Pouneh Fazeli and Lisa B. Nachtigall1
(1)
Neuroendocrine Clinical Center unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Lisa B. Nachtigall
Email: lnachtigall@partners.org
Abstarct
Pituitary causes of amenorrhea constitute approximately 18% of cases of secondary amenorrhea but only approximately 7% of cases of primary amenorrhea [1]. The most common pituitary cause of amenorrhea is hyperprolactinemia constituting 80% of all pituitary causes of secondary amenorrhea and approximately 15% of cases of secondary amenorrhea due to any cause [2]. In this chapter, we review the causes, clinical presentation, diagnostic evaluation, and current treatment strategies for amenorrhea due to hyperprolactinemia and other pituitary disorders. We present an illustrative case of secondary amenorrhea due to a pituitary cause.
Introduction
Pituitary causes of amenorrhea constitute approximately 18% of cases of secondary amenorrhea but only approximately 7% of cases of primary amenorrhea [1]. The most common pituitary cause of amenorrhea is hyperprolactinemia constituting 80% of all pituitary causes of secondary amenorrhea and approximately 15% of cases of secondary amenorrhea due to any cause [2]. In this chapter, we review the causes, clinical presentation, diagnostic evaluation, and current treatment strategies for amenorrhea due to hyperprolactinemia and other pituitary disorders. We present an illustrative case of secondary amenorrhea due to a pituitary cause.
Case
The patient is a 33-year-old woman with a history of running competitively beginning at the age of 12 years. She had her first menstrual period at the age of 15 years and then was oligoamenorrheic until the age of 18 years when she was started on oral contraceptives. She stopped running competitively after graduating from college but continued to run 7 miles daily, 6 days per week. At the age of 32 years, she stopped the oral contraceptive pill in order to attempt to become pregnant. Three months after discontinuing the oral contraceptive pill, she remained amenorrheic and her gynecologist initiated a work-up and asked that she decrease her activity level. History was notable for no other past medical history, and current medications included only a pre-natal vitamin. Physical examination was notable for a BMI of 20.5 kg/m2. She appeared non-Cushingoid and non-acromegalic. Visual fields were intact to confrontation. Laboratory studies demonstrated a negative HCG, normal thyroid function studies, a slightly elevated prolactin level, low-normal FSH and LH, and a low estradiol level of 30 pg/ml (Table 6.1).
Table 6.1
Case
|
History |
|
33-year-old woman presenting with amenorrhea |
|
Competitive runner since the age of 12 years |
|
Menarche at 15 years of age |
|
Oligoamenorrhea until 18 years old when started oral contraceptives |
|
Stopped oral contraceptives at age 32 years |
|
Amenorrhea >3 months after stopping oral contraceptives |
|
Physical examination |
|
BMI: 20.5 kg/m2 |
|
Non-Cushingoid, non-acromegalic appearing |
|
Visual fields intact to confrontation |
|
Laboratory studies |
|
Prolactin: 45 ng/ml (normal range: 0–20 ng/ml) |
|
Serum HCG: undetectable |
|
TSH: 1.3 mIU/L (normal range: 0.5–5 mIU/L) |
|
Free T4: 1.2 ng/dl (normal range: 0.8–1.8 ng/dl) |
|
LH: 5 U/L |
|
FSH: 3 U/L |
|
Estradiol: 30 pg/ml (normal range: Follicular phase: <20–145 pg/ml |
|
Mid-cycle peak: 112–443 pg/ml |
|
Luteal phase: <20–241 pg/ml |
|
Post-menopausal: <59 pg/ml) |
Causes of Hyperprolactinemia
The most common cause of hyperprolactinemia is a lactotroph-secreting adenoma [2]. There are other causes of an elevated prolactin level which can also lead to the development of the sequelae of hyperprolactinemia. A non-adenomatous cause of hyperprolactinemia will rarely lead to a prolactin level greater than 200–300 ng/ml [3] (Table 6.2). Extremely elevated prolactin levels generally indicate the presence of a lactotroph adenoma.
