HCG and its respective place within TRT for secondary hypogonadism in men of reproductive age

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Induction of fertility in men with secondary hypogonadism

Peter J Snyder, MD
Section Editor
Alvin M Matsumoto, MD
Deputy Editor
Kathryn A Martin, MD

September 2010

INTRODUCTION — Sperm production cannot be stimulated in men who are infertile as a result of primary hypogonadism (due to damage to the seminiferous tubules). On the other hand, sperm production can usually be stimulated to a level sufficient to restore fertility in men who are infertile as a result of secondary hypogonadism, ie, due to damage to the pituitary or hypothalamus. Men who have pituitary disease can be treated with gonadotropins, while those with hypothalamic disease can be treated with gonadotropins or gonadotropin-releasing hormone (GnRH). (See "Causes of secondary hypogonadism in males".)

INDUCTION OF FERTILITY USING GONADOTROPINS — Secondary hypogonadism is associated with decreased secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), resulting in reductions in testosterone secretion and sperm production. This disorder should, in theory, respond to the administration of LH and FSH. In practice, testosterone secretion virtually always increases to normal after replacement of LH, and sperm production more often than not increases after replacement of LH alone or LH plus FSH. Testosterone replacement alone will not restore spermatogenesis.

Which patients are likely to respond? — The diagnosis of secondary hypogonadism must be firmly established before therapy is begun, since only patients whose infertility is due to this disorder will respond. (See "Clinical features and diagnosis of male hypogonadism".) Gonadotropin treatment will not increase the sperm count in men who have idiopathic oligospermia, in which a subnormal sperm count is associated with a normal serum testosterone concentration [1].

Several factors enhance the likelihood that the sperm count will be increased, and increased sooner after gonadotropin administration:


Development of hypogonadism after puberty rather than before. In one study, as an example, all six men whose hypogonadism occurred postpubertally experienced an increase in total sperm count from less than one million to above 40 million per ejaculate when treated with hcg alone; in comparison, only one of eight men whose hypogonadism occurred prepubertally (but without cryptorchidism) had a similar response [2].
Partial hypogonadism, rather than complete, as judged by less severe abnormalities of testicular size [3-5] and reductions in the serum concentrations of FSH, inhibin, and testosterone.
Descent of both testes into the scrotum at birth or by one year of age, rather than unilateral or bilateral cryptorchidism (which may damage the seminiferous tubules) requiring surgical correction [2,6]. In one report, as an example, only one of the seven men with prepubertal hypogonadism and cryptorchidism had an increase in sperm count to within the normal range in response to hCG and hMG [2].

Use of gonadotropin with assisted reproductive technologies — Gonadotropin treatment of men with hypogonadotropic hypogonadism results in the appearance of sperm in the ejaculate in up to 90 percent of these men, but often not to normal [4]. Even if pregnancy does not occur spontaneously, the number of sperm is often sufficient that pregnancy can be achieved with the help of an assisted reproductive technique, which may be as simple as insemination with the patient's semen (intrauterine insemination, IUI) or as elaborate as intracytoplasmic sperm injection (ICSI) [7]. (See "Intracytoplasmic sperm injection".) or in vitro fertilization (see "In vitro fertilization").

Use of human chorionic gonadotropin — Human chorionic gonadotropin (hCG) has the biologic activity of LH but a longer half life in the circulation; it stimulates the Leydig cells of the testes to synthesize and secrete testosterone. hCG is used to replace LH in men who have secondary hypogonadism and desire to become fertile. It is approved by the Food and Drug Administration for this purpose. Both urinary and recombinant hCG preparations are available. There is no theoretical reason to use recombinant human LH, since it has a shorter half life (10 hours) than hCG and therefore would probably not be effective given three times a week.

LH, by the use of its substitute hCG, is always replaced before FSH for three reasons:


LH stimulates the Leydig cells to secrete testosterone, which results in an intratesticular testosterone concentration 100 times that in the peripheral circulation, a concentration essential to stimulate spermatogenesis. (See "Male reproductive physiology".)
hCG alone may be sufficient for stimulation of spermatogenesis [2]; FSH alone is not effective [8].
hCG treatment costs approximately $2500 a year; replacement of FSH (recombinant FSH or human menopausal gonadotropins (hMG)) costs $9000 to $18,000 a year (hMG) and even more for recombinant FSH.

