Severe oligozoospermia in a patient with myxedema coma

Abstract

A case of severe oligozoospermia with myxedema coma is herein presented. The patient was referred to a male infertility clinic with a 5‐year history of primary infertility. Decreased serum testosterone and elevated serum prolactin without abnormal MRI findings in the hypothalamus, and decreased semen volume and sperm motility were noted. A GnRH test revealed a decreased luteinizing hormone response, whereas the HCG test showed a normal testosterone increase. Because a urinalysis after ejaculation indicated retrograde ejaculation, imipramine administration was started. However, the semen quality deteriorated, so the patient was referred to an ART clinic. Twenty‐one months from the initial visit, the patient developed a loss of consciousness and edema due to myxedema coma, a life‐threatening state of hypothyroidism. The patient recovered after 1 month of thyroid hormone replacement therapy (HRT) with corticosteroids. Three months after the myxedema coma, a semen analysis showed a decreased semen volume (0.2 mL) and severe oligozoospermia (two spermatozoa/ejaculate). Elevated prolactin and decreased testosterone levels were still present. These parameters gradually improved after restoration of euthyroidism by HRT. In conclusion, physicians should confirm the thyroid function in the management of male infertility, especially in patients with elevated prolactin levels.

Introduction and purpose

Hormonal disorders are the most important causes of infertility. Hypothyroidism is associated with decreased libido or erectile dysfunction [1] and is also a possible cause of abnormal testicular function as a result of disorder in the hypothalamic–pituitary–gonadal axis, as well as a systemic metabolic derangement [2]. Hypothyroidism stimulates the secretion of thyrotropin‐releasing hormone (TRH) in the hypothalamus, which stimulates the release of prolactin. In the state of hyperprolactinemia, the gonadotrophic‐releasing hormone (GnRH) release is impaired due to elevated dopamine metabolism and increased endorphin activity. A disruption in the GnRH release leads to a lack of testosterone and a cessation in sperm production [3]. While the effects of hypothyroidism on the female gonadal function are well‐established, controversies exist regarding the impact of this disease on male reproductive function. This is due mainly to the clinical irrelevance of the signs and symptoms related to male gonadal function compared with the systemic effects of hypothyroidism [4]. Therefore, an evaluation of thyroid function is not common during the initial routine examination for male infertility.

In this report, we present a rare case of a male infertility patient with severe oligozoospermia, in which the patient experienced a myxedema coma, a rare, severe and life‐threatening form of decompensated hypothyroidism, and this case was managed by intensive medical care. We present his clinical data, including hormone levels and semen parameters, before and after the occurrence of the myxedema coma.

Subject, methods and results

A 44‐year‐old male was referred to our Male Infertility Clinic at Toyama University Hospital with a 5‐year history of primary infertility in July 2006. His partner was a 34‐year‐old healthy female. He had a history of tonsillectomy at 10 years of age. He had been taking allopurinol to treat hyperuricemia since his twenties. At the initial screening, the physical examinations were unremarkable. His height, weight, and body mass index were 165 cm, 62 kg and 22.8 kg/m², respectively. His testicular volumes were 19 mL in the left and 16 mL in the right, as measured by a pouched‐out orchidometer. No varicoceles were found [5]. A digital rectal examination and transrectal ultrasound revealed no abnormal findings in the prostate. His answer to the International Index of Erectile Function Questionnaire (IIEF) [6] showed impaired erectile function; his erectile function total score was 27 (no dysfunction), orgasmic function total score was 4 (moderate dysfunction), sexual desire total score was 4 (moderate dysfunction), intercourse satisfaction total score was 8 (mild to moderate dysfunction), and overall satisfaction total score was 6 (mild to moderate dysfunction).

The patient's blood tests revealed decreased serum total testosterone (1.42 ng/mL), decreased free testosterone (2.3 pg/mL) [7] and decreased serum luteinizing hormone (1.6 mIU/mL) levels. His serum prolactin was elevated (33.8 ng/mL) without abnormal findings in the MRI of the hypothalamus. The semen analyses showed a decreased semen volume (1.0–1.5 mL) and sperm motility (35–36 %, Table 1). The gonadotropin releasing hormone (GnRH) stimulation test showed a decreased luteinizing hormone (LH) response (LH, 2.8X; FSH, 1.5X), whereas the human chorionic gonadotropin (HCG) stimulation test showed a normal testosterone increase (Table 2). A urinalysis after ejaculation indicated retrograde ejaculation (5000–10000 spermatozoa per mL urine). Therefore, treatment with imipramine was started. However, the patient's semen quality became progressively worse. A repeated GnRH test, HCG test, and MRI of the hypothalamus revealed similar findings. Although androgen replacement therapy by HCG + HMG was considered, the patient was introduced to a private clinic for treatment using assisted reproductive technologies.

