Fertility preservation in men with hypogonadotropic hypogonadism secondary to germinoma: two cases of gonadotropin replacement therapy before induction of anticancer chemotherapy

Abstract

Hypogonadotropic hypogonadism can be caused by brain tumors. For a malignancy such as a germ cell tumor, chemotherapy combined with radiation is administered. In patients who wish for children, the inability to undergo sperm cryopreservation before treatment because of impaired spermatogenesis and/or ejaculation dysfunction can be problematic. We herein present two cases involving a 26-year-old man and a 30-year-old man with hypogonadotropic hypogonadism due to an intracranial germinoma and both wished to have children. Gonadotropin replacement therapy prior to anticancer chemotherapy resulted in subsequent spontaneous pregnancy or assisted reproductive therapy. Subsequent treatment of the tumor resulted in no recurrence for 9 and 2 years, respectively. Close consultation with an oncologist is mandatory in such cases. Depending on the tumor prognosis, however, it may be possible to delay tumor treatment and prioritize fertility because there is a possibility of impaired spermatogenesis due to additional chemotherapy.

Introduction

Hypogonadotropic hypogonadism (HH) is a congenital or acquired disorder caused by abnormal function of the hypothalamus and/or pituitary gland [1]. Acquired HH can arise from pituitary disorders caused by brain tumors, brain trauma, or drugs. Typical clinical manifestations include decreased libido, ejaculation dysfunction, hot flashes, and infertility in patients with onset after adolescence [2]. Infertility is one of the most common complaints among the latter patients and significantly impacts their quality of life [1].

As noted above, HH can be caused by brain tumors. For a malignancy such as a germ cell tumor, chemotherapy combined with radiation (CRT) may be administered [3]. For young patients who are scheduled to undergo chemotherapy and desire fertility preservation, sperm cryopreservation is typically performed before the initiation of chemotherapy. This safeguards their reproductive potential in case of impaired spermatogenesis after treatment [4].

However, patients with HH are often unable to freeze their sperm because of impaired spermatogenesis and ejaculation dysfunction secondary to gonadotropin deficiency [5]. Generally, if no ejaculated sperm are present, onco-testicular sperm extraction (onco-TESE) is performed for sperm retrieval. In patients with gonadotropin deficiency, however, sperm retrieval by onco-TESE is expected to be difficult. We herein describe two men with HH secondary to intracranial germ cell tumors (germinomas) in whom CRT was postponed and preceded by gonadotropin replacement therapy.

Case Report

Case 1

A 26-year-old man presented to our hospital with chief complaints of insomnia, anhidrosis, and hyposalivation. He was also experiencing polyuria and enuresis.

Magnetic resonance imaging (MRI) of the head showed tumors with abnormal contrast effects in the lateral ventricles, pineal gland, and pituitary gland (Fig. 1). Endoscopic biopsy was conducted, confirming a diagnosis of germinoma. Distant metastasis was not observed.

Fig. 1.

Coronal and sagittal sections of head MRI (Case1)

CRT was scheduled. The patient was referred to our department for sperm cryopreservation.

Blood tests showed HH, with the luteinizing hormone level below the detection sensitivity, follicle-stimulating hormone (FSH) level at 0.3 mIU/mL, and total testosterone level below the detection sensitivity. The testicles were atrophic, with a volume of 8 mL on the right and 6 mL on the left. Ejaculation was not possible.

After a discussion of the spermatogenic defects caused by chemotherapy, the patient expressed a desire for future children. Following consultation with the oncologist, chemotherapy was postponed in favor of gonadotropin replacement therapy to facilitate sperm cryopreservation. Administration of human chorionic gonadotropin (5000 IU twice a week) and recombinant FSH (150 IU twice a week) was initiated. Sperm were found in the ejaculate after 2 months. However, the sperm count was too low (5 motile sperm in all fields of view), and TESE was performed 4 months after the start of treatment. Motile sperm were confirmed intraoperatively, and the sperm were cryopreserved.

Subsequently, chemotherapy combined with radiation was administered. The chemotherapy protocol included three courses of carboplatin at a dosage of 450 mg/m² administered on day 2, and etoposide at 150 mg/m² administered on days 2 to 4. Fortunately, the anticancer drugs resulted in only mild spermatogenic dysfunction and pituitary function improved after treatment. Testicular volume after treatment was unknown. He married his 28-year-old wife after completing treatment for a germinoma. The patient thereafter naturally conceived two children. Nine years after cancer treatment, the germinoma had not recurred.