After stopping testosterone therapy, hCG is administered according to the following regimen:


Patients are taught to self-administer the medication intramuscularly in the thigh at an initial dose of 2000 units three times a week (the recombinant preparation, which is dosed differently, is administered subcutaneously). (See "In vitro fertilization".)
The serum testosterone concentration is measured every one to two months and, if it is not between 400 and 900 ng/dL within three to four months, the dose is increased accordingly. Some patients require as little as 500 units per dose and others as much as 10,000 units. On rare occasions the serum testosterone concentration fails to respond to hCG, a problem thought to be due to antibodies to hCG [9,10].
The sperm count is measured every two to four weeks, but the value is not used to adjust the hCG dose. Most patients who eventually reach a normal sperm count (over 20 million/mL or 40 million/ejaculate) do so within six months, but some require 12 to 24 months [3]. The addition of hMG should be considered if the sperm count does not reach one-half normal by 12 to 24 months. The sperm produced by this regimen are qualitatively normal; thus, less than a normal number of sperm is usually sufficient to restore fertility (figure 1) [11].

Adverse effects of hCG therapy are few and generally similar to those of testosterone. (See "Testosterone treatment of male hypogonadism".) The frequency of gynecomastia, however, may be greater with hCG.

Use of hMG — hMG contains FSH and is the pharmaceutical preparation used to replace FSH in stimulating spermatogenesis in men who are infertile due to secondary hypogonadism. Recombinant human follicle stimulating hormone (rhFSH) is also available, but has been less well studied in men [12-14] and is more expensive. This effect of FSH is probably exerted via the Sertoli cells of the seminiferous tubules. FSH appears to be necessary for the initiation of spermatogenesis, but not for its maintenance or reinitiation. As mentioned above, only one of eight men with a prepubertal onset of secondary hypogonadism responded to hCG alone; five of the seven nonresponders showed an increase in sperm count to above 40 million per ejaculate when hMG was added [2]. The likelihood of a response was much less (one of seven men) when prepubertal hypogonadism was accompanied by cryptorchidism, presumably due to seminiferous tubular damage induced by the cryptorchidism (figure 2). (See "Clinical features and diagnosis of male hypogonadism".)

After stopping testosterone therapy, the following regimen is used to administer hMG:


The initial dose is 75 units (the contents of one vial) by intramuscular injection three times a week (although an hMG preparation is now available that can be given subcutaneously); it is most conveniently administered in the same syringe as hCG. Recombinant FSH preparations are also administered subcutaneously.
The sperm count is measured once every two to four weeks. The reason for such frequent measurement of the sperm count is that individual values fluctuate considerably, so that many samples are needed to detect a trend. The maximum count is usually achieved within three to 24 months.
The hMG dose can be increased to 150 units if the sperm count does not reach 20 million per ejaculate within six months. This will increase the serum FSH concentration from low-normal to high-normal, but it is less certain that it will increase the sperm count. As long as the sperm count is at least a few million, however, continuation of hCG and hMG administration is probably worthwhile, because even values this low can result in impregnation spontaneously [10] and is more than sufficient for assisted reproductive technologies.

The only undesirable feature of hMG administration is its cost: $9000/year for 75 units/dose and $18,000 for 150 units/dose. RhFSH is even more expensive.

hMG should be discontinued once pregnancy occurs because of its high cost. On the other hand, hCG (which is much less expensive) should be continued if the couple is considering another pregnancy. Monotherapy with hCG in this setting will usually keep the serum testosterone concentration in the normal range and maintain at least some degree of spermatogenesis. hMG can be added again if the sperm count is not near-normal when another pregnancy is considered. When the couple does not wish to have more children, virilization can be maintained by continuing HCG alone or by using testosterone. (See "Testosterone treatment of male hypogonadism".)

INDUCTION OF FERTILITY USING GNRH — Spermatogenesis can also be stimulated in men who have secondary hypogonadism by GnRH, as long as the hypogonadism is the result of hypothalamic disease. The rationale for this treatment is that replacement of GnRH in a physiologic manner, in pulses every two hours, will stimulate the gonadotroph cells of the pituitary to secrete LH and FSH, which in turn will stimulate the testes to produce testosterone and sperm. (See "Physiology of gonadotropin-releasing hormone" and "Male reproductive physiology".)

