ORIGINAL CASE : Ulcer et al
“A 26-year-old female patient was referred to our clinic with a 3 yr history of amenorrhea”
Q. Define Secondary amenorrhea ?
Absence of menses for a period of 3 pervious cycles or for a period of upto 6 months in a patient who previously had menses
Q. Define primary amenorrhea ?
Absent menarche at age 15 years with normal secondary sexual characteristics or
Absent menarche at age 13 without secondary sexual characteristics
Q. What are the causes of secondary amenorrhea ?
o Hypothalamic amenorrhea
o Pituitary amenorrhea
o Pituitary surgery
o Pituitary adenoma
o Suprasellar tumors – craniopharyngioma
o Lymphocytic hypophysitis
o Pituitary irradiation
o Pituitary apoplexy
o Sheehan’s syndrome
o Premature ovarian failure
o Androgen secreting ovarian tumors
o Androgen secreting Adrenal tumors
“Medical history showed a diagnosis of 𝛽-thalassemia major since the age of one and treatment with regular blood transfusions (once a month until the age of seven, thereafter twice a month) to maintain adequate levels of hemoglobin. She had also undergone splenectomy due to hypersplenism and massive splenomegaly at eight years old. She received iron chelation therapy with deferasirox (500 mg t.i.d.) for the last 6 years, having had irregular desferroxamine treatment before this”
Q. What are the endocrinal complications of beta thalassemia major ?
1. Hypogonadism- Most common
4. Growth failure
5. Vitamin D deficiency
Q. What are the reasons for hypogonadism in thalassemia patients ?
1. Zinc deficiency
2. Iron overload
Q. What is the cause for diabetes in thalassemia ?
1. Insulin resistance- initially
2. Lack of insulin production- later because of hemosiderosis
“Her menarche was at the age of 13 years. She had a regular menstrual cycle over the next 10 years. There were no other possible causes of functional hypothalamic amenorrhea such as weight loss, eating disorders, excessive exercise, and psychosocial stress”
Q. What is the normal age of menarche ?
Normal age for menarche is 12.5 years (a girl is typically in her 7th to 8th standard)
“Her blood pressure was 110/65 mmHg, she was 168 cm tall, and she weighed 53 kg. Stages of female breast and pubic hair development, according to Marshall and Tanner, were stages B-4 and P-5, respectively. There were no pathological findings except for skin hyperpigmentation on physical examination”
Q. What is B4 and P5 in Tanner staging in girls ?
B4- Aerola and breast form a secondary mound above the level of the breast
P5- Adult type and quantity with horizontal distribution
“There were no pathological findings except for skin hyperpigmentation on physical examination. The patient had low LH and FSH levels in association with the low estradiol levels. A bolus of 100 g synthetic LHRH was administered intravenously, and serum samples for gonadotropin measurements were drawn 0, 30, 60, 90, and 120 minutes after LHRH injection. Even after stimulation with LHRH, pituitary response was subnormal, consistent with hypogonadotropic hypogonadism. Peak levels of growth hormone and cortisol with insulin tolerance test were 11.6 ng/mL and 26.3 μg/dL, respectively. Her serum ferritin was 887 ng/mL (normal range 4.6–204) and transferrin saturation was 66.4%. Other laboratory test results were normal except for the anemia and thrombocytosis”
Q. What is your evaluation of the hormonal tests ?
1. Hypogonadotropic hypogonadism
2. Vitamin D deficiency with secondary hyperparathyroidism
Q. What is your interpretation of the dynamic tests ?
1. Subnormal response to LHRH (GnRH) stimulation
2. Normal response to GH stimulation (>10 ng/ml)
3. Normal response to Cortisol stimulation (>18 ug/dl)
Q. Describe the GnRH stimulation test ?
• Measure LH and FSH
• Give GnRH in dose of 100 mcg
• After 30-45 min repeat FSH and LH
• LH increases by 3-6 times
• FSH increases by 20-50%
Abdominal magnetic resonance imaging was unremarkable except for asplenia. Magnetic resonance imaging (MRI) showed decreased signal intensity of the pituitary gland on T2-weighted images. Additionally, bone densitometry (BMD) showed osteopenia, with a score of −1.8 in the femur and −2.1 in the spine
Q. What is the importance of reduced signal intensity of pituitary in T2 images in this case ?
According to a study : “The degree of reduction of the pituitary-to-fat signal intensity ratio correlated with the presence of hypogonadotropic hypogonadism, with a sensitivity of 90%, a specificity of 89%, and an overall accuracy of 89%. In addition, the reduction of pituitary signal intensity was greater in patients with higher ferritin levels”
DIAGNOSIS AND TREATMENT
Q. What is the final diagnosis in this case ?
Hypogonadotrophic hypogonadism because of secondary hemochromatosis in a case of beta thalassemia major
Q. What are the causes of hypogonadotrophic hypogonadism ?
KAL1- X linked
FGFR1- autosomal dominant
PROK2 and PROKR2- Autosomal dominant
GnRH receptor gene
1. Hypothalamic amenorrhea
b. Weight loss
c. Systemic illness
2. Pituitary tumors / Prolactinoma /
3. Inflammatory disorders of pituitary
4. Sheehan’s syndrome
5. Pituitary apoplexy
8. Other suprasellar tumors
9. Drugs – opioids
10. Cushing’s syndrome
Q. What is the treatment for this patients ?
1. Combined OC pills if pregnancy is not planned
2. HMG/HCG if pregnancy is planned
3. Proper chelation
4. Vitamin D supplementation