Category: Reproductive Endocrinology

Monitor: 22

22 - Case Report: Homozygous C677T MTHFR Gene Mutation in Male with Hypogonadism

Friday, Apr 26
11:30 AM – 12:00 PM

Objective : MTHFR is a key enzyme in the folate pathway, and it plays an essential role in homocysteine metabolism. Homozygous C677T individuals have decreased activity of MTHFR enzyme, thus having an increased risk for hyperhomocysteinemia when deficient in folate, vitamin B12 or Pyridoxine. Elevated homocysteine is associated with increased risk of venous thrombosis, stroke, coronary artery disease and recurrent pregnancy loss in females. There has also been reports of association between C677T variant and male infertility.

Methods : We report a case of a 44-year old male, who was a semi-professional football player, with history of multiple head concussions between age 15-25. He was diagnosed with hypogonadotropic hypogonadism in 2013, when he complained of erectile dysfunction and generalized fatigue after having bilateral varicocele surgery, and was started on testosterone replacement therapy. Patient continued to complain of fatigue despite increasing dose of testosterone for at least two years. He underwent genetic testing that showed homozygous C677T MTHFR gene mutation.

Results : His folate: 3.1 ng/mL( normal range: 4.2-19.9), B12: 333 pg/mL( normal range: 210-934). His hemoglobin was at normal levels, but interestingly it did not increase as expected with the use of testosterone. He was started on folate and B12 supplements, which made his symptoms resolve completely.

Discussion :

G Bezold reported in 2001 that the prevalence of the homozygous C677T mutation was 18.8% in infertile males as compared with 9.5% in normal fertile males, so it was concluded that MTHFR products may play a role in the pathogenesis of male infertility.

Other studies have shown that there is an association between C677T variant and male infertility in Indian, African and Southeast Asian populations, but the data from Europe regarding this association is conflicting. The lack of similar association in western populations could be due to the overall dietary enrichment with folate.

F Lombardo who studied the role of C677T MTHFR mutation with subsequent hyperhomocysteinemia in erectile dysfunction also concluded that hyperhomocysteinemia in those patients may interfere with erection mechanisms and thus cause erectile dysfunction.

Patients with hyperhomocysteinemia should be treated with folic acid, B12 and B6 vitamins. Homocysteine tend to normalize in 1-2 months after initiation of treatment, but it is still unclear whether normalization of homocysteine levels would improve male infertility.

Conclusion : Our case emphasizes other important etiologies for fatigue and erectile dysfunction in a male with hypogonadism on testosterone therapy as well as shows the possible association between MTHFR gene mutation and male hypogonadism.


Rami Salameh

Endocrinology Fellow
Albert Einstein Medical Center
Philadelphia, Pennsylvania


Catherine Anastasopoulou

Associate Professor of Medicine
Sidney Kimmel Medical College at Thomas Jefferson University, Albert Einstein Medical Center
eLKINS pARK, Pennsylvania


Mumtaheena Miah

Endocrinology Fellow
Albert Einstein Medical Center