Table 1.

Changes in the semen quality and sexual hormone levels

a. Before the myxedema coma
Parameters (Reference range)	2006/07	2006/08 a	2006/09	2006/11	2007/09	2007/10
Semen volume (≥1.5 mL)	1.0	1.5	1.8	1.0	1.2
Sperm count (≥15 × 106/mL)	84	42	30	46	4
Sperm motility (≥40 %)	35	36	13.6	40	11
Sperm normal morphology (≥4 %)	64	58	69	62	7
Total testosterone (2.01–7.50 ng/mL)	1.42	2.01	1.58		0.96	0.67
Free testosterone (≥11.8pg/mL)	2.3	5.6	4.9		3.3	2.7
LH (0.79–5.72 mIU/mL)	1.6		2.5		2.3
FSH (2.00–8.30 mIU/mL)	1.6		2.5		2.5
Prolactin (4.3–13.7 ng/mL)	33.8		31.6		23.9	21.2
b. After the initiation of thyroid hormone replacement therapy
Parameters (Reference range)	2009/07	2009/10 b	2010/01	2011/09
Semen volume (≥1.5 mL)	0.2	0.3	0.2	0.8
Sperm count (≥15 × 106/mL)	0	0.02	0.01	20
Sperm motility (≥40 %)	0	18	0	29
Sperm normal morphology (≥4 %)	0	0	0	2
Total testosterone (2.01–7.50 ng/mL)	0.68	1.93	0.94	2.42
Free testosterone (≥11.8 pg/mL)	0.9	3.4	1.5	6.0
LH (0.79–5.72 mIU/mL)	4.3	3.6	1.5	4.0
FSH (2.00–8.30 mIU/mL)	5.1	6.7	7.8	4.2
Prolactin (4.3–13.7 ng/mL)	14.8	12.6	7.9	4.2

LH luteinizing hormone, FSH follicle stimulating hormone

^aStart of imipramine administration

^bNo spermatozoa were found in the post‐ejaculate urine

Table 2.

Results of the hormone stimulation tests

a. Gonadotropin releasing hormone stimulation tests
	Before	30 min	60 min	90 min
2006/07
LH (mIU/mL)	2.4	6.4	6.7	6.7
FSH (mIU/mL)	2.0	2.6	2.8	3.0
2007/11
LH (mIU/mL)	1.6	5.7	5.4	5.0
FSH (mIU/mL)	1.7	2.5	2.7	2.7
b. HCG stimulation test
	Serum total testosterone (ng/mL)
	Before	72 h
2006/07	0.8	2.01
2007/11	0.8	1.8

LH luteinizing hormone, FSH follicle stimulating hormone, HCG human chorionic gonadotropin

Twenty months after his initial visit to our institution, the patient was diagnosed with hypothyroidism at another institution during examinations for insomnia, lethargy and general malaise. In spite of his receiving 1 month of thyroid hormone replacement therapy, the patient was hospitalized with edema and a loss of consciousness. Systemic examinations confirmed the existence of severe hypothyroidism with pancytopenia. After 1 month of thyroid hormone replacement therapy plus corticosteroids, his general condition improved, and the patient was discharged (Table 3). Four months after the episode of myxedema coma, a follow‐up semen analysis showed a decreased semen volume (0.2 mL) and severe oligozoospermia; only 2 spermatozoa were found in the centrifuged ejaculate. Elevated levels of serum prolactin and decreased serum testosterone were still present. These parameters gradually recovered after restoration of euthyroidism with continuous thyroid hormone replacement therapy without any specific urological treatment. The patient's sperm count, serum total testosterone level and serum prolactin level were normal at his last visit (September 2011, Table 1).

Table 3.

Changes in thyroid function

Parameters (Reference range)	1991/12	2009/03 a	2009/04	2009/07	2009/11	2010/03
TSH (0.35–3.73 μIU/mL)	11.0	>100	0.03	<0.03	<0.03	0.06
Free T3 (2.20–4.10 pg/mL)	3.5	1.30	3.56	2.60	3.78	1.88
Free T4 (0.90–1.90 ng/dL)	0.8	0.50	1.76	0.98	1.14	1.14

TSH thyroid‐stimulating hormone

^aStart of thyroid hormone replacement therapy

Discussion

In general, approximately half of all cases of infertility are caused by factors related to the male partner [8]. In spite of the fact that it is an uncommon cause of male subfertility, up to 3 % of infertile males will have an underlying endocrinopathy [9]. Among the possible hormonal disorders causing male infertility, the incidence of hypothyroidism seems to be low. For example, Kolettis and Sabaegh [10] reported only one case of hypothyroidism among 536 patients presenting with either primary or secondary infertility.

