Clinical Manifestations and Diagnosis of Gonadotroph and Other Clinically Nonfunctioning Pituitary Adenomas - UpToDate

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Manifestaciones clínicas y diagnóstico de gonadotroph y

otros adenomas hipofisarios clínicamente no funcionales.
Autor: Peter J Snyder, MD
Editor de sección: David S Cooper, MD
Subdirector: Kathryn A Martin, MD
Todos los temas se actualizan a medida que hay nuevas pruebas disponibles y nuestro proceso de revisión por pares
está completo.
Revisión de literatura actualizada hasta: septiembre de 2019. | Última actualización de este tema: 18 de mayo
de 2018.
INTRODUCCIÓN
La mayoría de los pacientes con adenomas hipofisarios presentan signos y síntomas de

hipersecreción hormonal (p. Ej., Hiperprolactinemia, exceso de hormona del crecimiento [GH] o
hipercortisolismo). Sin embargo, del 25 al 35 por ciento de los adenomas pituitarios son
clínicamente no funcionales o "silenciosos"; Del 70 al 90 por ciento de estos son adenomas
gonadotróficos, lo que los convierte en el tipo más común de macroadenoma pituitario. Los
pacientes con adenomas clínicamente no funcionales suelen presentar síntomas neurológicos
debido a efectos masivos, mientras que otros pueden ser completamente asintomáticos y ser
detectados por primera vez en un estudio de imagen realizado por razones distintas a los
síntomas o la enfermedad de la hipófisis. Para cuando los pacientes presentes, un alto porcentaje
tiene evidencia bioquímica de hipopituitarismo debido a la compresión de las células pituitarias
normales por el macroadenoma.
Aquí se revisan las características clínicas, la evaluación y el diagnóstico de adenomas

hipofisarios clínicamente no funcionales. El tratamiento de estos tumores y una descripción
general de las masas selares descubiertas incidentalmente (incidentalomas pituitarios) se
analizan por separado. (Ver "Tratamiento de gonadotroph y otros adenomas clínicamente no
funcionales" y "Masas sellares descubiertas incidentalmente (incidentalomas pituitarios)" .)
RESUMEN
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Los adenomas hipofisarios se clasifican por su célula de origen (lactotroph, gonadotroph,

somatotroph, corticotroph y thyrotroph) y su tamaño (microadenomas <1 cm, macroadenomas ≥1
cm). La mayoría de los adenomas (65 a 70 por ciento) secretan una cantidad excesiva de
hormona, incluida la prolactina, la hormona del crecimiento (GH), la corticotropina (ACTH) o la
hormona estimulante de la tiroides (TSH). (Ver "Causas de hiperprolactinemia" y "Causas y
manifestaciones clínicas de la acromegalia" y "Causas y fisiopatología del síndrome de Cushing"
y "Adenomas hipofisarios secretores de TSH" ).
El resto de los adenomas pituitarios (25 a 35 por ciento) no funcionan clínicamente o son
"silenciosos". De estos, del 70 al 90 por ciento son adenomas gonadotróficos [ 1 ]. También hay
adenomas clínicamente no funcionales somatotroph [ 2,3 ], lactotroph y corticotroph [ 4 ], aunque
estos son menos comunes.
La mayoría de los adenomas de gonadotrofos son clínicamente "silenciosos" y difíciles de

identificar porque están pobremente diferenciados y producen y secretan hormonas de manera
ineficiente. Las gonadotropinas, la hormona luteinizante (LH) y la hormona foliculoestimulante
(FSH) consisten en una subunidad alfa común y una subunidad beta única. La TSH y la
gonadotropina coriónica humana (hCG) también consisten en la subunidad alfa común y una
subunidad beta única. Las hormonas secretadas por los adenomas gonadotróficos en orden
decreciente de frecuencia incluyen: FSH, FSH-beta, subunidad alfa, LH y LH-beta [ 5 ].
Alpha subunit is not biologically active and also does not result in a clinical symptom due to its
secretion. However, it is measured to evaluate patients with sellar masses to determine if the
mass is pituitary in origin and whether there is accompanying hormonal hypersecretion. (See
'Hormone hypersecretion' below.)
EPIDEMIOLOGY
Estimates of the prevalence of pituitary adenomas are variable and are often based upon autopsy
or magnetic resonance imaging (MRI) series. In a report from a single community of over 80,000
inhabitants in England, the prevalence of nonfunctioning pituitary adenomas (that had come to the
attention of a clinician) was 22 per 100,000 [6]. This is likely an underestimate of the true
prevalence, as many nonfunctioning pituitary adenomas go undiagnosed until they are very large
or are identified on an imaging study done for unrelated reasons.
Gonadotroph adenomas are thought to be most common in men over age 50 years [1] and less
common in similar aged women, but this could be due to difficulty in recognizing gonadotroph
adenomas in this population. High serum gonadotropins would be unlikely to raise suspicion for a
gonadotroph adenoma in a woman over 50 years since she is likely to have elevated basal serum
gonadotropin concentrations from the normal menopause [7]. (See "Clinical manifestations and
diagnosis of menopause".)
PATHOGENESIS
Gonadotroph adenomas, like other pituitary adenomas, appear to be true clonal neoplasms [8,9],
but the mutations that cause them are not known. Genes that have been found to be
overexpressed include the pituitary tumor transforming gene, Ki-67, and FGF-R [10-12]. The
maternally-expressed gene 3 (MEG3) is underexpressed [13].
CLINICAL PRESENTATIONS
Nonfunctioning pituitary adenomas (including the majority of gonadotroph adenomas) are difficult
to recognize clinically until they are large enough to cause symptoms due to a mass effect. The
three most common presentations include the following (table 1) [14]:
● Neurologic symptoms – Most commonly, visual symptoms; less commonly, headache
● A pituitary mass that is discovered as an incidental finding when an imaging procedure is