Table 6.2
Causes of hyperprolactinemia
|
Physiologic causes |
|
Pregnancy |
|
Nipple stimulation |
|
Macroprolactinemia |
|
Stress |
|
Medications a |
|
Antipsychotics |
|
Haloperidol |
|
Phenothiazines |
|
Risperidone |
|
Olanzapine |
|
Molindone |
|
Gastric motility agents |
|
Metoclopramide |
|
Domperidone |
|
Cimetidine |
|
Antihypertensives |
|
Methyldopa |
|
Verapamil |
|
Reserpine |
|
Pathophysiologic causes |
|
Lactotroph adenoma |
|
Mass effect/stalk interruption |
|
Trauma (chest wall/CNS) |
|
Primary hypothyroidism |
|
Chronic renal failure |
aThis list is a summary of common medications associated with hyperprolactinemia and does not include all medications associated with hyperprolactinemia
Physiologic Causes
Pregnancy
Pregnancy is a common physiologic cause of both amenorrhea and hyperprolactinemia. Prolactin levels increase progressively during pregnancy and are the highest at the time of delivery [4]. Prolactin levels have been shown to be as high as nearly 600 ng/ml at the time of delivery [4]; therefore, women with amenorrhea and hyperprolactinemia should be evaluated for pregnancy prior to any other diagnostic work-up. Within the first 72 h post-partum, the prolactin levels drop precipitously unless a woman is nursing, since the prolactin levels will increase in response to suckling [4].
Nipple Stimulation
Nipple stimulation can cause a rise in serum prolactin levels but usually only during the first 6 weeks of lactation [4]). This is likely due to the fact that estradiol levels fall precipitously in the post-partum period and, therefore, the lactotroph hypertrophy subsides, diminishing the rise in the prolactin level post-suckling. Therefore, in women who choose to breast feed, prolactin levels should not be checked until at least 6 weeks post-partum. In non-lactating women, nipple stimulation has not been shown to lead to significant increases in serum prolactin levels [5].
Macroprolactinemia
Prolactin circulates in multiple forms. The predominant form is a 23-kD form but rare individuals may have other forms of prolactin, with much higher molecular masses, which predominate. These individuals may have elevated levels of a 150-kD form of prolactin, referred to as big prolactin or macroprolactin [6]. This form of prolactin is thought to be a macromolecule consisting of the 23-kD form of prolactin and an immunoglobulin [6], and has been shown to be cleared from the circulation more slowly, which is likely the cause of the elevated prolactin levels [7].
Macroprolactinemia has historically been considered an asymptomatic condition. Individuals with macroprolactinemia may still experience amenorrhea or galactorrhea, although much less frequently compared to individuals with true hyperprolactinemia [8, 9]. A polyethylene glycol (PEG) precipitation test can be used to determine whether an individual’s hyperprolactinemia is due to macroprolactinemia [10]. Macroprolactinemia must be considered in the differential diagnosis for hyperprolactinemia in patients with high serum prolactin concentrations who do not exhibit clinical signs of hyperprolactinemia.
Medications
Psychiatric Medications
Antipsychotics
As dopamine suppresses the production of prolactin, any medications that block dopamine receptors may increase prolactin levels. Such medications include antipsychotic medications including haloperidol (a typical antipsychotic) and risperidone (an atypical antipsychotic), as well as many others (see Table 6.2). Antipsychotics have been shown to be associated with higher prolactin levels in women compared to men [11, 12]. Although both acute and chronic therapy with antipsychotic agents has been shown to increase prolactin levels, acute therapy tends to be associated with a greater elevation [11]; therefore, prolactin levels should likely not be checked in the first 4 weeks of treatment. Risperidone, an atypical antipsychotic agent, has been shown to be associated with significantly greater prolactin levels when compared to the typical antipsychotic haloperidol, but generally the newer atypical agents are thought to induce less of an increase in prolactin levels compared to the typical agents [12, 13].
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs), specifically fluoxetine, have been shown to increase prolactin levels only minimally [14], whereas less commonly used antidepressants, such as the tricyclics, have only rarely been associated with hyperprolactinemia [13].
