SAT-171 - Recovery of Gonadal Axis Function after Treatment of Iron Overload in Hereditary Hemochromatosis

Introduction:
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by
progressive over accumulation of parenchymal iron. The most common non-diabetic
endocrinopathy is male hypogonadotropic hypogonadism. Hypogonadism in HH is largely
permanent and requires life-long testosterone therapy. We describe a male with
hypogonadotropic hypogonadism due to HH with reversible hypogonadism after a short course
of treatment for iron overload.

Case Description:
A 32-year-old male was referred for low testosterone levels. Symptoms included fatigue,
decreased libido, and erectile dysfunction. Health history was notable for obesity (BMI 40.67
kg/m2), obstructive sleep apnea treated with CPAP, and type 2 diabetes mellitus. Morning LH
(1.4-1.5 mIU/mL, ref range 1.24-8.62), total testosterone (114-138 ng/dL, 241-827), and free
testosterone (3.87 ng/dL, 4.70-24.40) levels indicated secondary hypogonadism, and
hyperferritinemia (331-478 ng/mL, 26-300) and elevated transferrin saturation (TSAT 53-54%,
20-50) indicated iron excess per AASLD diagnostic criteria (ferritin > 200 mg/dL and TSAT ≥
45%). Genetic testing confirmed homozygosity for the C282Y HFE gene mutation that accounts
for > 90% of HH in Caucasian populations. Sella MRI did not show a hypointense pituitary on
T2-weighted images, and there were no clinical, laboratory, or imaging findings to indicate
cirrhosis. After three months of serial phlebotomy on a bi-weekly schedule, abnormalities of
ferritin and transferrin saturation corrected, free testosterone level returned to reference
range, and the patient’s symptoms of hypogonadism resolved.

Discussion:
This case of HH is highly unusual because secondary hypogonadism reversed after a short
course of therapeutic phlebotomy. There are five published cases of men with HH and one with
juvenile hemochromatosis (due to HJV gene mutation) experiencing recovery of gonadotroph
axis function, with an age range of 25-42 years at diagnosis and treatment. Since onset of
complications from HH is usually in the fifth decade of life or later, early diagnosis and
treatment of iron overload may be an important factor limiting gonadotroph iron accumulation
and creating potential for axis recovery. Absence of cirrhosis and ferritin level < 1,500 ng/mL
are atypical for HH complicated by secondary hypogonadism and indicate a lesser degree of
iron overload in this patient than others with longer duration of disease prior to diagnosis.
Obesity and sleep apnea may have augmented effects of relatively modest iron over
accumulation and predisposed the patient to early onset hypogonadism and diagnosis of HH.
There are few reports, but this case appears to indicate that patients with early diagnosis of HH
have potential for improvement of gonadotroph axis function in response to treatment of iron
overload.

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