentations include the following :
• Neurologic symptoms, most commonly visual symptoms; less commonly headache.
• as an incidental finding
• Pituitary hypofunction
Less commonly, patients with gonadotroph adenomas may present with clinical syndromes due to hypersecretion of FSH or, less commonly, LH (ovarian hyperstimulation or precocious puberty).
Visual impairment —
The most common type of vision impairment is visual field loss, typically diminished vision in the temporal fields (superior temporal quadrantanopsia or temporal hemianopsia). One or both eyes may be affected.
Diminished visual acuity, which occurs when the optic chiasm is more severely compressed,was reported in approximately 30 percent of patients in one series .
• Diplopia, induced by oculomotor nerve compression resulting from lateral extension, occurring in up to 10 to 15 % of patients.
Headache — Headaches, the second most common neurologic symptom, occur in 30 to 40 % of patients , they are usually diffuse.
Cerebrospinal fluid rhinorrhea,
• Pituitary apoplexy (sudden hemorrhage into a pituitary macroadenoma), is also rare. This may occur spontaneously, but has also been reported during pregnancy, surgery, and with anticoagulant use
• It has been described less commonly after (TRH) and (GnRH) stimulation tests and with (GnRH) agonist therapy for prostate cancer
Incidental finding on imaging —
Symptoms due to hormonal abnormalities — evidence of hypopituitarism (usually biochemical).
On rare occasions, a clinical syndrome such as ovarian hyperstimulation or precocious puberty.
can occur as part of the MEN-1 syndrome,
Hormone deficiencies —
these symptoms tend to be nonspecific (fatigue and lethargy.
The most common clinical hormone deficiency is impaired secretion of gonadotropins resulting in hypogonadism.
in biocmicl tests , the most common pituitary hormone deficiencies were:
• (GH) (87 %). Testing for GH deficiency was less common in older series, because GH deficiency was not thought to have important clinical consequences.
• LH/FSH (72 %).
• ACTH ( 30 % ).
• TSH (24 %).
Gonadotroph adenomas: hormone excess —
most do produce intact gonadotropins or their subunits. However, these adenomas are typically poorly differentiated and inefficient producers/secretors and do not raise serum gonadotropin concentrations.
However, about 35 % of gonadotroph adenomas secrete enough LH or FSH to raise serum gonadotropin levels , but clinical syndromes due to hypersecretion of intact gonadotropins are rare. However, several syndromes have been recognized :
• Ovarian hyperstimulation has been reported in premenopausal women and rarely in prepubertal girls . Because the multiple follicles are not triggered to ovulate, women present with amenorrhea or oligomenorrhea , and prepubertal girls present with breast development, vaginal bleeding, and abdominal distension .
• An LH-secreting pituitary adenoma resulting in precocious puberty has been reported in two boys .
Although gonadotroph adenomas are thought to occur most commonly in middle-aged men, clinical findings due to hypersecretion of intact LH or FSH are rare in this group.
The majority of gonadotroph adenomas that secrete intact gonadotropins occur in middle aged adults and do not result in a clinical syndrome.
In postmenopausal women, a gonadotroph adenoma that secretes intact gonadotropins would not result in a clinical syndrome
In postmenopausal women, a sellar mass can be recognized as a gonadotroph adenoma biochemically by the combination of an elevated FSH and/or alpha subunit and a suppressed LH . They can also be identified by an LH beta subunit response to TRH.
In men, an intrasellar mass can be recognized as a gonadotroph adenoma by a supranormal basal serum FSH concentration .
A supranormal response of intact FSH and LH or LH beta subunit to (TRH) has also been described in men with gonadotroph adenomas.
Elevated prolactin — compression of pituitary stalk resulting in modestly elevated PRL (usually 1 cm) by imaging
Elevation of the optic chiasm or extension into the cavernous sinuses or sphenoid sinus can also be detected.
General approach —
Take a detailed history and perform a physical examination, recognizing that any visual abnormalities or other neurologic symptoms could represent a sellar mass.
The history should also focus on possible symptoms of hypopituitarism, including symptoms of hypogonadism in men (fatigue, decreased libido, erectile dysfunction) and women (amenorrhea/oligomenorrhea).
• Confirm the presence of a sellar mass by an MRI
• Perform visual field and visual acuity testing
• Perform biochemical testing to detect (eg, lactotroph, somatotroph and, less commonly, corticotroph adenomas)
• Test for excessive secretion of gonadotropins and their subunits, as they are characteristic of gonadotroph adenomas. This includes measurement of serum LH, FSH, and alpha subunit concentrations
• Test also for pituitary hypofunction due to compression of normal pituitary cells by the adenoma
• The Endocrine Society Clinical Practice Guidelines on Pituitary Incidentaloma agree with our approach and suggest MRI, visual field testing and biochemical evaluation for hormone hypersecretion and hypopituitarism for patients with pituitary incidentalomas that are >1 cm in size .