Other Medications
Gastric motility agents that block dopamine receptors, for example, metoclopramide and domperidone, also raise prolactin levels [13]. Antihypertensive drugs that block dopamine synthesis, such as methyldopa, have also been shown to raise prolactin levels as quickly as 2–6 h after oral administration [15]. Verapamil is the only calcium-channel blocker that has been shown to increase prolactin levels [16]; the mechanism is thought to be due to decreased hypothalamic production of dopamine [17].
Pharmacologic doses of estradiol have been shown to increase prolactin secretion [18]. Estradiol is thought to increase prolactin levels by stimulating lactotroph cell proliferation, likely through a mechanism involving the transforming growth factor-β isoforms [19]. Supra-physiologic levels of estradiol, as occur during pregnancy or with assisted reproductive technologies such as ovulation induction or in vitro fertilization, may cause lactotroph cell hyperplasia leading to hyperprolactinemia. Yet oral contraceptive pills are not typically thought to cause hyperprolactinemia [13].
Pathophysiologic Causes
Lactotroph Adenoma
Lactotroph adenomas are responsible for 80% of amenorrhea due to a pituitary cause [2]. Lactotroph adenomas are the most common hyper-secreting pituitary adenomas and are almost always benign but very rarely they can be malignant and metastasize extra-cranially [20]. Prolactin secretion is typically proportional to the size of the adenoma in well-differentiated adenomas and can be very high – in fact, levels on the order of 104 ng/ml have been measured [21]. Poorly differentiated lactotroph adenomas may be large but secrete less prolactin than expected based on their size.
Mass Effect/Trauma
The pituitary gland is connected to the median eminence of the hypothalamus via a stalk. Dopamine, produced in the hypothalamus, suppresses the production of prolactin in the pituitary gland. Any compression or interference of the stalk, for example, by a mass or trauma, can lead to an interruption of the flow of dopamine into the pituitary gland and subsequent hyperprolactinemia.
Traumatic injury to the chest wall can lead to hyperprolactinemia [22]. The mechanism is thought to be due to neurogenic stimulation as intercostal nerve blockade was found to reduce serum prolactin levels in a patient with elevated prolactin levels after a traumatic burn injury to the chest wall [22]. Traumatic brain injury can also result in hyperprolactinemia [23] even 12 months after the initial trauma [24].
Primary Hypothyroidism
Thyrotropin releasing hormone, secreted by the hypothalamus, can stimulate pituitary lactotroph cells to secrete prolactin in individuals with hypothyroidism [25]. Primary hypothyroidism can also cause enlargement of the pituitary gland due to thyrotroph hyperplasia and possibly lactotroph hyperplasia. Therefore, primary hypothyroidism can be associated with an enlarged pituitary gland, hyperprolactinemia, and all of its sequelae including amenorrhea and evaluation of an individual with hyperprolactinemia should always include a TSH level. Treatment for the hypothyroidism should result in resolution of the pituitary enlargement and hyperprolactinemia [26].
Chronic Renal Failure
Individuals with chronic renal failure, particularly those receiving hemodialysis, may have elevated prolactin levels [27]. The mechanism by which chronic renal failure leads to hyperprolactinemia appears to be one of both decreased responsiveness of the pituitary to dopamine suppression and therefore increased secretion, and decreased clearance [27].
Clinical Findings in Hyperprolactinemia
Reproductive Dysfunction
Hyperprolactinemia can cause hypogonadotropic hypogonadism. Therefore, common clinical findings in women with hyperprolactinemia include menstrual irregularities, typically oligoamenorrhea or amenorrhea [28]. One mechanism by which elevated prolactin levels decrease gonadotropin levels is thought to be mediated by inhibition of gonadotropin releasing hormone (GnRH) secretion from the hypothalamus by corticotrophin releasing factor, the secretion of which is thought to be stimulated by hyperprolactinemia [29].
