Male infertility associated with obesity and diabetes

Case history

A 32-year-old man and his 29-year-old wife presented with the complaint of inability to conceive even after almost 2 years of unprotected intercourse. The man was obese and suffering from type 2 diabetes for the past 4 years. He had been prescribed some oral antidiabetic drugs but was not taking them regularly.

There was no history of testicular trauma, torsion, or infections. The patient did not take alcohol, tobacco, marijuana or other illegal drugs. His father was also a diabetic and had died of diabetes-related complications.

Examination findings

The patient was a young man, grossly overweight and alert. His pulse was 88/min, blood pressure 128/82 mmHg, height 170 cm, weight 144 kg, BMI 49.8 kg/m². There was central obesity and testicular volumes were normal, being 20 cm³ on the right side and 19 cm³ on the left. Hair distribution was of normal male-pattern type. Systemic examination was unremarkable, with intact peripheral sensation and pulsation.

Investigations

The patient’s routine investigations were normal. His fasting blood glucose was 325 mg/dL and HbA1c was 12.2%. Lipid profile was normal, and so were liver and kidney function tests. Semen analysis revealed severe oligospermia (count of 4 million per mL) and testicular biopsy showed hypospermatogenesis. Genetic testing yielded 46XY, but no chromosomal mutations, deletions or other abnormalities could be detected.

Management

The patient’s infertility was felt to be due to obesity and diabetes. Appropriate treatment was given to control both these conditions with strict instructions to adhere to it religiously. The patient complied and his serum testosterone levels and spermatogenesis became normal. One year later, his wife conceived and gave birth to a normal, healthy daughter in due course.

Discussion

Male factor infertility (or subfertility) accounts for about one third of all infertility cases. The common correctable causes of male subfertility are varicocele,¹Sigman M, Lipshultz LI, Howards SS. Evaluation of the sub-fertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997:173-93.  ^,2World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril. 1992;57:1289-93.   post-vasectomy obstruction,¹Sigman M, Lipshultz LI, Howards SS. Evaluation of the sub-fertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997:173-93.  ^,3Belker AM, Thomas AJ Jr, Fuchs EF, Konnak JW, Sharlip ID. Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol. 1991;145:505-11.   ejaculatory dysfunction, infection, medications, and hormonal deficiency. More than 50% cases of male subfertility are potentially correctable.

Proper evaluation of a subfertile man can help identify correctable causes of infertility and thus facilitate conception by the most natural, least invasive means possible. Evaluation may also reveal significant underlying medical or genetic disorders.

A careful history can point towards the underlying cause of infertility and enable an assessment of the man’s fertility potential. Questions should be asked regarding the duration of the infertility, previous evaluation and treatment, previous pregnancies (for either partner), difficulty, if any, in establishing these pregnancies, frequency or timing of intercourse, sexual dysfunction, and lubricant use.⁴Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med. 1995;333:1517-21.  

History can also aid in identifying some specific risk factors, such as diabetes mellitus, disorders of the testes (e.g., cryptorchidism, spermatic cord torsion), and surgery of inguinal, scrotal or retroperitoneal regions. Other risk factors include use of prescription or illicit drugs, exposure to environmental toxins,¹Sigman M, Lipshultz LI, Howards SS. Evaluation of the sub-fertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997:173-93.  ^,5Kolettis PN, Thomas AJ. Andrology. In: Ransom SB, Dombrowski MP, eds. Practical strategies in obstetrics and gynecology. Philadelphia: Saunders, 2000: 631.  ^,6Hakim LS, Oates RD. Nonsurgical treatment of male infertility: specific therapy. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997:395-402.   underlying hypothalamic etiology (such as Kallmann’s syndrome), pituitary pathology, and frequent respiratory infections. A history of headaches and visual field disturbances points towards a tumor of the central nervous system.¹Sigman M, Lipshultz LI, Howards SS. Evaluation of the sub-fertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997:173-93.  

