Possible Relationship Between Infertility and Alkaptonuria

Alkaptonuria is a rare metabolic disease which is not known to cause infertility up to now. Reported manifestations are mainly darkening of urine, ochronotic pigmentation of skin and various musculoskeletal symptoms. We aimed to report a family having many members affect-ed with alkaptonuria and infertility. For the couple first we met from this family, after diagnosis of alkaptonuria, noticed them to have infertility. Infertility test including hysterosalpingography and sperm analysis are performed. After detailed investigation we noticed coex-istence of infertility and alkaptonuria in three of eight couples. All three couples have desired to have children and asked medical help in the past. Hereby, presentation of close relation between alkaptonuria and infertility was pointed out.


INTRODUCTION
Alkaptonuria is a metabolic disease caused by mutations in the homogentisic acid oxidize (HGO) gene causing deficiency in its level, accumulation of tyrosine degradation product-homogentisic acid (HGA), ochronosis, and destructions in the connective tissue. Incidence is estimated to be 1 case in 250,000 to 1 million live births. This inborn error of metabolism has autosomal recessive inheritance (1)(2)(3)(4). We reported a family which of several members having alkaptonuria and infertility.

CASE
Main symptom for admission of the first patient we deal with was back pain and darkening of the urine upon waiting ( Figure 1). Second and third degree relatives of this patient were also suffering from similar problems. They had thoracic kyphosis, loss of lumbar lordosis and limitation of back movement. Plain films of lumbar and thoracal spine showed narrowing of the intervertebral spaces, multiple disc calcification and vertebral body osteoporosis. Laboratory revealed blood and urine sample results consistent with the diagnosis of alkaptonuria (Table 1). Generalized degenerative changes associated with osteophytes were present. Degenerative changes of the spine were far more advanced than would be anticipated for the patients' age. Using analgesic and antiinflammatory drugs and rehabilitation program including physical therapy and exercise were diminished their complaints. Infertility was the accompanying symptom of the first patient beside these musculoskeletal complaints. Totally we investigated eight families including sixteen persons and all had diagnosis of alkaptonuria. Among them, three families had infertility problem. These couples have undergone detailed infertility investigations including hormone profile and hysterosalpingography in the past.
Along the treatment of infertile couples, clomiphene citrate and recombinant FSH treatments have been useless. Other medical histories were unremarkable. Another interesting issue for this family was consanguineous marriage.

DISCUSSION
All members of the family were second or third degree relatives. Since alkaptonuria is an autosomal recessive disease, consanguineous marriage may be the reason of high incidence in this family. Although we hypothesized relation of the alkaptonuria with infertily, also determined that; neither all infertile couples have alkaptonuria nor all alkaptonuria couples are infertile. The region where this family lives is a part of country having high fertility rate (above 4). For this reason and also according to the investigations it is feasible to say that all couples in this family desire to have children. Also we know that these infertile couples have not used any contraceptive method.  HGO deficiency causes large amount of HGA excretion through urine turning into dark over time (1), which is the major symptom for diagnosis of alkaptonuria. This darkening is the result of oxidation and polymerization of the HGA in an alkaline medium. As a matter of fact, acid urine may not darken unless it is kept waiting. Hence darkening of the urine can not be noted in several under-diagnosed patients. The main clinical symptom is degeneration of the articular cartilage. Osteoarthritis, scoliosis and fusion of the vertebra can be observed in further stages. Pigment deposition can cause valvular abnormalities of the heart. There is no definitive therapy for this disease, however protein restrictionespecially phenylalanine and tyrosine-and ascorbic acid treatment are advised to diminish plasma HGA levels.
In the previous literature, findings are related with HGA deposition especially in musculoskeletal and cardiovascular system in addition to urinary darkening due to homogentisic aciduria. Furthermore prostatic calculi (2) and urinary lithiasis (3) and vaginal hyperpigmentation (4) are among other reported manifestations. Up to now preferential site for pigment deposition has been indefinite. Infertility affects approximately 15% of couples (5). The etiologies of infertility in couples include ovulatory dysfunction (15%), tubal and pelvic pathologies (35%), male factor (35%), unexplained infertility (10%) and other factors (5%) (6). Therefore still approximately 15% of the couples remain to be diagnosed.
In the pertinent articles we could not come across any information related with association of alkaptonuria and infertility. We likeminded that alkaptonuria may become one of the problems causing infertility. There are many idiopathic infertility patients and an expected high percentage of undiagnosed alkaptonuria patients exist. These two groups of patients may have been intercepted in a certain rate.