done for reasons other than pituitary symptoms or disease
● Pituitary hypofunction due to compression of normal pituitary tissue by the adenoma
Less commonly, patients with gonadotroph adenomas may present with clinical syndromes due to
hypersecretion of follicle-stimulating hormone (FSH) or, less commonly, luteinizing hormone (LH)
(ovarian hyperstimulation or precocious puberty). (See 'Gonadotroph adenomas: Hormone
excess' below.)
Neurologic symptoms
Visual impairment — Impaired vision, caused by suprasellar extension of the adenoma that
compresses the optic chiasm, is the most common symptom that leads a patient with a
gonadotroph or other clinically nonfunctioning adenoma to seek medical attention (image 1) [14-
16].
● 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. In a review of eight series of 1719 patients with clinically
nonfunctioning pituitary adenomas, visual field disturbances were present in 798 (46 percent)
[14], while in a single-center series of 295 patients, the frequency was even higher (192 of
295, 65 percent) [15].
● Diminished visual acuity, which occurs when the optic chiasm is more severely compressed
[16], was reported in approximately 30 percent of patients in one series [15]. Thus, an
intrasellar lesion should be suspected when there is any unexplained pattern of visual loss.
● The onset of visual deficits is usually so gradual that many patients do not seek
ophthalmologic consultation for months or even years.
● Diplopia, induced by oculomotor nerve compression resulting from lateral extension of the
adenoma may occur, but it is less common, occurring in up to 10 to 15 percent of patients in
several large series [14].
Headache — Headaches, the second most common neurologic symptom, occur in 30 to 40

percent of patients [14,15] and are thought to be due to sellar expansion. There is no
distinguishing characteristic of the headaches, although they are usually diffuse.
Other — Other less common neurologic symptoms include [16]:
● Cerebrospinal fluid rhinorrhea, caused by inferior extension of the adenoma, rarely occurs
spontaneously [17].
● Pituitary apoplexy (sudden hemorrhage into a pituitary macroadenoma), is also rare. It causes
excruciating headache and visual impairment [18]. This may occur spontaneously but has
also been reported during pregnancy, surgery, and with anticoagulant use [19]. It has been
described less commonly after thyrotropin-releasing hormone (TRH) and gonadotropin-
releasing hormone (GnRH) stimulation tests [20,21] and with gonadotropin-releasing hormone
(GnRH) agonist therapy for prostate cancer [22,23].
Incidental finding on imaging — The common use of magnetic resonance imaging (MRI) to
evaluate symptoms in the head or neck has resulted in the incidental discovery of many intrasellar
lesions. In two MRI series of 100 [24] and 52 [25] normal volunteers, 10 (10 percent) and 25 (38
percent), respectively, had previously unsuspected sellar lesions, but almost all were <10 mm.
However, in one review of eight series of pituitary "incidentalomas" discovered on MRI, 68 percent
were macroadenomas [14]. This percentage is much higher than other imaging series, suggesting
that patients likely had symptoms suggestive of a sellar mass that led to the imaging study.
The evaluation and management of these adenomas are reviewed separately. (See "Incidentally
discovered sellar masses (pituitary incidentalomas)".)
Symptoms due to hormonal abnormalities — Clinically nonfunctioning adenomas often present

with evidence of hypopituitarism (usually biochemical). On rare occasions, gonadotroph
adenomas present with hormonal hypersecretion causing a clinical syndrome such as ovarian
hyperstimulation or precocious puberty.
Gonadotroph adenomas, like all other types of pituitary adenomas, can occur as part of the
multiple endocrine neoplasia type 1 (MEN1) syndrome, a rare heritable disorder classically
characterized by a predisposition to tumors of the parathyroid glands, anterior pituitary, and
pancreatic islet cells. (See "Multiple endocrine neoplasia type 1: Definition and genetics", section
on 'MEN1 gene'.)
Hormone deficiencies — Patients who present with neurologic symptoms, when carefully
questioned, may acknowledge symptoms of pituitary hormone deficiencies that are due to
compression of nonadenomatous cells by the macroadenoma. However, these symptoms tend to
be nonspecific (fatigue and lethargy) and are not usually the reason that the patient seeks medical
attention.
The most common clinical hormone deficiency is impaired secretion of gonadotropins resulting in
hypogonadism. In a series of 295 patients with nonfunctioning pituitary adenomas, 61 of 161 men
(38 percent) had low serum gonadotropins, resulting in low serum testosterone, decreased libido,
and erectile dysfunction [15]. In the same report, 33 percent of the women of reproductive age had
menstrual cycle disorders.
Higher percentages of hypopituitarism may be detected biochemically in patients with clinically