Case 2

A 30-year-old man presented to our hospital with a 4 year history of gradually decreasing erectile function and difficulty in ejaculation, and he expressed a wish for children. He was married to 27 years old wife. His bilateral testicular volume was 8 mL. Blood tests showed HH, with the luteinizing hormone level below the detection sensitivity, FSH level at 0.2 mIU/mL, and total testosterone level below the detection sensitivity.

Head MRI for pituitary tumor investigation revealed a tumorous lesion with contrast enhancement in the suprasellar region (Fig. 2).

Fig. 2.

Coronal and sagittal sections of head MRI (Case2)

The patient underwent tumor resection, and the pathological findings revealed a germinoma. CRT was therefore planned. However, because of the patient’s inability to ejaculate, sperm cryopreservation was not possible. Following a discussion with the oncologist regarding the risk of impaired spermatogenesis due to chemotherapy, chemotherapy was postponed and gonadotropin replacement therapy was prioritized while conducting follow-up monitoring with head MRI.

Human chorionic gonadotropin (5000 IU twice a week) and recombinant FSH (150 IU twice a week) supplementation was initiated, and ejaculated sperm were confirmed 7 months after the start of treatment. The semen parameters showed an improving trend thereafter. At 10 months after treatment initiation, semen analysis revealed a volume of 1.24 mL, concentration of 2.5 million/mL, and motility of 28%. Intracytoplasmic sperm injection was performed with the ejaculated motile sperm, multiple fertilized eggs were frozen, and pregnancy followed by live birth was achieved.

At 13 months after gonadotropin replacement therapy, chemotherapy combined with radiation was administered for the brain tumor. The chemotherapy protocol included three courses of carboplatin at a dosage of 450 mg/m² administered on day 2, and etoposide at 150 mg/m² administered on days 2 to 4. After treatment, the testicular volume was 14 ml on both sides. Semen analysis after treatment showed cryptozoosperima, and no motile sperm were observed and pituitary function was abolished. Two years after cancer treatment, the germinoma had not recurred.

Discussion

CRT regimens such as CARE (carboplatin and etoposide) and ICE (ifosfamide, cisplatin, and etoposide) are commonly included in the treatment of primary central nervous system germinoma [6]. The prognosis after treatment is relatively good, with reported 5-year and overall survival rates of more than 90% even in the presence of metastases [7].

Generally, when a malignancy is diagnosed and chemotherapy is scheduled, sperm cryopreservation is performed in patients who wish to conceive before chemotherapy [8]. However, patients with HH are often unable to ejaculate, and even if ejaculation is possible, there is a high probability of azoospermia [1]. Onco-TESE is usually an option in such cases, but patients with HH have impaired spermatogenesis due to gonadotropin deficiency, making sperm cryopreservation difficult with little chance of sperm retrieval [9]. In this case, both patients had testicular atrophy with HH secondary to germinoma. Although the testicular toxicity of certain anticancer drugs is partly understood, the risk of infertility varies and is difficult to predict, especially with the use of multiple drugs and varying treatment plans [10], (11).

The key point of these two cases is the prioritization of treatment for patients with HH who are not expected to produce sperm, considering the favorable prognosis of the tumor and the impact of treatment on reproductive function. This decision underscores that tumor treatment may not always take precedence, particularly when considering its potential effects on reproductive function. Because acquiring fertility may take some time, thorough discussion with an oncologist is mandatory. However, prioritizing cancer treatment is not necessarily the optimal choice because fertility acquisition may also be a crucial consideration.

Conclusion

Close consultation with an oncologist is mandatory. However, depending on the tumor prognosis, it may be possible to delay tumor treatment and prioritize fertility because there is a possibility of impaired spermatogenesis due to additional chemotherapy.

Author contributions

Yasuhiro Kaku: Writing—original draft, writing—review and editing. Koji Chiba: Conceptualization; writing—original draft, writing—review and editing. Yosuke Yamashita: Supervision. Shun Kawamura: Supervision. Katsuya Sato: Supervision. Takuto Hara: Supervision. Keisuke Okada: Supervision. Hideaki Miyake: Supervision,—review and editing.

Data availability

Data will be made available on reasonable request.

Declarations

Conflict of interest

The authors have no conflict of interest.

Ethical approval

Not applicable.

Informed consent

Informed consent has been obtained from the patient.