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Induction of fertility in men with secondary hypogonadism
Author
Peter J Snyder, MD
Section Editor
Alvin M Matsumoto, MD
Deputy Editor
Kathryn A Martin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2015. | This topic last updated: Jan 13, 2014.
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".)
GONADOTROPIN THERAPY — 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. We recommend treatment with gonadotropins for most men who have secondary hypogonadism due to either hypothalamic or pituitary disease who wish to become fertile. (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 human chorionic gonadotropin (hCG) (see 'Use of human chorionic gonadotropin' below). 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 testes that are not as small [3-6], and serum concentrations of FSH, inhibin B, and testosterone that are not as low [7].
●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 [2,8]. 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 human menopausal gonadotropins (hMG; a preparation containing LH and FSH) [2]. (See 'Use of human menopausal gonadotropin (hMG)' below.)
●Prior treatment with testosterone or with gonadotropins. Many patients have been described in which gonadotropin stimulation led to spermatogenesis even though they had received prior treatment with testosterone. However, in one study, prior testosterone treatment independently predicted a slower spermatogenic response to gonadotropin treatment than no prior treatment [6]. Prior gonadotropin treatment, in contrast, predicted a faster response.
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 by insemination with the patient's semen (intrauterine insemination, IUI) or with the help of an assisted reproductive technique such as in vitro fertilization with or without intracytoplasmic sperm injection (ICSI) [9]. (See "In vitro fertilization" and "Intracytoplasmic sperm injection".)
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. Both purified 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 hormone, hCG, is always replaced before FSH for three reasons:
●hCG 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 [10].
●hCG preparations are considerably less expensive than exogenous FSH preparations, in particular, recombinant FSH.
After stopping testosterone therapy, hCG is administered according to the following regimen:
●Patients are taught to self-administer hCG. Urinary hCG is given intramuscularly in the thigh at an initial dose of 2000 units three times a week. Although the package insert recommends intramuscular administration, some clinicians use the subcutaneous route. The recombinant preparation is administered subcutaneously.
●The serum testosterone concentration is measured every one to two months and, if it is not between 400 and 800 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 [11,12]. Men with a history of cryptorchidism may also have a poor response.
●The sperm count is measured every one to three months once the serum testosterone concentration is 400 to 800 ng/dL, but the value is not used to adjust the hCG dose. Most patients who eventually reach a normal sperm count (over 15 million/mL or 40 million/ejaculate) do so within six months, but some require 12 to 24 months [3]. An increase in testicular volume is usually associated with an increase in sperm count. If the sperm count does not reach one-half normal by 12 to 24 months, FSH should be added, as described in the following section. Some patients are reluctant to wait this long, however, so if the sperm count is still <5 million/mL after six months of hCG alone, it is reasonable to consider adding hMG (a preparation that contains both LH and FSH) then. 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) [13].
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 human menopausal gonadotropin (hMG) — hMG contains purified extracts of FSH and LH and is the pharmaceutical preparation usually used to replace FSH in stimulating spermatogenesis in men who are infertile due to secondary hypogonadism. 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".)
Once the serum testosterone concentration has been maintained within the normal range for several months yet the sperm count has not reached at least half-normal, the following regimen is used to add hMG:
●The initial dose is 75 units (the contents of one vial) three times a week (an hMG preparation is now available that can be given subcutaneously); it is most conveniently administered in the same syringe as hCG.
●The sperm count is measured once every one to three months. 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 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 [12]. The time to achieve the first sperm in the ejaculate and the maximum amount varies considerably from patient to patient, partly due to the degree of hypogonadism, history of cryptorchidism, and prior testosterone or gonadotropin treatment, as described above. In a study of 75 men with hypogonadotropic hypogonadism treated with hCG and then hMG, the median time to achieve first sperm was 7.1 months (95% CI 6.3-10.1) [6]. The average time for conception in the 38 men who became fathers was 28.2 months (95% CI 21.6-38.5).
●If pregnancy does not occur spontaneously within 6 to 12 months of achieving any sperm in the ejaculate, assisted reproductive techniques should be recommended. (See "In vitro fertilization" and "Intracytoplasmic sperm injection".)
●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. hCG administration alone 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. Cryopreservation of sperm can be offered, especially if the sperm count is normal, for possible future attempts to achieve pregnancy. 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".)