Although the actual incidence and impact of hypothyroidism in the setting of male infertility is not clear, recent clinical studies have demonstrated that thyroid hormone plays an important role in testicular development and function. Triiodothyronine (T3) represents one of the major hormonal signals to Sertoli cell proliferation during testicular development, and ultimately affecting the establishment of the adult Sertoli cell population [11]. Thyroid hormones are also known to affect Leydig cells proliferation and function. Evidence of direct actions of thyroid hormones on Leydig cell steroidogenesis has been demonstrated [12]. Hypothyroidism appears to cause alterations in the sex steroid hormone metabolism, as well as in spermatogenesis and fertility, although the available data are scarce [4]. Testicular biopsies of adult hypothyroid patients have revealed morphological and spermatogenic alterations, such as fibrosis and hyalinization of tubular walls, fibroblastic proliferation, peritubular and interstitial fibrosis with sparse Leydig cells, as well as reduction of tubular diameter, interstitial edema and tubular basal membrane stickiness [12, 13, 14]. Among semen parameters, sperm motility is mainly affected, as our case showed asthenozoospermia with a normal sperm count. These abnormalities are usually reversed after restoration of euthyroidism, which was also found in our current case.

The laboratory data from this patient revealed persistently decreased testosterone and increased prolactin levels before thyroid hormone replacement. The GnRH test showed an impaired hypothalamus‐pituitary response. The semen analyses showed decreased semen volumes and sperm motility. In addition, the patient's semen quality became progressively worse. The IIEF score indicated that there was impaired male sexual function, including loss of libido. All of these can be explained by hypogonadotropic‐hypogonadism and hyperprolactinemia, possibly due to hypothyroidism, which we failed to confirm.

Normal ejaculation may be affected by neuromyopathy because antegrade ejaculation, consisting of seminal emission, bladder neck closure and seminal expulsion through the penile urethra, is controlled by autonomic and somatic nerves [15]. Hypothyroidism has been associated with the clinical features of proximal muscle weakness, mononeuropathy, and sensorimotor polyneuropathy resulted from either disordered Schwann cell metabolism or a disease of axis cylinders with secondary demyelination or remyelination [16, 17]. In addition, neuropathy due to hypothyroidism can be reversible by appropriate thyroid hormone replacement therapy [18]. Therefore, retrograde ejaculation found and recovered in this patient could have been related to neuropathy due to hypothyroidism and successfully treated by thyroid hormone replacement therapy.

By reviewing the current patient's old medical records, we found the laboratory data showing his thyroid function when he was 29 years old. TSH elevation had been noted; however, the patient had not undergone a further examination or received treatment for thyroid dysfunction. The patient's prolonged hyperprolactinemia can also be explained by TRH stimulation due to hypothyroidism. It is currently recommended that the thyroid profile should be examined in patients with elevated prolactin because primary hypothyroidism can be associated with moderate hyperprolactinemia (up to 100 μg/L) [19]. Such alterations were reversible by thyroid hormone replacement in this case, similar to the cases described in the previous literature [4, 11]. After this patient experienced myxedema coma, his semen count was close to azoospermia. This could have been due not only to his hypothyroidism, but also to the direct effects of the life‐threatening condition [20]. However, the causes of the hypothyroidism and myxedema coma remain unclear in this case.

Myxedema coma or myxedema crisis is a severe and life‐threatening form of decompensated hypothyroidism with an underlying precipitating factor. The mortality rates may be as high as 25–60 % even with best possible treatment [21]. At present, the incidence of myxedema coma is thought to be about 0.22 per million per year based on data in Western countries [22]. A low intracellular T3 level secondary to hypothyroidism is the basic underlying pathology in myxedema coma [21]. Patients with suspected myxedema coma should be admitted to an intensive care unit. Most authorities recommend treatment with intravenous levothyroxine (T4). Hydrocortisone should also be administered until a coexisting adrenal insufficiency is ruled out [22]. Because of its life‐threatening characteristics, the impact on male reproductive/sexual function is not discussed in the literature related to myxedema coma.

In conclusion, we herein presented a rare case of oligozoospermic male infertility, which was related to hypothyroidism and that was finally recognized when the patient experienced a life‐threatening myxedema coma. We also present the associated changes in the patient's hormone profiles and semen parameters. Although the actual incidence and clinical impact of hypothyroidism and myxedema coma is not clear in male patients presenting with infertility, physicians should confirm thyroid function in patients if their serum prolactin level is elevated.