nonfunctioning adenomas. In a review of eight series of 1719 patients, 993 (58 percent) had
laboratory evidence of pituitary hormone deficiency [14]. The most common pituitary hormone
deficiencies were:
● Growth hormone (GH) (87 percent, 220 of 252 tested). Testing for GH deficiency was less
common in older series because GH deficiency was not thought to have important clinical
consequences. (See "Growth hormone deficiency in adults".)
● LH/FSH (hypogonadotropic hypogonadism; 1216 of 1699 patients tested, 72 percent).
● Corticotropin (ACTH) (secondary adrenal insufficiency; 514 of 1699, 30 percent).
● Thyroid-stimulating hormone (TSH) (central hypothyroidism; 402 of 1699, 24 percent).
Gonadotroph adenomas: Hormone excess — Although gonadotroph adenomas are

considered to be "nonfunctioning," 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. Thus, they are usually clinically "silent" and
cannot be distinguished from other clinically nonfunctioning adenomas until immunohistochemistry
is performed after pituitary surgery.
However, approximately 35 percent of gonadotroph adenomas secrete enough LH or FSH to raise

serum gonadotropin levels [26], but clinical syndromes due to hypersecretion of intact
gonadotropins are rare. However, several syndromes have been recognized (table 2) [27]:
● Ovarian hyperstimulation has been reported in premenopausal women [28-34] and, rarely, in
prepubertal girls [35,36]. The slight, but persistently, elevated serum FSH concentrations lead
to recruitment of multiple dominant follicles, high serum estradiol (E2) concentrations (>500
pg/mL), and thickened endometrium on pelvic ultrasound (potentially suggestive of
endometrial hyperplasia). The clinical picture is similar to ovarian stimulation with exogenous
FSH when administered for fertility treatment (image 2).
Because the multiple follicles are not triggered to ovulate, women present with amenorrhea or
oligomenorrhea [28-34], and prepubertal girls present with breast development, vaginal
bleeding, and abdominal distension [35,36]. If pituitary surgery is successful in removing the
adenoma but not removing the normal pituitary, gonadotropin secretion and ovarian function
returns to normal [33,37-40].
● An LH-secreting pituitary adenoma resulting in precocious puberty has been reported in two
boys [41,42].
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, for example, a
gonadotroph adenoma that secretes intact gonadotropins would not result in a clinical syndrome,
because gonadotropin levels are already high and a postmenopausal ovary cannot be stimulated
to produce follicles or E2. However, in males, elevated serum testosterone concentration due to
hypersecretion of intact LH and testicular enlargement due to FSH hypersecretion have been
described [5,43,44].
Other pituitary adenomas: Hormone excess
● In 100 consecutive patients with pituitary adenomas that were surgically excised, 24 had
somatotroph adenomas by immunochemical staining [3]. Of these, eight (one-third) had an
elevated insulin-like growth factor-1 (IGF-1) concentration but not even subtle manifestations
of acromegaly and could therefore be considered to be clinically silent.
● Clinically silent corticotroph adenomas might be recognizable by higher plasma ACTH

concentrations than other macroadenomas [4].
Elevated prolactin — Macroadenomas often compress the pituitary stalk and obstruct the
normal inhibitory hypothalamic influence on the prolactin producing cells, resulting in modestly
elevated serum prolactin concentrations (usually <100 ng/mL but sometimes as high as 200
ng/mL). Illustrated in one study of 226 patients with nonfunctioning macroadenomas, a serum
prolactin concentration >94 ng/mL reliably distinguished between lactotroph adenomas and
nonfunctioning adenomas [45]. Rarely, gonadotroph adenomas cosecrete prolactin and
gonadotropins.
Characteristic imaging features — As noted, gonadotroph adenomas are generally hormonally