A thorough examination can also identify underlying causes of subfertility. One should especially look for abnormal distribution of hair and fat, position and size of the urethral meatus, size of the testes (a size smaller than 20 cm³ suggests decreased sperm production and may occur in hypogonadal men as well1), induration or engorgement of vasa deferentia and epididymides.

Laboratory investigations are no less important in determining the cause of infertility. Semen analysis is the

basic investigation. In addition to the number of sperm per mL, other parameters, such as motility, are important in assessing a man’s fertility potential.⁷World Health Organization. Reference values of semen variables. In: WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. Cambridge: Cambridge University Press, 1999:60-1.   If leukocytospermia is present, empiric antibiotic therapy with doxycycline should be initiated in a dosage of 100 mg twice a day for two weeks, after which semen analysis should be repeated. Evaluation of sperm function, however, can be done only in specialized fertility laboratories.

The levels of serum testosterone and follicle-stimulating hormone (FSH) are adequate to assess the pituitarytesticular axis in most cases. A sperm concentration of less than 10 million per mL warrants measurement of the serum testosterone and FSH levels.⁸Sigman M, Jarow JP. Endocrine evaluation of infertile men. Urology. 1997;50:659-64.   If the total testosterone level is normal, no further endocrine testing is needed; but if it is low, serum luteinizing hormone (LH) and prolactin levels should be checked to detect a pituitary cause. An elevated FSH suggests testicular failure, while a low level may indicate an underlying FSH deficiency, as in hypogonadotropic hypogonadism.

More specialized testing may be required based on the outcome of this initial evaluation (Fig. 1). These tests include:

• Post-ejaculatory urine sample analysis to rule out retrograde ejaculation in men with low ejaculate volume (< 1 mL)
• Testicular biopsy in cases of azoospermia to evaluate the level of sperm production and differentiate between testicular failure and obstruction (i.e., normal sperm production)
• Transrectal ultrasonography to evaluate for possible ejaculatory duct obstruction in patients with azoospermia, low semen volume (< 1 mL), and a normal FSH level⁹Goluboff ET, Stifelman MD, Fisch H. Ejaculatory duct obstruction in the infertile male. Urology. 1995;45:925-31.  

Genetic testing and counseling are indicated in specific instances.

If correctable causes are found on initial evaluation, specific corrective measures can be undertaken. If there is no correctable problem, the option of assisted reproductive technologies (ART), such as intrauterine insemination, can be offered.¹¹Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Lit-vak P, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med. 1999;340:177-83.   An alternative to ART is empiric treatment with clomiphene citrate.¹²Jarow JP. In: Nonsurgical treatment of male infertility: empiric therapy. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997: 410-22.  

Clomiphene citrate is an orally active synthetic nonsteroidal drug that acts as an antiestrogen and competitively binds to estrogen receptors in the hypothalamus and pituitary. This blocks the action of the normally low levels of estrogen on the male hormone axis and results in increased secretion of GnRH, FSH and LH. The enhanced output of these hormones increases testosterone and sperm production.

The efficacy of clomiphene citrate in male infertility has been established in many clinical trials.

In a non-randomized clinical trial,¹³Zaman S, Zulfiqar S, Khan MS. Evaluation of effects of clomiphene citrate on serum testosterone and FSH levels and seminal parameters in idiopathic oligospermia. Biomedica 2009;25:48-51.   21 idiopathic oligospermic men were administered clomiphene citrate in a dose of 100 mg/day for five days. It resulted in:

• Significant increase in mean serum testosterone
• Significant increase in mean serum FSH levels
• Statistically significant increase in the mean semen volume at day 6
• Increase in the sperm density at day 74
• Increase in the total sperm motility at day 6

In another study, Patankar et al¹⁴Patankar SS, Kaore SB, Sawane MV, Mishra NV, Deshkar AM. Effect of clomiphene citrate on sperm density in male partners of infertile couples. Indian J Physiol Pharmacol. 2007 Apr-Jun;51(2):195-8.   administered clomiphene citrate in the dose of 25 mg daily for 25 days with five days’ rest to 25 extreme oligozoospermic men (group I) and 40 moderate oligozoospermic men (group II). The cycle was continued for three months. Increases in the mean sperm count and mean motile sperm count after the treatment are depicted in Table 1.

