Neuroendocrine Case 3

26 years healthy transgender male without any medical history came to see you for cross-sex hormone therapy. 

Testosterone IM injection 50 mg weekly was initiated. Follow up lab result 4 months after initiation of Testosterone therapy;  Total Testosterone level 350 ng/dL ( normal value 250-1100 ng/dL) and Estradiol level 50 pg/mL ( normal value for male <31 pg/mL) , CBC, chemistry panel and liver function test were normal.  Patient noticed development of mild facial hair and amenorrhea after 5 months of Testosterone therapy. After 8 months of testosterone therapy, patient called your office for the complaint of recurrence of menstrual cycle (mostly spotting) and abdominal cramping. He was concerned that hormone therapy became less effective and wanted to discuss about other treatment option.  

Question 1

What is your appropriate response to the patient?  

A. Increase the dose of Testosterone dosage
B. Change to GnRH analogue injection
C. Suggest total hysterectomy and oophorectomy
D. Start Estrogen receptor blocker (Tamoxifen) as Estradiol level is too high
E. Assure the patient that small amount of menstrual bleeding (spotting) is very common within first year of therapy and continue with current Rx
Incorrect!
Correct!
Correct Answer
E. Assure the patient that small amount of menstrual bleeding (spotting) is very common within first year of therapy and continue with current Rx

Testosterone is the most effect cross-sex hormone therapy for female to male transgender. Testosterone therapy not only can result in desired masculinity (facial and body hair and increase in muscle mass) but also effectively block the hypothalamus-pituitary-gonadal axis. It will result in oligomenorrhea initially and then amenorrhea. This process usually takes at least few months to two year of testosterone therapy. The response to testosterone therapy can vary widely and individually. Some transgender males can achieve complete amenorrhea within few months of therapy while other can take longer. Breakthrough bleeding (recurrence of menstrual cycle during testosterone therapy) is a common phenomenon within the first year of therapy. Small amount of menstrual bleeding will cease spontaneously by continuation of testosterone therapy at current dose. Prolonged and heavy menstrual cycle should be thoroughly examined by OG/GYN to rule out common causes of menorrhagia such as uterine fibroid or endometriosis.  Non-hormonal intervention such as copper IUD (preferred option) or progesterone depo IM injection every 3 months can be used to prevent breakthrough bleeding.  

Young and healthy ovaries can produce a good level of Estradiol and will take longer to achieve normal estradiol level of male. Even though Estradiol level is slightly higher than male range, it is not the reason for breakthrough bleeding.  Tamoxifen (Estrogen receptor blocker) should not be used for this purpose due to undesired side effect. 

Neuroendocrine Case 2

A 45-year-old man who underwent transsphenoidal resection of a clinically non-functioning pituitary macroadenoma 6 months ago returns for endocrine follow-up. He says that his stamina and overall well-being have diminished since he underwent pituitary surgery. He has gained 10 lb postoperatively. He reports no headache, visual symptoms, nausea, constipation, dizziness, polyuria, low libido, erectile dysfunction, edema. His past medical history is otherwise significant for gastro-esophageal reflux disease but no diabetes mellitus or malignancy. His only medication includes omeprazole 20 mg daily. On examination, he appears well. His blood pressure is 125/84 mm Hg and his pulse is 78 / min. His weight is 210 lb with a height of 5’7” (body mass index: 32.7 kg/m2). There are no features of acromegaly or Cushing’s on exam. Visual fields are full on confrontation testing. There is no goiter. Muscle strength is intact. 

A recent postoperative MRI examination shows anticipated postoperative findings and a small tumor remnant (measuring 3 mm by 3 mm by 4 mm) present in the right cavernous sinus. 

Recent laboratory tests include: prolactin: 10 ng/ml (normal, 0 to 23); IGF-I: 95 ng/ml (normal, 50 to 320); TSH: 2.5 mcu/ml (normal, 0.4 to 4.5); free T4: 1.2 ng/dl (normal, 0.8 to 1.8); ACTH: 22 pg/ml (normal, 5 to 60); morning cortisol: 18.2 mcg/dl; LH: 2.1 U/l (normal, 1 to 8); FSH: 3.4 U/l (normal, 1 to 8); total testosterone: 420 ng/dl (normal, 250 to 800). 

He undergoes a glucagon stimulation test, during which his growth hormone reaches a peak level of 2.1 ng/ml. 

Question 1

How would you interpret these data and approach this patient’s endocrine management? 