Use of GnRH — GnRH is administered in a pulsatile fashion by a pump and syringe that is programmed to deliver a bolus of GnRH every two hours and is connected to a subcutaneous needle. The apparatus is worn continuously until pregnancy occurs. The dose of GnRH initially is about 25 ng/kg body weight and is increased, as necessary, until the serum testosterone concentration is normal. Doses as high as 600 ng/kg body weight are necessary in some cases [15]. Sperm may appear in the ejaculate as soon as 12 months after the initiation of treatment but more often three years or more are required. (See "Congenital gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Pulsatile GnRH'.)

Virtually all patients treated with this regimen attain a normal serum testosterone concentration, and most develop some sperm in the ejaculate. In one study of 23 men with idiopathic hypogonadotropic hypogonadism, as an example, 20 showed an increase in sperm count from less than one million to a mean of 96 million sperm/mL of ejaculate [15]. The best predictors of a favorable response are a history of prior sexual maturation, absence of a history of cryptorchidism, and a serum inhibin B concentration >60 pg/mL [16]. Studies comparing gonadotropin to pulsatile GnRH treatment showed similar stimulation of spermatogenesis with both therapies [17,18]. GnRH is currently unavailable in the United States.

RECOMMENDATIONS — We recommend treatment with gonadotropins for most men who have secondary hypogonadism due to either hypothalamic or pituitary disease who wish to become fertile. Gonadotropin is more convenient to administer than GnRH and, if the onset of the hypogonadism was postpubertal, less expensive, because it is likely that only hCG will be necessary. We recommend treating initially with hCG alone and, if the sperm count is not normal within 6 to 12 months, adding hMG. If pregnancy has not occurred spontaneously after a year or more of combined treatment, an assisted reproductive technique, using the patient's semen, should be strongly considered.

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REFERENCES

Knuth, UA, Hönigl, W, Bals-Pratsch, M, et al. Treatment of severe oligospermia with human chorionic gonadotropin/human menopausal gonadotropin: a placebo-controlled, double blind trial. J Clin Endocrinol Metab 1987; 65:1081.

Finkel, DM, Phillips, JL, Snyder, PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med 1985; 313:651.

Burris, AS, Rodbard, HW, Winters, SJ, Sherins, RJ. Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 1988; 66:1144.

Büchter, D, Behre, HM, Kliesch, S, Nieschlag, E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol 1998; 139:298.

Miyagawa, Y, Tsujimura, A, Matsumiya, K, et al. Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: a 30-year retrospective study. J Urol 2005; 173:2072.

Ley, SB, Leonard, JM. Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. J Clin Endocrinol Metab 1985; 61:746.

Zorn, B, Pfeifer, M, Virant-Klun, I, Meden-Vrtovec, H. Intracytoplasmic sperm injection as a complement to gonadotrophin treatment in infertile men with hypogonadotrophic hypogonadism. Int J Androl 2005; 28:202.

Schaison, G, Young, J, Pholsena, M, et al. Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1993; 77:1545. Erratum in: J Clin Endocrinol Metab 1994.

Claustrat, B, David, L, Faure, A, Francois, R. Development of anti-human chorionic gonadotropin antibodies in patients with hypogonadotropic hypogonadism. A study of four patients. J Clin Endocrinol Metab 1983; 57:1041.

Thau, RB, Goldstein, M, Yamamoto, Y, et al. Failure of gonadotropin therapy secondary to chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab 1988; 66:862.

Burris, AS, Clark, RV, Vantman, DJ, Sherins, RJ. A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin therapy. Fertil Steril 1988; 50:343.

Liu, PY, Turner, L, Rushford, D, et al. Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men. Hum Reprod 1999; 14:1540.

Bouloux, P, Warne, DW, Loumaye, E, FSH Study Group in Men's Infertility. Efficacy and safety of recombinant human follicle-stimulating hormone in men with isolated hypogonadotropic hypogonadism. Fertil Steril 2002; 77:270.

Bouloux, PM, Nieschlag, E, Burger, HG, et al. Induction of spermatogenesis by recombinant follicle-stimulating hormone (puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone. J Androl 2003; 24:604.

Spratt, DI, Finkelstein, JS, O'Dea, LS, et al. Long-term administration of gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism. A model for studies of the hormone's physiologic effects. Ann Intern Med 1986; 105:848.

Pitteloud, N, Hayes, FJ, Dwyer, A, et al. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002; 87:4128.

Liu, L, Banks, SM, Barnes, KM, Sherins, RJ. Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1988; 67:1140.

Kliesch, S, Behre, HM, Nieschlag, E. High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men. Eur J Endocrinol 1994; 131:347.