Women with hyperprolactinemia who have regular ovulatory cycles may still have difficulty achieving a pregnancy. Infertility in the setting of ovulatory cycles may be due to a shortened luteal phase [30, 31]. Any woman with hyperprolactinemia and otherwise unexplained infertility may benefit from a trial of treatment for hyperprolactinemia prior to initiating more aggressive treatments for infertility.
Galactorrhea
Individuals with hyperprolactinemia may experience galactorrhea [28]. The galactorrhea may be spontaneous or may only be expressible in nature [28]. Galactorrhea is less frequently a symptom of hyperprolactinemia compared to oligoamenorrhea or amenorrhea [28], and importantly is a frequent finding in individuals without hyperprolactinemia [3], particularly in parous women.
Bone Loss
Other findings in hyperprolactinemia include bone loss, which has been shown to be primarily due to hypo-estrogenemia [32]. Treatment of hyperprolactinemia has been shown to improve bone mineral densities in women with hyperprolactinemia [32]. Also, individuals with elevated prolactin levels with regular menstrual cycles have been found to have bone mineral densities comparable to those of women with normal prolactin levels and regular menstrual cycles [32].
CNS Disturbances
New visual problems, particularly new peripheral field cuts, are a worrisome sign and may indicate a rapidly expanding tumor or a tumor which is impinging on the optic chiasm. These individuals should be imaged with a pituitary-protocol MRI and have visual field testing immediately. Headaches may also be associated with pituitary adenomas and may be a sign of rapid tumor expansion. Rarely, hyperprolactinemia may cause headaches independently of tumor mass [33]. Dopamine agonist therapy may relieve headaches, especially migraine-type, associated with hyperprolactinemia [34].
Treatment of Hyperprolactinmeia
If there is an underlying cause of hyperprolactinemia, such as a medication, the offending agent should be stopped or changed if this is possible without significant risk to the patient. If this is not possible, then treatment is indicated if the individual is symptomatic (reproductive dysfunction or galactorrhea); treatment with a dopamine agonist (cabergoline or bromocriptine) may be initiated if there is no contraindication. If the individual is on a dopamine-blocking agent for psychiatric illness, then a dopamine agonist may exacerbate the underlying psychiatric disorder and in that case dopamine agonists should be avoided. In these cases, oral contraceptives will protect against the harmful consequences of amenorrhea on bone mineral density (Table 6.3).
Table 6.3
Indications for treatment of hyperprolactinemia
|
Indications for medical therapy |
|
Macroadenoma |
|
Hypogonadism |
|
Reproductive dysfunction |
|
Amenorrhea |
|
Infertility |
|
Acne and/or hirsutisma |
|
Bothersome galactorrheaa |
|
Headaches (controversial)a |
|
Indications for surgical therapy |
|
Optic nerve compression |
|
Intolerance of dopamine agonists |
|
Dopamine agonists ineffectiveb |
|
Predominantly cystic macroadenomab |
|
Apoplexy or hemorrhage within tumor |
|
Patients on psychiatric medicationsb |
aRelative indication
bIf tumor mass is a concern
Microprolactinomas that are not associated with hypogonadism, menstrual irregularity, infertility, or disruptive galactorrhea do not require treatment but should be observed with a pituitary-protocol MRI. Treatment should be initiated if tumor growth occurs. Growing or symptomatic microprolactinomas should be treated with dopamine agonists unless contraindicated or if acute visual field cuts mandate urgent surgical intervention. If compressive symptoms are noted or a dopamine-agonist is contraindicated, such as in the case of an individual with psychiatric illness on dopamine blocking agents, then surgery is the treatment of choice. Surgery may also be indicated in individuals who are intolerant of dopamine agonist therapy or who do not respond to dopamine agonist therapy, such as patients with predominantly cystic tumors.