A. Based on the result of the glucagon stimulation test, the patient has documented growth hormone deficiency and may begin a trial of growth hormone replacement.
B. This patient’s serum IGF-I level is within the normal range; therefore, he does not have growth hormone deficiency.
C. The results of the glucagon stimulation test suggest the presence of growth hormone deficiency but the presence of residual adenoma is a contraindication to growth hormone replacement.
D. This patient’s growth hormone response to glucagon stimulation is normal; therefore, growth hormone replacement is not indicated.
E. This patient’s serum IGF-I level is normal but his growth hormone response to glucagon stimulation is abnormally low; in light of the discrepancy, he should undergo a different growth hormone stimulation test in order to establish the diagnosis of grow
Incorrect!
Correct!
Correct Answer
D. This patient’s growth hormone response to glucagon stimulation is normal; therefore, growth hormone replacement is not indicated.

This patient is at risk for growth hormone deficiency in light of his history of pituitary macroadenoma and transsphenoidal pituitary surgery. His presentation has reasonably raised concerns for possible pituitary dysfunction. His thyroid, adrenal and gonadal axes are intact based on available data. However, the presence of obesity is associated with decreased growth hormone response to glucagon stimulation testing in healthy adults. In this patient, the peak growth hormone response to glucagon stimulation is normal (>1 ng/ml) taking obesity into account. Therefore, there is no indication for growth hormone replacement in this case (answer D is correct and answers A, C and E are incorrect). If the patient was lean, then a growth hormone cutpoint of 3 ng/ml would be appropriate to establish the diagnosis of growth hormone deficiency based on the result of the glucagon stimulation test. The presence of a small residual adenoma is not a contraindication for growth hormone replacement (answer C is incorrect). Available data suggest that growth hormone replacement does not increase the risk of progression of pituitary adenomas. However, regular periodic imaging of the sella would be advisable as part of good clinical practice. In adults with growth hormone deficiency, serum IGF-I levels are often within the normal reference range (albeit in the lower half of the range). Therefore, a normal serum IGF-I level does not exclude the possibility of growth hormone deficiency in this patient (answers B and E are incorrect).  

 

Reference: 

  1. Yuen KCJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care. Endocrine Practice. 2019;25(11):1191-1232. 

This patient is at risk for growth hormone deficiency in light of his history of pituitary macroadenoma and transsphenoidal pituitary surgery. His presentation has reasonably raised concerns for possible pituitary dysfunction. His thyroid, adrenal and gonadal axes are intact based on available data. However, the presence of obesity is associated with decreased growth hormone response to glucagon stimulation testing in healthy adults. In this patient, the peak growth hormone response to glucagon stimulation is normal (>1 ng/ml) taking obesity into account. Therefore, there is no indication for growth hormone replacement in this case (answer D is correct and answers A, C and E are incorrect). If the patient was lean, then a growth hormone cutpoint of 3 ng/ml would be appropriate to establish the diagnosis of growth hormone deficiency based on the result of the glucagon stimulation test. The presence of a small residual adenoma is not a contraindication for growth hormone replacement (answer C is incorrect). Available data suggest that growth hormone replacement does not increase the risk of progression of pituitary adenomas. However, regular periodic imaging of the sella would be advisable as part of good clinical practice. In adults with growth hormone deficiency, serum IGF-I levels are often within the normal reference range (albeit in the lower half of the range). Therefore, a normal serum IGF-I level does not exclude the possibility of growth hormone deficiency in this patient (answers B and E are incorrect).  

 

Reference: 

  1. Yuen KCJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care. Endocrine Practice. 2019;25(11):1191-1232. 

Neuroendocrine Case 1

James is 5 years old and has had worsening headaches for several weeks. He awakens with repeated vomiting. His parents rush him to the emergency room where he has a generalized seizure. A computerized tomography (CT) scan shows a posterior fossa tumor and hydrocephalus. He is admitted to the hospital and an emergency ventriculoperitoneal shunt is placed. Magnetic resonance imaging (MRI) confirms a likely medulloblastoma. In discussion with oncology, parents ask about future effects of treatment for the tumor.

Question 1

What empiric endocrine treatment should be started prior to the patient's craniotomy to remove the tumor?