Pituitary imaging —
(MRI) for the initial imaging study
Visual field testing — All patients with sellar masses elevating the optic chiasm, including those who deny visual symptoms, should undergo baseline Humphrey visual field testing and evaluation of visual acuity.
Hormonal evaluation — (both hyper- and hypofunction) should be evaluated whenever a large sellar mass is seen on MRI to determine if it is functioning or nonfunctioning.
Hormone hypersecretion —
measurements of serum prolactin (lactotroph adenomas), insulin-like growth factor-1 (IGF-1) (somatotroph adenomas), and 24-hour urine free cortisol (corticotroph adenomas).
We also suggest measuring serum LH, FSH, and alpha subunit,
An FSH response to thyrotropin-releasing hormone (TRH) also indicates a gonadotroph adenoma .
• 8 AM cortisol
• T4 (if elevated, measure TSH to evaluate the possibility of a thyrotroph adenoma)
• Testosterone in men
• Estradiol (E2) in women of premenopausal age with amenorrhea
DIAGNOSIS — A definitive diagnosis of a gonadotroph adenoma is made by pathologic evaluation of the excised tissue. Immunochemical staining is positive for FSH beta, LH beta, and/or alpha subunit.
However, the diagnosis of a gonadotroph adenoma can be made with a reasonable degree of certainty preoperatively in a patient with a large sellar mass in the following circumstances:
• Serum prolactin concentration less than 100 ng/mL
• No symptoms or signs of acromegaly and serum concentration of (IGF-1) not elevated.
• No signs or symptoms of Cushing’s syndrome and 24-hour urine cortisol excretion not elevated.
• In men, elevated basal serum concentrations of intact FSH and/or of alpha subunit . In countries where TRH is available, an FSH response to TRH. Rarely, elevated LH and testosterone. Elevated FSH and LH and subnormal testosterone indicate primary hypogonadism
• In premenopausal women, irregular menses, elevated FSH and estradiol, low LH, and on pelvic ultrasound, massive polycystic ovaries and thickened endometrium.
• In postmenopausal women, elevated FSH and/or alpha subunit and low LH . Elevation of both FSH and LH likely indicate only normal postmenopausal gonadotropin secretion.
DIFFERENTIAL DIAGNOSIS —
craniopharyngioma, meningioma, malignant tumors, Rathke’s cleft cysts, and hypophysitis.
Lactotroph macroadenoma —
Large sellar masses result is a mild elevation of serum prolactin (>20 ng/mL [eg, higher than normal] but usually 500pg/mL should strongly raise the suspicion that the multiple ovarian cysts are due to a gonadotroph adenoma rather than polycystic ovary syndrome.
• Approximately 25 to 30 percent of all pituitary adenomas are clinically nonfunctioning or “silent”; 80 to 90 percent of these are gonadotroph adenomas
• Clinically nonfunctioning adenomas (including gonadotroph adenomas) usually come to clinical attention when they become large enough to cause neurologic symptoms such as impaired vision (diminished vision in the temporal fields [bitemporal hemianopsia], and diminished visual acuity), nonspecific headaches, diplopia, cerebrospinal fluid rhinorrhea, and pituitary apoplexy
• Some are detected as an incidental finding when an MRI is done for other reasons
• Approximately 60 percent of patients at the time of diagnosis have hypopituitarism due to compression by the macroadenoma, but the hormonal deficiencies are usually not the presenting symptoms and not detected until the patient undergoes biochemical testing
• Gonadotroph adenomas are difficult to recognize because they secrete variably and inefficiently, and the resulting products often do not cause a clinical syndrome. Only 35 percent secrete enough intact FSH or alpha subunit to raise their serum levels. Uncommonly, however, gonadotroph adenomas hypersecrete FSH in premenopausal women and cause ovarian hyperstimulation and, rarely, some hypersecrete LH in a boy or man and cause an increased serum testosterone concentration
• Evaluation of the patient who presents with neurological symptoms suggestive of a clinically nonfunctioning sellar mass should include:
• Pituitary MRI
• Visual field testing
• Biochemical testing for hormone hypersecretion (serum prolactin, insulin-like growth factor-1 (IGF-1), and 24-hour urine free cortisol)
• Testing for hypopituitarism: 8AM cortisol, T4 (plus TSH if the T4 is high), testosterone in men and estradiol in women of premenopausal age, FSH, LH and alpha subunit
• The diagnosis of a gonadotroph adenoma is likely if there is a large sellar mass, no clinical or biochemical evidence of acromegaly or Cushing’s syndrome, the serum prolactin is <100 ng/mL, and the concentrations of gonadotropins are characteristic
• In men, characteristic patterns are an elevated serum FSH and/oralpha subunit or, rarely, elevated LH and testosterone.
• In women of premenopausal age, characteristic patterns are an elevated FSH, with or without alpha subunit, and estradiol.
• In postmenopausal women, the patterns are an elevated FSH and/oralpha subunit but low LH. The diagnosis is confirmed if histologic examination of the excised tissue shows a pituitary adenoma and immunocytochemical staining shows staining for FSH, LH, and/oralpha subunit.
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