inefficient; as a result, by the time a gonadotroph adenoma produces supranormal serum
concentrations of intact gonadotropins or their subunits, it is a macroadenoma (>1 cm) by imaging
(image 1). MRI in a patient with neurologic symptoms usually shows a large intrasellar mass that
is frequently extending outside of the sella. Elevation of the optic chiasm or extension into the
cavernous sinuses or sphenoid sinus can also be detected. MRI with gadolinium is preferred to
computed tomography (CT) because it provides superior resolution of the mass and its relation to
surrounding structures. (See 'Pituitary imaging' below and "Causes, presentation, and evaluation
of sellar masses", section on 'MRI'.)
EVALUATION
General approach — Our approach to the patient whose presenting signs, symptoms, or prior
imaging suggests a sellar mass includes the following:
● 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). (See 'Neurologic symptoms' above and 'Hormone deficiencies'
above.)
● Confirm the presence of a sellar mass by a magnetic resonance imaging (MRI) dedicated to
this region, if not already done. If a sellar mass is confirmed, assess its size, relationship to
chiasm, and cavernous sinuses.
● Visual field and visual acuity testing. (See 'Visual field testing' below.)
● Biochemical testing to detect other kinds of pituitary adenomas by their excessive hormonal
secretion (eg, lactotroph, somatotroph, and, less commonly, corticotroph adenomas). (See
● Biochemical testing for excessive secretion of gonadotropins and their subunits, as they are
characteristic of gonadotroph adenomas. This includes measurement of serum luteinizing
hormone (LH), follicle-stimulating hormone (FSH), and alpha subunit concentrations. (See
● Biochemical testing also for pituitary hypofunction due to compression of normal pituitary cells
by the adenoma. (See 'Hypopituitarism' below.)
We agree with the Endocrine Society Clinical Practice Guidelines on Pituitary Incidentaloma 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 [46].
Pituitary imaging — We suggest MRI for the initial imaging study for suspected adenomas
because of its superior resolution and its ability to demonstrate the optic chiasm. MRI with
gadolinium is preferred to computed tomography (CT) because it provides superior resolution of
the mass and its relation to surrounding structures. MRI is also able to detect blood, thereby
permitting recognition of hemorrhage into the pituitary and distinction of an aneurysm from other
intrasellar lesions (image 1).
However, MRI will not distinguish adenomatous tissue from normal pituitary tissue. MRI will also
not distinguish a gonadotroph adenoma from other pituitary macroadenomas and often not even
from nonpituitary lesions. This topic is reviewed in more detail separately. (See "Causes,
presentation, and evaluation of sellar masses", section on 'MRI'.)
Visual field testing — All patients with sellar masses >1 cm or elevating the optic chiasm,
including those who deny visual symptoms, should undergo baseline Humphrey visual field testing
and evaluation of visual acuity. A clinician experienced in evaluating visual field abnormalities,
such as a neuro-ophthalmologist, should interpret the results.
Hormonal evaluation — Hypothalamic-pituitary hormonal function (both hyper- and hypofunction)

should be evaluated whenever a large sellar mass (>1 cm) is seen on MRI to determine if it is a
pituitary adenoma that can be recognized by hormonal hypersecretion.
Hormone hypersecretion — The possibility of hormone excess should be evaluated to detect

the presence of functioning pituitary adenomas. We therefore suggest measurements of:
● Serum LH, FSH, and alpha subunit (gonadotroph adenoma). In countries where thyrotropin-
releasing hormone (TRH) is available, the FSH and alpha subunit response to TRH will also
identify a gonadotroph adenoma (table 2).
● Serum prolactin (lactotroph adenomas).
● Insulin-like growth factor-1 (IGF-1) (somatotroph adenomas).
● 24-hour urine free cortisol (corticotroph adenomas).
Gonadotroph adenomas — 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 (table 2) [16].
Alpha subunit values should be interpreted in the context of normal values for the specific patient
group and specific assay. The serum concentration of uncombined alpha subunit is elevated in
women in three physiologic conditions [47-49]:
● Menopause, in which the gonadotroph cells of the pituitary hypersecrete intact FSH and LH
and uncombined alpha subunit
● Pregnancy, in which the placenta secretes intact human chorionic gonadotropin (hCG) and
uncombined alpha subunit
● Ovarian stimulation with exogenous gonadotropins (hCG, human menopausal gonadotropins
[hMG], FSH) for the treatment of infertility
In men, a sellar mass can be recognized as a gonadotroph adenoma by a supranormal basal

serum FSH concentration (figure 1) [50]. An elevated concentration of alpha subunit indicates a
gonadotroph adenoma, thyrotroph adenoma, or less differentiated glycoprotein adenoma. A
supranormal response of intact FSH or alpha subunit to TRH also indicates a gonadotroph
adenoma.
Finding evidence for a gonadotroph adenoma will not influence the choice of therapy (which is
pituitary surgery), but recognizing that a sellar mass is a gonadotroph adenoma and not a
nonpituitary lesion could influence the route of surgery and can be used as a tumor marker by
which to evaluate the result of surgery and for subsequent monitoring. Finding evidence for one of
the other types of clinically nonfunctioning adenomas could also open the possibility of
pharmacologic treatment. (See "Treatment of gonadotroph and other clinically nonfunctioning
adenomas".)
Somatotroph adenomas — Although somatotroph adenomas typically cause the

characteristic clinical syndrome of acromegaly, some are silent. They can result in excessive
hormonal secretion without even the subtlest clinical change ("clinically silent") or no clinical or
biochemical evidence of excessive hormonal secretion ("totally silent"). In 100 consecutive
patients with pituitary adenomas that were surgically excised, 24 had somatotroph adenomas by
immunochemical staining [3]. Of these, eight (one-third) had an elevated IGF-1 concentration but
not even subtle manifestations of acromegaly and could therefore be considered to be clinically
silent.
Corticotroph adenomas — Corticotroph macroadenomas, unlike microadenomas, do not