There are two dopamine agonists currently used in the treatment of hyperprolactinemia: bromocriptine and cabergoline. Cabergoline has been shown to achieve normal prolactin levels and ovulatory cycles or pregnancy more often than bromocriptine and has been associated with fewer side effects than bromocriptine therapy [35]. Yet in women attempting to conceive, bromocriptine therapy is preferred because of greater experience with the use of bromocriptine during pregnancy [36]. Also, there has been recent data demonstrating an increased incidence of cardiac valve regurgitation in individuals taking high doses of cabergoline for the treatment of Parkinson’s disease [37, 38]. In patients using cabergoline for hyperprolactinemia, clinically significant valvular disease has not been demonstrated, although an increased incidence of aortic valve calcification has been shown [37], and recent cross-sectional, observational studies and a meta-analysis have demonstrated an increased incidence of clinically insignificant, mild to moderate tricuspid regurgitation [39–41]. Yet a number of studies have also demonstrated no difference in the prevalence of valvular regurgitation when comparing hyperprolactinemic patients treated with cabergoline to controls [42–44]. Although no clinically significant valvular disease has been demonstrated in patients receiving cabergoline for hyperprolactinemia, the potential risk of valvular dysfunction should be discussed with the patient prior to initiating dopamine agonist therapy. Once a pregnancy has been confirmed, we recommend that the dopamine agonist be stopped.
Women with hyperprolactinemia and regular ovulatory cycles may still be infertile due to a luteal phase defect [30, 31]. Administration of bromocriptine in these women may help lengthen the luteal phase and may result in achievement of a pregnancy.
Other Pituitary Causes of Amenorrhea
Non-Lactotroph Adenomas and Sellar Masses
While the most common cause of pituitary-associated amenorrhea is a lactotroph-secreting adenoma, other pituitary adenomas can also cause amenorrhea. Cushing’s disease and acromegaly are the result of hyper-functioning pituitary adenomas of the corticotroph and somatotroph cells of the pituitary, respectively. Amenorrhea is a common finding in Cushing’s disease, usually due to increased circulating androgens made by the adrenal gland. In acromegaly, amenorrhea may result from hyperprolactinemia, either due to concomitant production of prolactin by the tumor or stalk compression, compression of the pituitary gonadotrophs, or hyperandrogenism. Therefore, Cushing’s and acromegaly should be considered in any individual presenting with amenorrhea and clinical evidence of either cortisol or growth hormone excess, respectively. However, in individuals presenting with primary or secondary amenorrhea, these diagnoses are rare. In a series of 252 patients presenting with primary amenorrhea, Cushing’s accounted for one case [1]. Similarly, in a series of 262 individuals presenting with secondary amenorrhea, Cushing’s accounted for two of those cases [2]. However, it is possible that these small numbers represent under-reporting and/or failure to diagnose these diseases when present.
Any pituitary adenoma, especially those ≥1 cm in size (macroadenomas), can cause amenorrhea due to mass effect on the gonadotrophs or due to stalk compression. Therefore, in individuals with amenorrhea of unknown cause who do not have an elevated serum FSH, a pituitary-protocol MRI should be part of the initial diagnostic work-up. Similarly, any sellar mass, including craniopharyngiomas and meningiomas, can cause amenorrhea through mass effect or interruption of the stalk (Table 6.4). Craniopharyngiomas may be associated with diabetes insipidus and, therefore, should be considered in the differential diagnosis of an individual presenting with amenorrhea and diabetes insipidus. In adults with craniopharyngiomas, CT scan of the sellar area usually demonstrates calcifications within the tumor.