A study by Hammami and colleagues¹⁵Hammami MM. Hormonal evaluation in idiopathic oligozoospermia: correlation with response to clomiphene citrate therapy and sperm motility. Arch Androl. 1996 May-Jun;36(3):225-32.   recruited 17 patients with idiopathic oligozoospermia with a mean ± SE sperm density of 7.3 ± 1.2 x 10⁶ sperm/mL, and mean FSH of 5 ± 0.5 IU/L. They were treated with clomiphene citrate for 7.2 ± 0.6 months. The treatment led to a significant increase in total sperm count (mean percent change 261 ± 117) and in total motile sperm count (mean percent change 370 ± 216).

Another study¹⁶Moradi M, Moradi A, Alemi M, Ahmadnia H, Abdi H, Ahmadi A, Bazargan-Hejazi S. Safety and efficacy of clomiphene citrate and L-carnitine in idiopathic male infertility: a comparative study. Urol J. 2010; 7(3): 188-93.   evaluated the effects of clomiphene citrate and L-carnitine in idiopathic male infertility. In this randomized controlled trial, 52 men with idiopathic

infertility were randomly assigned into 2 treatment groups for 3 months:

• Group 1 – Clomiphene citrate 25 mg/day (n = 20)
• Group 2 – L-carnitine 2 gr/day (n = 32)

Both medications were found to influence sperm count and motility. While L-carnitine significantly increased semen volume, clomiphene citrate significantly improved sperm motility and morphology (Table 2).

Thus, use of clomiphene citrate and L-carnitine, either individually or in combination, is a safe and effective treatment for idiopathic male infertility.

References

1. Sigman M, Lipshultz LI, Howards SS. Evaluation of the sub-fertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997:173-93.
2. World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril. 1992;57:1289-93.
3. Belker AM, Thomas AJ Jr, Fuchs EF, Konnak JW, Sharlip ID. Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol. 1991;145:505-11.
4. Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med. 1995;333:1517-21.
5. Kolettis PN, Thomas AJ. Andrology. In: Ransom SB, Dombrowski MP, eds. Practical strategies in obstetrics and gynecology. Philadelphia: Saunders, 2000: 631.
6. Hakim LS, Oates RD. Nonsurgical treatment of male infertility: specific therapy. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997:395-402.
7. World Health Organization. Reference values of semen variables. In: WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. Cambridge: Cambridge University Press, 1999:60-1.
8. Sigman M, Jarow JP. Endocrine evaluation of infertile men. Urology. 1997;50:659-64.
9. Goluboff ET, Stifelman MD, Fisch H. Ejaculatory duct obstruction in the infertile male. Urology. 1995;45:925-31.
10. Kolettis PN. Evaluation of the Subfertile Man. Am Fam Physician. 2003 May 15;67(10):2165-2172.
11. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Lit-vak P, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med. 1999;340:177-83.
12. Jarow JP. In: Nonsurgical treatment of male infertility: empiric therapy. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3rd ed. St. Louis: Mosby, 1997: 410-22.
13. Zaman S, Zulfiqar S, Khan MS. Evaluation of effects of clomiphene citrate on serum testosterone and FSH levels and seminal parameters in idiopathic oligospermia. Biomedica 2009;25:48-51.
14. Patankar SS, Kaore SB, Sawane MV, Mishra NV, Deshkar AM. Effect of clomiphene citrate on sperm density in male partners of infertile couples. Indian J Physiol Pharmacol. 2007 Apr-Jun;51(2):195-8.
15. Hammami MM. Hormonal evaluation in idiopathic oligozoospermia: correlation with response to clomiphene citrate therapy and sperm motility. Arch Androl. 1996 May-Jun;36(3):225-32.
16. Moradi M, Moradi A, Alemi M, Ahmadnia H, Abdi H, Ahmadi A, Bazargan-Hejazi S. Safety and efficacy of clomiphene citrate and L-carnitine in idiopathic male infertility: a comparative study. Urol J. 2010; 7(3): 188-93.