Recombinant human FSH (r-hFSH) — R-hFSH was developed for use in ovulation induction to avoid the small amount of LH present in hMG preparations. Although there is no advantage for such purity of FSH in stimulation of spermatogenesis, r-hFSH has been tested in men with hypogonadotropic hypogonadism and is commercially available. One report describes 100 men with severe hypogonadotropic hypogonadism, as indicated by azoospermia in all and baseline serum testosterone concentrations <100 ng/dL and testicular volume <7 mL in most of them, but no history of cryptorchidism. Administration of the r-hFSH, in doses from 150 to 300 units subcutaneously every other day for 18 months increased the sperm density to >1.5 million/mL in 46.2 to 88.9 percent of them [14].
R-hFSH and urinary hMG (contains both LH and FSH) preparations have not been compared directly, but their efficacy when added to hCG in stimulating spermatogenesis in men with hypogonadotropic hypogonadism seems similar. Because the improved purity of r-hFSH is not necessary in men, the increased cost of r-hFSH (almost double that of urinary FSH products) does not seem warranted.
PULSATILE 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 'Induction of spermatogenesis in men'.)
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.
CLOMIPHENE CITRATE — Clomiphene citrate is a weak estrogen receptor antagonist that stimulates gonadotropin secretion in normal women and men. Many reports describe the use of clomiphene to attempt to increase sperm density in men with oligospermia or azoospermia and normal to mildly low serum testosterone concentrations with variable results, but few reports describe the use of clomiphene in men who have unequivocal secondary hypogonadism. One report, however, described three men with idiopathic hypogonadotropic hypogonadism, including markedly low serum testosterone concentrations and azoospermia or severe oligospermia, who demonstrated increases in testosterone and sperm density to normal or near-normal following administration of clomiphene [19]. Clomiphene has not been reported to improve sperm density in men who have secondary hypogonadism due to damage to the pituitary, nor would it be expected to. Clomiphene citrate is ineffective in treating idiopathic infertility in men. (See "Treatment of male infertility".)
SUMMARY AND 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 (Grade 1B). (See 'Which patients are likely to respond?' above.) We suggest not using clomiphene citrate in these patients (Grade 2C).
●Gonadotropins are more convenient to administer than pulsatile GnRH and GnRH is not widely available. In the United States, it is available only on an experimental basis.
●Patients should be treated initially with hCG alone to increase serum and intratesticular testosterone concentrations. If the sperm count is not normal within 12 to 24 months, an FSH preparation should be added (hMG or another FSH preparation), although adding FSH as early as six months is reasonable if the patient does not wish to wait longer. (See 'Use of human chorionic gonadotropin' above.)
●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
1Knuth 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.
2Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med 1985; 313:651.
3Burris 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.
4Büchter 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.
5Miyagawa 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.
6Liu PY, Baker HW, Jayadev V, et al. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab 2009; 94:801.
7McLachlan RI, Finkel DM, Bremner WJ, Snyder PJ. Serum inhibin concentrations before and during gonadotropin treatment in men with hypogonadotropic hypogonadism: physiological and clinical implications. J Clin Endocrinol Metab 1990; 70:1414.
8Ley 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.
9Zorn 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.
10Schaison 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.
11Claustrat 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.
12Thau RB, Goldstein M, Yamamoto Y, et al. Failure of gonadotropin therapy secondary to chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab 1988; 66:862.
13Burris 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.
14Warne DW, Decosterd G, Okada H, et al. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril 2009; 92:594.
15Spratt 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.
16Pitteloud 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.
17Liu 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.
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Disclosures
Disclosures: Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Testosterone (Testosterone gel)]; Novartis [Cushing's syndrome, acromegaly (Pasireotide, octreotide)]; Cortendo [Cushing's syndrome (COR203)]; Novo Nordisk [Growth hormone (Growth hormone)]; Ipsen [Acromegaly (Lanreotide)]. Consultant/Advisory Boards: Novartis [Cushing's syndrome (Pasireotide)]; Novo Nordisk [Growth hormone (Growth hormone)]; Pfizer [Acromegaly (Pegvisomant)]. Alvin M Matsumoto, MD Grant/Research/Clinical Trial Support: AbbVie (testosterone [AndroGel]); GSK (BPH [Dutasteride]). Consultant/Advisory Boards: Endo Pharmaceuticals (testosterone [Delatestryl, Fortesta, AVEED]); AbbVie (testosterone [AndroGel]) Lilly (testosterone [Axiron]); Clarus (testosterone [Rextoro]). Kathryn A Martin, MD Employee of UpToDate, Inc.
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I dunno man. With the whole thing now posted, what I read is LH+FSH (HMG) is the most effective way. Rather than just LH alone. (HCG). It does however give HCG more credit as a cure on it's own. My experience and others I have read about that is not the case. If I am trying to get my girl pregnant, I'd get on HMG and get LH and FSH going right away to save trial and error and wasted time.
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