typically cause Cushing's syndrome. However, they may be clinically silent and recognizable by
elevated plasma corticotropin (ACTH) concentrations [4].
Lactotroph adenomas — Most lactotroph macroadenomas produce very high serum

prolactin concentrations, but some are inefficient and do not. These may be difficult to distinguish
from other sellar lesions that compress the pituitary stalk and obstruct the normal inhibitory
hypothalamic influence on the prolactin producing cells, resulting in modestly elevated serum
prolactin concentrations (usually <100 ng/mL but sometimes as high as 200 ng/mL). Illustrated in
one study of 226 patients with nonfunctioning macroadenomas, a serum prolactin concentration
>94 ng/mL reliably distinguished between lactotroph adenomas and nonfunctioning adenomas
[45]. Rarely, gonadotroph adenomas cosecrete prolactin and gonadotropins.
Hypopituitarism — Deficient secretion of other pituitary hormones often occurs due to the
mass effect of the typically large gonadotroph adenomas and should always be investigated.
Additional testing for hormone deficiencies due to compression of the normal pituitary tissue
includes measurement of the serum concentrations of:
● 8 AM cortisol
● Thyroxine (T4) (if elevated, measure thyroid-stimulating hormone [TSH] to evaluate the
possibility of a thyrotroph adenoma)
● Testosterone in men
● Estradiol (E2) in women of premenopausal age with amenorrhea
The interpretation of pituitary tests and the diagnosis of hypopituitarism are discussed separately.
(See "Diagnostic testing for hypopituitarism".)
DIAGNOSIS
A definitive diagnosis of a gonadotroph adenoma is made by pathologic evaluation of the excised

tissue. Pituitary adenomas typically show effacement of the normal lobular pituitary architecture
and instead show a monomorphic population of cells and loss of the normal reticulin pattern.
Immunochemical staining is positive for follicle-stimulating hormone (FSH)-beta, luteinizing
hormone (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. (See 'Elevated prolactin' above.)
● No symptoms or signs of acromegaly and serum concentration of insulin-like growth factor-1

(IGF-1) not elevated. (See "Causes and clinical manifestations of acromegaly" and "Diagnosis
of acromegaly".)
● No signs or symptoms of Cushing's syndrome and 24-hour urine cortisol excretion not
elevated. (See "Epidemiology and clinical manifestations of Cushing's syndrome" and
"Establishing the diagnosis of Cushing's syndrome".)
● In men, elevated basal serum concentrations of intact FSH and/or of alpha subunit (table 2).
In countries where thyrotropin-releasing hormone (TRH) is available, an FSH response to
TRH. Rarely, elevated LH and testosterone. Elevated FSH and LH and subnormal
testosterone indicate primary hypogonadism. (See 'Primary hypogonadism' below.)
● In premenopausal women, irregular menses, elevated FSH and estradiol (E2), low LH, and on
pelvic ultrasound, massive polycystic ovaries and thickened endometrium.
● In postmenopausal women, elevated FSH and/or alpha subunit and low LH (table 2).
Elevation of both FSH and LH likely indicate only normal postmenopausal gonadotropin
secretion.
DIFFERENTIAL DIAGNOSIS
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Pituitary adenomas are the most common cause of a large sellar mass, but other causes include
craniopharyngioma, meningioma, malignant tumors, Rathke's cleft cysts, and hypophysitis. Any
sellar masses >1 cm may present with neurologic symptoms similar to clinically nonfunctioning
pituitary adenomas. Evaluation of a large sellar mass includes imaging with magnetic resonance
imaging (MRI), and hormonal evaluation for pituitary hyper- and hypofunction. (See "Causes,
presentation, and evaluation of sellar masses", section on 'Evaluation of a sellar mass' and
"Incidentally discovered sellar masses (pituitary incidentalomas)", section on 'Lesions 10 mm or
larger'.)
Lactotroph macroadenoma — As noted above, a large sellar mass associated with a prolactin
concentration <100 ng/mL probably does not represent a lactotroph adenoma. Large sellar
masses compress the pituitary stalk and thereby prevent dopamine from the hypothalamus from
reaching the pituitary, thus decreasing normal inhibition of prolactin secretion. The result is a mild
elevation of serum prolactin (>20 ng/mL [eg, higher than normal] but usually <100 ng/mL) [45,51].
(See 'Elevated prolactin' above and "Clinical manifestations and evaluation of
hyperprolactinemia".)
Primary hypogonadism — Longstanding primary hypogonadism can cause gonadotroph cell

hypertrophy and therefore overall pituitary enlargement [52,53] and, in this way, as well as in
elevated gonadotropin concentrations, is similar to gonadotroph adenomas. Primary
hypogonadism differs from gonadotroph adenomas in several ways:
● The degree of pituitary enlargement is much less

● Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are elevated
● Neither intact gonadotropins nor their subunits respond to thyrotropin-releasing hormone
(TRH) [50,54]
Polycystic ovary syndrome — Women with polycystic ovary syndrome (PCOS) have multiple
follicles on pelvic ultrasound. However, they are small and arranged in a peripheral pattern, unlike
the follicles described in the cases of ovarian hyperstimulation syndrome in women with
gonadotroph adenomas (image 2) [28-34]. In addition, serum FSH concentrations are low in
PCOS, not normal or high as they would be with a gonadotroph adenoma. Lastly, a serum
estradiol (E2) concentration >500 pg/mL should strongly raise the suspicion that the multiple
ovarian cysts are due to a gonadotroph adenoma (image 2) rather than PCOS.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Pituitary tumors and
hypopituitarism".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Pituitary adenoma (The Basics)")
SUMMARY
● Approximately 25 to 35 percent of all pituitary adenomas are clinically nonfunctioning or

"silent"; 70 to 90 percent of these are gonadotroph adenomas. (See 'Overview' above.)
● 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. (See 'Neurologic symptoms' above.)
● Some are detected as an incidental finding when magnetic resonance imaging (MRI) is done
for other reasons. (See 'Incidental finding on imaging' above.)
● 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. (See
'Hormone deficiencies' above.)
● 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 follicle-stimulating hormone (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
luteinizing hormone (LH) in a boy or man and cause an increased serum testosterone
concentration. (See 'Gonadotroph adenomas: Hormone excess' above.)
● Evaluation of the patient who presents with neurologic symptoms suggestive of a clinically
nonfunctioning sellar mass should first include pituitary MRI (see 'Evaluation' above). If a
sellar mass >1 cm is detected on pituitary MRI, the following should be performed:
• Visual field testing
• Biochemical testing for hormone hypersecretion (serum prolactin, insulin-like growth

factor-1 [IGF-1], and 24-hour urine free cortisol) (see 'Gonadotroph adenomas: Hormone
excess' above)
• Testing for hypopituitarism – 8 AM cortisol, thyroxine (T4) (plus TSH if the T4 is high),
testosterone in men and estradiol (E2) in women of premenopausal age, FSH, LH, and
alpha subunit (see 'Hypopituitarism' above)
● 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 (table 2). (See 'Diagnosis'
above.)
• In men, characteristic patterns are an elevated serum FSH and/or alpha subunit or,
rarely, elevated LH and testosterone.
• In women of premenopausal age, characteristic patterns are an elevated FSH, with or

without alpha subunit, and E2.
• In postmenopausal women, the patterns are an elevated FSH and/or alpha 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/or alpha subunit.
Use of UpToDate is subject to the Subscription and License Agreement.
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adenomas. J Clin Endocrinol Metab 2014; 99:4423.
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secreting follicle-stimulating hormone and causing ovarian hyperstimulation. J Clin
Endocrinol Metab 1995; 80:591.
29. Christin-Maitre S, Rongières-Bertrand C, Kottler ML, et al. A spontaneous and severe

hyperstimulation of the ovaries revealing a gonadotroph adenoma. J Clin Endocrinol Metab
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30. Välimäki MJ, Tiitinen A, Alfthan H, et al. Ovarian hyperstimulation caused by gonadotroph
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31. Pentz-Vidovíc I, Skorić T, Grubisić G, et al. Evolution of clinical symptoms in a young woman
with a recurrent gonadotroph adenoma causing ovarian hyperstimulation. Eur J Endocrinol
2000; 143:607.
32. Shimon I, Rubinek T, Bar-Hava I, et al. Ovarian hyperstimulation without elevated serum
estradiol associated with pure follicle-stimulating hormone-secreting pituitary adenoma. J
Clin Endocrinol Metab 2001; 86:3635.
33. Castelbaum AJ, Bigdeli H, Post KD, et al. Exacerbation of ovarian hyperstimulation by
leuprolide reveals a gonadotroph adenoma. Fertil Steril 2002; 78:1311.
34. Murata Y, Ando H, Nagasaka T, et al. Successful pregnancy after bromocriptine therapy in
an anovulatory woman complicated with ovarian hyperstimulation caused by follicle-
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gonadotroph adenoma with ovarian enlargement in a 10-year-old girl. Fertil Steril 1999;
72:158.
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syndrome caused by a follicle-stimulating hormone-secreting pituitary macroadenoma in an
early pubertal girl. Horm Res Paediatr 2010; 73:293.
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to follicle-stimulating hormone-secreting gonadotroph adenoma. BJOG 2004; 111:1297.
38. Sugita T, Seki K, Nagai Y, et al. Successful pregnancy and delivery after removal of
gonadotrope adenoma secreting follicle-stimulating hormone in a 29-year-old amenorrheic
woman. Gynecol Obstet Invest 2005; 59:138.
39. Roberts JE, Spandorfer S, Fasouliotis SJ, et al. Spontaneous ovarian hyperstimulation
caused by a follicle-stimulating hormone-secreting pituitary adenoma. Fertil Steril 2005;
83:208.
40. Mor E, Rodi IA, Bayrak A, et al. Diagnosis of pituitary gonadotroph adenomas in
reproductive-aged women. Fertil Steril 2005; 84:757.
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LH and prolactin by a pituitary adenoma. Acta Endocrinol (Copenh) 1983; 102:167.
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43. Snyder PJ, Sterling FH. Hypersecretion of LH and FSH by a pituitary adenoma. J Clin
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45. Karavitaki N, Thanabalasingham G, Shore HC, et al. Do the limits of serum prolactin in
disconnection hyperprolactinaemia need re-definition? A study of 226 patients with
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65:524.
46. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society
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47. Papapetrou PD, Anagnostopoulos NI. A gonadotropin and alpha-subunit suppression test for
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49. Unkila-Kallio L, Tiitinen A, Alfthan H, et al. Effect of an in vitro fertilization program on serum
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74:1125.
50. Daneshdoost L, Gennarelli TA, Bashey HM, et al. Identification of gonadotroph adenomas in
men with clinically nonfunctioning adenomas by the luteinizing hormone beta subunit
response to thyrotropin-releasing hormone. J Clin Endocrinol Metab 1993; 77:1352.
51. Hansen KA, Tho SP, Gomez F, McDonough PG. Nonfunctioning pituitary macroadenoma
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Topic 6627 Version 21.0
GRAPHICS
Clinical presentations of gonadotroph adenomas
Neurologic symptoms (most common)