Table 6.4
Differential diagnosis for sellar masses
|
Adenomas |
|
Hyperfunctioning |
|
Prolactinomas |
|
Corticotroph adenomas (cause of Cushing’s disease) |
|
Somatotroph adenomas (cause of acromegaly) |
|
Somatomammotroph adenomas (adenoma which co-secretes prolactin and growth hormone) |
|
Thyrotroph adenomas (excess TSH secretion) |
|
Pleurihormonal adenomas (rare) |
|
Non-functioning |
|
Craniopharyngioma |
|
Chordoma |
|
Germ cell tumor |
|
Granular cell tumor |
|
Metastatic disease |
|
Meningioma |
|
Primary lymphoma |
|
Sarcoma |
|
Schwannoma |
|
Vascular tumor/aneurysms/AV fistula of cavernous sinus |
|
Cysts |
|
Rathke’s cleft |
|
Dermoid |
|
Epidermoid |
|
Infections/Infiltrative disorders |
|
Hemochromatosis |
|
Hypophysitis |
|
Lymphocytic |
|
Granulomatous |
|
Xanthomatous |
|
Langerhans cell histiocytosis |
|
Sarcoidosis |
|
Giant cell granuloma |
|
Infections/abscess |
Sheehan’s Syndrome
The pituitary gland derives its blood supply from both systemic and hypothalamic sources. The inferior hypophyseal arterial branches comprise the systemic circulation, although the predominant supply to the anterior pituitary is from the hypothalamic-portal circulation. The hypothalamic-portal circulation is derived from the superior hypophyseal arteries which branch from the internal carotid arteries. During pregnancy, increased levels of estrogen can potentiate lactotroph cell growth [19]. The increased size of the pituitary can cause compression of the superior hypophyseal artery and can make it very sensitive to sudden changes in blood supply or hypotension [45]. Therefore, cases of massive postpartum hemorrhage requiring multiple transfusions can result in ischemic necrosis of the pituitary gland, causing postpartum hypopituitarism referred to as Sheehan’s syndrome. Postpartum hemorrhage is a rare complication of births in the developed world and therefore Sheehan’s syndrome is most commonly seen in developing countries [46, 47].
Sheehan’s typically presents months to years after delivery and the most common presenting symptoms of Sheehan’s syndrome include inability to lactate and failure to resume menses, although an acute presentation with severe pituitary hypo-functioning resulting in death can also occur [45]. Therefore, clinicians must remain alert to this possibility, particularly in women who have had deliveries complicated by >500 ml of blood loss or the requirement for blood transfusions. Treatment for Sheehan’s consists of replacing pituitary hormone deficiencies.
Infiltrative and Infectious Causes
Lymphocytic Hypophysitis
Lymphocytic hypophysitis is an inflammatory condition that affects the pituitary gland. It affects predominantly females (8.5:1) and tends to occur during the latter stages of pregnancy or the postpartum period [48]. A case series of 16 histologically proven cases of lymphocytic hypophysitis found that 71% of the cases were associated with pregnancy [48]. Of all patients studied, 63% had anterior pituitary hypo-functioning and 19% had posterior pituitary dysfunction in the form of diabetes insipidus [48]. This cause of hypopituitarism should be high on the differential diagnosis of individuals presenting with both anterior and posterior pituitary dysfunction, who are pregnant or postpartum. These patients commonly present with symptoms of an expanding sellar mass with headaches and visual field defects, although this is not always the case and patients may present with associated autoimmune dysfunction, such as autoimmune thyroid disease [48]. This condition can be lethal if not detected early as 3/16 patients in the case series died as a result of undiagnosed hypopituitarism [48]. Compressive symptoms usually require surgical intervention, and high-dose corticosteroid treatment has been shown to be effective in some patients [49], although its efficacy has not yet been proven.
Hereditary Hemochromatosis
Hereditary hemochromatosis is a cause of gonadal insufficiency in men due to damage caused to either the testes or the pituitary gonadotroph cells by excessive amounts of iron [50]. In women, hypogonadism is rarely seen [50] but must still be kept on the differential diagnosis, particularly in individuals with a family history of hemochromatosis.
Other
Rarer causes of pituitary-associated amenorrhea include sarcoidosis and tuberculosis. In sarcoidosis, granulomas may infiltrate the pituitary gland resulting in amenorrhea due to destruction of pituitary gonadotroph cells, but more commonly sarcoidosis results in granulomatous infiltration of the hypothalamus, resulting in amenorrhea due to decreased synthesis of GnRH by the hypothalamus [51]. Individuals with sarcoidosis and hypopituitarism may also have diabetes insipidus [51] and, therefore, this should be considered in the differential diagnosis of individuals presenting with amenorrhea and diabetes insipidus. Tuberculous meningitis in childhood has also been associated with amenorrhea. A study of 49 patients with a childhood history of tuberculous meningitis found that 10% had pituitary dysfunction in the form of gonadotropin deficiency [52].
