Congenital aromatase deficiency in an adult male: A case report of clinical course and symptom reversal with estrogen supplementation

[madman]

* This case demonstrates resolution of hypogonadal symptoms (despite the patient having normal testosterone levels), including fatigue and low libido, with restoration of physiologic estradiol levels

2. Case presentation​

A 43-year-old male with a known history of congenital aromatase deficiency due to a homozygous missense mutation in CYP19A1 (c.628G > A in exon 5) presented to our outpatient urology clinic with complaints of significant fatigue, low libido, and desire for future fertility. He reported significant fatigue upon waking and throughout the course of the day. On examination he was well appearing, notable for markedly tall stature.
--
He endorsed prior transdermal estrogen use for bone health about 8 years earlier, which was later discontinued for unknown reasons, and he is not currently on any form of hormone replacement therapy. His past medical history included diabetes mellitus, hyperlipidemia, hypertension, and osteopenia managed by Endocrinology. Surgical history was unremarkable. Physical examination was unremarkable with a normal genital examination without varicocele.
--
Family history was remarkable for heterozygous missense mutations in CYP19A1 c.628G > A in exon 5 in the mother and father, as well as homozygous missense mutations in c.628G > A in both sisters. Initial laboratory evaluation demonstrated normal testosterone (607 ng/dL), very low estradiol (3.0 pg/mL), and high normal FSH (10.77 mIU/mL) and LH (6.94 mIU/mL). Semen analysis showed normal volume (2.5 mL), concentration (34.4 million/mL), with 7% normal forms. Baseline and follow up hormonal and semen parameters are summarized in Table 1.

The patient was started on physiologic replacement of estrogen with 0.0375 mg transdermal estrogen applied twice weekly, with the goal of relieving hypoestrogenic symptoms while preserving fertility. At the three month follow up visit, the patient reported significant improvements in overall energy and libido. Follow-up lab tests showed that his serum estradiol increased from 3.0 to 20.5 pg/mL, FSH decreased from 10.77 to 3.90 mIU/mL, and LH decreased from 6.94 to 2.44 mIU/mL. His total testosterone decreased from 607 to 243 ng/dL (with free testosterone 54.9 pg/mL and SHBG 25.6 nmol/L at three months), which was consistent with restored estradiol-mediated negative feedback. Repeat semen analysis at three months showed sperm concentration within the laboratory reference range (19.6 million/mL) improved motility (45%), increased normal forms (11%), while total sperm number and total motile count fell below the lab reference range, which may reflect semen variability or volume effects due to a reduced ejaculate volume.
--
The patient was continued to be followed and actively monitored through serial hormone panels with estrogen dose titration as needed, semen cryopreservation and periodic semen analysis to ensure persistence of spermatogenesis, with continued resolution of hypoestrogenic symptoms at 6 month follow up.
-----

3. Discussion​

This case illustrates the reproductive and endocrine features of a man with congenital aromatase deficiency, and the beneficial impact of treatment with physiologic estradiol replacement on patient reported symptoms and hormonal profile. Few reports have included serial semen monitoring while supplementing estrogen in a man with aromatase deficiency.2,4 At baseline he had estrogen deficiency with high-normal gonadotropins, normal testosterone, and semen parameters that showed ongoing spermatogenesis. After three months of estradiol therapy, his symptoms significantly improved, estradiol improved, and gonadotropins normalized, accompanied by a decrease in total testosterone while free testosterone remained in the normal range. Semen parameters remained compatible with ongoing spermatogenesis, though total sperm number and total motile count decreased at 3 months. These changes reflect estrogen's role in the HPG axis in men as well as reproductive physiology.
-------

4. Conclusion​

This case demonstrates the clinical impact of hypoestrogenism in men and the role of estradiol in overall sexual health and reproductive endocrinology. Estradiol replacement improved patient-reported fatigue and libido, while semen analysis demonstrated ongoing spermatogenesis during short-term follow-up. Long-term reproductive outcomes in aromatase deficiency remain uncertain, so fertility counseling, cryopreservation, and serial monitoring should accompany treatment. Careful estrogen supplementation can be a viable therapeutic strategy in men with aromatase deficiency or analogous hypoestrogenism, balancing symptom relief with the goal of fertility preservation.