Visual impairment
Headache
Other (including diplopia, seizures, and CSF rhinorrhea)
Incidental finding
When an imaging procedure is performed because of an unrelated symptom
Hypopituitarism
Biochemical evidence (most common)
Clinical symptoms (less common, but include oligomenorrhea or amenorrhea in women, decreased libido and/or
erectile dysfunction in men)
Clinical syndromes due to hormonal hypersecretion (rare)

Ovarian hyperstimulation when FSH is secreted excessively in a premenopausal woman
Premature puberty when intact LH is secreted in a prepubertal boy
CSF: cerebrospinal fluid; FSH: follicle-stimulating hormone; LH: luteinizing hormone.
Graphic 58084 Version 3.0
MRI images of a large sellar mass after administration of

gadolinium
(A) MRI image, taken after the administration of gadolinium, depicting a coronal view of a
large sellar mass that was a gonadotroph adenoma. The arrow points to the mass. The
arrowhead points to the optic chiasm elevated by the mass.
(B) MRI image, taken after the administration of gadolinium, depicting a sagittal view of
the same large sellar mass that was a gonadotroph adenoma. The arrow points to the
mass.
MRI: magnetic resonance imaging.
Hormonal criteria for the diagnosis of gonadotroph adenomas* (any one or

combination of the following)
Men Women
Supranormal basal serum FSH ¶ FSH but not LH

concentrations alpha, LH-beta, or FSH-beta Any subunit relative to intact FSH
subunits and LH
LH and testosterone
Supranormal response to TRH FSH FSH

LH LH
LH-beta (most common) LH-beta (most common)
FSH: follicle-stimulating hormone; LH: luteinizing hormone; TRH: thyrotropin-releasing hormone.

* Assuming the patient has a sellar mass.
¶ Assuming the patient does not have a history of primary hypogonadism.
Transvaginal ultrasound examination of the ovary (A) and

uterus (B) of a 39-year-old woman with a gonadotroph
adenoma and FSH hypersecretion
(A) Multiple cysts (arrows) within the substance of the ovary.

(B) In a coronal view of the uterus (outlined by narrow arrows), a markedly thickened,
echogenic endometrial stripe (wide arrows) is shown.
Scale: distance between open arrows = 10 mm.
FSH: follicle-stimulating hormone.
Reproduced with permission from: Djerassi A, Coutifaris C, West VA. Gonadotroph adenoma in
a premenopausal woman secreting follicle-stimulating hormone and causing ovarian
hyperstimulation. J Clin Endocrinol Metab 1995; 80:591. http://jcem.endojournals.org/.
Copyright © 1995 The Endocrine Society.
Hormone levels in men with a gonadotroph adenoma
Basal serum concentrations of FSH, LH, free alpha subunit, and LHβ subunit in
38 men with clinically nonfunctioning gonadotroph macroadenomas. Each dot
represents the value in a single patient; the horizontal lines encompass the
ranges of an age-matched control group. Seventeen men had supranormal
levels of at least one intact hormone or subunit, and four had multiple basal
elevations.
FSH: follicle-stimulating hormone; LH: luteinizing hormone.
Data from: Daneshdoost L, Gennarelli TA, Bashey HM, et al. Identification of

gonadotroph adenomas in men with clinically nonfunctioning adenomas by the
luteinizing hormone beta subunit response to thyrotropin-releasing hormone. J Clin
Contributor Disclosures
Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism (Testosterone gel)];
Novartis [Cushing's (LCI699)]. Consultant/Advisory Boards: AbbVie [Hypogonadism (Testosterone gel)];
Novartis [Cushing's (LCI699)]; Pfizer [Acromegaly (Pegvisomant)]. David S Cooper, MD Nothing to
disclose Kathryn A Martin, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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Manifestaciones clínicas y diagnóstico de gonadotroph y