A. Thyroid hormone
B. Glucocorticoids
C. Gonadotropin-releasing hormone agonist (GnRH-a)
D. All of the above
E. No hormone treatment since he has not yet been identified with any deficiencies
Incorrect!
Correct!
Correct Answer
B. Glucocorticoids

Patients with a brain tumor have a high risk for various neuroendocrinopathies. Late-endocrine effects of cancer therapies can cause significant morbidity. Increased intracranial pressure from the tumor itself can alter hypothalamic-pituitary function and anatomy, including secondary empty sella.

Neurosurgery itself can add to the risk for pituitary deficiencies as a result of mechanical traction. Because most intracranial resections of tumors involve significant recovery, often with prolonged hospitalizations, glucocorticoids, such as oral dexamethasone or hydrocortisone, given in stress dose quantities (50-100 mg/m2/day of hydrocortisone equivalency), are recommended as a precaution in the event of corticotrophin-releasing hormone (CRH) and/or adrenocorticotropic hormone (ACTH) deficiency that may result from the tumor or its resection, collectively called central adrenal insufficiency (AI). Rapid clinical decompensation may occur in the setting of central AI unless exogenous glucocorticoids are provided. Mineralocorticoid replacement is not required in central AI as the renin-angiotensin-aldosterone system is not impacted.

Thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH) deficiency can occur as a result of tumor mass effect, cranial radiation, and/or injury to the hypothalamus or pituitary glands. However, little data is available to support the empiric use of thyroid hormone prior to craniotomy, in the absence of direct evidence of abnormal thyroid hormone function testing. GnRH agonist treatment may be indicated in the setting of precocious puberty caused by a primary brain tumor or its treatment but is not used in the acute setting of craniotomy. As time goes on after acute management of the brain tumor, at least yearly monitoring of growth and endocrine function should be performed. Radiation therapy can lead to gradual decline (over 6 to 10 years) in hypothalamic messages to the pituitary gland. Chemotherapy can augment the late endocrine effects of irradiation or occasionally cause hypopituitarism. In addition, chemotherapy can cause gonadotoxicity and primary hypogonadism and contributes to development of osteopenia. Growth hormone (GH) deficiency and hypothyroidism (central and primary taken together) are common following radiation doses as low as 15-20 Gy. Precocious or rapid puberty can occur in association with optic gliomas and after cranial irradiation. Late ACTH deficiency can develop after radiation doses greater than 25 Gy, and gonadotropin deficiency can develop after doses above 30 Gy.

Patients with a brain tumor have a high risk for various neuroendocrinopathies. Late-endocrine effects of cancer therapies can cause significant morbidity. Increased intracranial pressure from the tumor itself can alter hypothalamic-pituitary function and anatomy, including secondary empty sella.

Neurosurgery itself can add to the risk for pituitary deficiencies as a result of mechanical traction. Because most intracranial resections of tumors involve significant recovery, often with prolonged hospitalizations, glucocorticoids, such as oral dexamethasone or hydrocortisone, given in stress dose quantities (50-100 mg/m2/day of hydrocortisone equivalency), are recommended as a precaution in the event of corticotrophin-releasing hormone (CRH) and/or adrenocorticotropic hormone (ACTH) deficiency that may result from the tumor or its resection, collectively called central adrenal insufficiency (AI). Rapid clinical decompensation may occur in the setting of central AI unless exogenous glucocorticoids are provided. Mineralocorticoid replacement is not required in central AI as the renin-angiotensin-aldosterone system is not impacted.

Thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH) deficiency can occur as a result of tumor mass effect, cranial radiation, and/or injury to the hypothalamus or pituitary glands. However, little data is available to support the empiric use of thyroid hormone prior to craniotomy, in the absence of direct evidence of abnormal thyroid hormone function testing. GnRH agonist treatment may be indicated in the setting of precocious puberty caused by a primary brain tumor or its treatment but is not used in the acute setting of craniotomy. As time goes on after acute management of the brain tumor, at least yearly monitoring of growth and endocrine function should be performed. Radiation therapy can lead to gradual decline (over 6 to 10 years) in hypothalamic messages to the pituitary gland. Chemotherapy can augment the late endocrine effects of irradiation or occasionally cause hypopituitarism. In addition, chemotherapy can cause gonadotoxicity and primary hypogonadism and contributes to development of osteopenia. Growth hormone (GH) deficiency and hypothyroidism (central and primary taken together) are common following radiation doses as low as 15-20 Gy. Precocious or rapid puberty can occur in association with optic gliomas and after cranial irradiation. Late ACTH deficiency can develop after radiation doses greater than 25 Gy, and gonadotropin deficiency can develop after doses above 30 Gy.