Langerhans cell histiocytosis is a disease in which Langerhans cells, a form of dendritic cell, inappropriately proliferate and infiltrate various regions of the body including the hypothalamic-pituitary axis. The most common pituitary dysfunction noted in Langerhans cell histiocytosis is diabetes insipidus but anterior pituitary deficiencies, including gonadal dysfunction, have also been reported [53].
Other infiltrating and infectious diseases may infiltrate the hypothalamic-pituitary axis and cause gonadal dysfunction resulting in amenorrhea. Similarly, metastatic disease can also rarely infiltrate the pituitary gland and result in amenorrhea. Infiltrating disorders are commonly associated with diabetes insipidus and, therefore, these disorders should always be considered in the differential diagnosis of an individual presenting with both amenorrhea and diabetes insipidus.
Iatrogenic and Other Causes of Pituitary-Associated Amenorrhea
Surgery
Surgical treatment of a pituitary adenoma is a rare cause of hypogonadism [54], although most reports in the literature [55] likely reflect the rates of hypopituitarism for individuals undergoing surgery in the hands of a dedicated pituitary surgeon. As the rates of post-surgical complications have been shown to be higher in individuals undergoing pituitary surgery by surgeons with lower surgical volumes [56], the rates of post-surgical hypogonadism may be higher in individuals who have undergone pituitary surgery by a less-experienced surgeon.
Radiation
Pituitary dysfunction resulting in amenorrhea is a well-known complication of radiation therapy directed at the pituitary gland [54]. A series of 35 male patients were followed for a mean of 4.2 years after radiotherapy and 67% developed gonadal dysfunction if they had surgery followed by radiation compared to 50% who were treated with radiation alone [54]. Individuals who have undergone radio-therapy to the pituitary gland should be monitored closely for the development of pituitary dysfunction with long-term serial biochemical testing.
Radiation therapy for non-pituitary brain tumors has also been associated with hypothalamic-pituitary dysfunction, hyperprolactinemia, and gonadotropin deficiency [57]. Hypopituitarism has been shown to be positively correlated with time since the radiation therapy and with the dose of radiation, whereas hyperprolactinemia and hypogonadism are associated only with the dose of radiation therapy [58]. Therefore, both patients who have undergone radiation therapy for pituitary tumors and those who have undergone radiation for non-pituitary brain tumors should be closely followed for subsequent pituitary dysfunction.
Traumatic Brain Injury and Subarachnoid Hemorrhage
Traumatic brain injury and subarachnoid hemorrhage can cause pituitary dysfunction and amenorrhea. Individuals with traumatic brain injury associated with a coma are more likely to be affected by pituitary dysfunction, especially those who are comatose for days to weeks, but even individuals with a mild head injury can develop hypogonadism [59]. Importantly, even if hypopituitarism is not demonstrated immediately after trauma, it has been shown to present even one year after the injury; therefore, patients with a history of traumatic brain injury should be carefully monitored [24].
Genetic Causes
Recently, mutations in transcription factors involved in the cellular proliferation and differentiation of the pituitary gland have been shown to be the cause of anterior pituitary dysfunction and, therefore, should be on the differential diagnosis for primary amenorrhea. Typically mutations in these transcription factors are associated with other clinical findings that will be a clue to the diagnosis. For example, HESX1 mutations are associated with septo-optic dysplasia as well as pituitary hormone deficiencies and SOX2 mutations may be associated with sensorineural hearing loss, esophageal atresia, and learning difficulties in addition to hypogonadotropic hypogonadism [60]. LHX3 mutations and PROP1 mutations have also been associated with gonadotropin deficiency, and GLI2 and SOX3 mutations have been associated with hypopituitarism [60]. The inheritance pattern of these genes is variable and ranges from recessive, dominant, X-linked to de novo [60].