La mayoría de los pacientes con adenomas hipofisarios presentan signos y síntomas de

Aquí se revisan las características clínicas, la evaluación y el diagnóstico de adenomas

Los adenomas hipofisarios se clasifican por su célula de origen (lactotroph, gonadotroph,

La mayoría de los adenomas de gonadotrofos son clínicamente "silenciosos" y difíciles de

● Neurologic symptoms – Most commonly, visual symptoms; less commonly, headache

● A pituitary mass that is discovered as an incidental finding when an imaging procedure is

● Pituitary hypofunction due to compression of normal pituitary tissue by the adenoma

Headache — Headaches, the second most common neurologic symptom, occur in 30 to 40

Other — Other less common neurologic symptoms include [16]:

Symptoms due to hormonal abnormalities — Clinically nonfunctioning adenomas often present

Higher percentages of hypopituitarism may be detected biochemically in patients with clinically

● LH/FSH (hypogonadotropic hypogonadism; 1216 of 1699 patients tested, 72 percent).

● Corticotropin (ACTH) (secondary adrenal insufficiency; 514 of 1699, 30 percent).

● Thyroid-stimulating hormone (TSH) (central hypothyroidism; 402 of 1699, 24 percent).

Gonadotroph adenomas: Hormone excess — Although gonadotroph adenomas are

However, approximately 35 percent of gonadotroph adenomas secrete enough LH or FSH to raise

Other pituitary adenomas: Hormone excess

● Clinically silent corticotroph adenomas might be recognizable by higher plasma ACTH

Characteristic imaging features — As noted, gonadotroph adenomas are generally hormonally

Hormonal evaluation — Hypothalamic-pituitary hormonal function (both hyper- and hypofunction)

Hormone hypersecretion — The possibility of hormone excess should be evaluated to detect

● Serum prolactin (lactotroph adenomas).

● Insulin-like growth factor-1 (IGF-1) (somatotroph adenomas).

● 24-hour urine free cortisol (corticotroph adenomas).

Gonadotroph adenomas — In postmenopausal women, a sellar mass can be recognized

In men, a sellar mass can be recognized as a gonadotroph adenoma by a supranormal basal

Somatotroph adenomas — Although somatotroph adenomas typically cause the

Corticotroph adenomas — Corticotroph macroadenomas, unlike microadenomas, do not

Lactotroph adenomas — Most lactotroph macroadenomas produce very high serum

● Estradiol (E2) in women of premenopausal age with amenorrhea

A definitive diagnosis of a gonadotroph adenoma is made by pathologic evaluation of the excised

● No symptoms or signs of acromegaly and serum concentration of insulin-like growth factor-1

Primary hypogonadism — Longstanding primary hypogonadism can cause gonadotroph cell

● The degree of pituitary enlargement is much less

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topics (see "Patient education: Pituitary adenoma (The Basics)")

● Approximately 25 to 35 percent of all pituitary adenomas are clinically nonfunctioning or

● Clinically nonfunctioning adenomas (including gonadotroph adenomas) usually come to

● Approximately 60 percent of patients at the time of diagnosis have hypopituitarism due to

• Visual field testing

• Biochemical testing for hormone hypersecretion (serum prolactin, insulin-like growth

• In women of premenopausal age, characteristic patterns are an elevated FSH, with or

Use of UpToDate is subject to the Subscription and License Agreement.

1. Chaidarun SS, Klibanski A. Gonadotropinomas. Semin Reprod Med 2002; 20:339.

5. Chamoun R, Layfield L, Couldwell WT. Gonadotroph adenoma with secondary

6. Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: a community-

7. Daneshdoost L, Gennarelli TA, Bashey HM, et al. Recognition of gonadotroph adenomas in

11. Vlotides G, Eigler T, Melmed S. Pituitary tumor-transforming gene: physiology and

15. Ferrante E, Ferraroni M, Castrignanò T, et al. Non-functioning pituitary adenoma database: a

20. Szabolcs I, Késmárki N, Bor K, et al. Apoplexy of a pituitary macroadenoma as a severe

21. Frankart L, De Hertogh R, Donckier J, et al. [Pituitary apoplexy of a gonadotrophinoma and

27. Ntali G, Capatina C, Grossman A, Karavitaki N. Clinical review: Functioning gonadotroph

29. Christin-Maitre S, Rongières-Bertrand C, Kottler ML, et al. A spontaneous and severe

35. Tashiro H, Katabuchi H, Ohtake H, et al. A follicle-stimulating hormone-secreting

37. Murakami T, Higashitsuji H, Yoshinaga K, et al. Management of ovarian hyperstimulation due

Topic 6627 Version 21.0

Clinical presentations of gonadotroph adenomas

Neurologic symptoms (most common)

Other (including diplopia, seizures, and CSF rhinorrhea)