Diagnostic Evaluation
History
A thorough history of duration of amenorrhea, pregnancy, changes in weight, changes in terminal hair growth, headache, visual changes, increases in shoe size or ring size, galactorrhea, history of renal disease, and medication history should be obtained from each patient. In adolescents and young women, growth curves may be useful, and in patients with primary amenorrhea, a history of pubertal development should be reviewed. Patients with polycystic ovary syndrome (PCOS) are likely to have had normal breast development, whereas patients with genetic hypopituitarism will usually not report a history of spontaneous breast development.
Pregnancy is a common cause of amenorrhea and physiologic hyperprolactinemia. Weight gain and terminal hair growth are common findings in Cushing’s disease as well as other causes of amenorrhea including PCOS. Headache and visual changes can be found in individuals with pituitary tumors and may signal tumor growth. Changes in shoe and ring size are common signs of acromegaly. Galactorrhea is a common symptom of hyperprolactinemia, and renal disease and medications (as discussed above) can cause hyperprolactinemia and subsequent menstrual disturbances.
Physical Examination
Physical examination findings that are helpful in determining a pituitary cause of amenorrhea include a Cushingoid or acromegalic body habitus. Individuals with Cushing’s may have disproportionate centripetal obesity (obese abdomen and thin extremities due to muscle atrophy), supraclavicular fullness, a posterior cervical hump, and thin skin which often manifests as easy bruising and violaceous striae on the abdomen, flank, axilla, or thighs. Individuals with acromegaly may demonstrate evidence of soft tissue growth including acral changes, large lips and/or nose, frontal skull bossing, widening of the spaces between teeth, and a pronounced jaw and underbite.
In any woman with primary or secondary amenorrhea, we recommend that a prolactin level be checked as part of the work-up. If the value is <50 ng/ml but is elevated above the normal range, we repeat the measurement to ensure that the elevation is chronic and not due to a transient cause, such as nipple stimulation in a lactating woman, stress [61], recent sexual intercourse [62], or carbohydrate intake [63].
In individuals with any degree of prolactin elevation, pituitary-dedicated MRI imaging is indicated. Individuals with even slightly elevated prolactin levels may have large, non-functioning pituitary adenomas that compress the stalk, thereby causing the prolactin elevation, or their prolactin level may be underestimated secondary to the Hook effect. The Hook effect occurs in the setting of large amounts of antigen (in this case prolactin) saturating both antibodies present in the immunoradiometric sandwich assay: the antibody capturing the antigen and the signaling antibody. When both the capturing and signaling antibody are saturated by the high levels of prolactin, they are not able to sandwich together and give a falsely low prolactin value. Thus, women with macroadenomas (adenomas ≥1 cm) and normal or only mildly elevated prolactin levels should have a prolactin level checked after dilution of the serum sample in order to ensure that a large, well-functioning prolactinoma is not being missed.
Case Correlation
The patient had a pituitary-protocol MRI performed which demonstrated a 3-mm hypo-dense lesion on the right side of the pituitary gland, consistent with a pituitary adenoma. The patient was interested in becoming pregnant. She was subsequently started on low dose bromocriptine (1.25 mg po daily). Her menstrual periods resumed within 6 weeks. A follow-up prolactin level was found to be at our goal of mid-normal range in women attempting to achieve a pregnancy. Within 12 weeks of initiating bromocriptine therapy, a pregnancy was confirmed and the bromocriptine was stopped. As microprolactinomas rarely grow during pregnancy [64], typically patients may be observed for any signs or symptoms that might indicate tumor growth during the pregnancy. If she develops symptoms consistent with tumor growth including headache or visual symptoms, a visual field examination and, if necessary, a non-contrast pituitary-protocol MRI can be performed. The incidence of tumor growth during pregnancy is higher in women with macroprolactinoma (≥1 cm) [64] and therefore in this group of patients, baseline visual field testing prior to pregnancy and during each trimester is recommended. In our patient, we will repeat endocrine testing at least 6 weeks after delivery. This patient illustrates the importance of checking a prolactin level and performing pituitary imaging even when many aspects of the initial presentation are suggestive of hypothalamic amenorrhea due to exercise.
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