Induction of fertility in males with secondary hypogonadism

INTRODUCTION — Sperm production cannot be stimulated in males 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 achieve or restore fertility in males who are infertile as a result of secondary hypogonadism, ie, due to disorders of the pituitary or hypothalamus. Males who have pituitary disease can be treated with gonadotropins, while those with hypothalamic disease can be treated with gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH). (See "Causes of secondary hypogonadism in males".)

PRETREATMENT EVALUATION

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 males desiring fertility 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 males who have idiopathic oligospermia, in which a subnormal sperm count is associated with a normal serum testosterone concentration [1]. (See "Approach to the male with infertility", section on 'Sperm concentration <5 million/mL'.)

Several factors enhance the likelihood that the sperm count will increase after gonadotropin administration:

●Development of hypogonadism after puberty rather than before. In one study, as an example, all six males whose hypogonadism occurred postpubertally experienced an increase in total sperm count from less than 1 million to above 40 million per ejaculate when treated with human chorionic gonadotropin (hCG) (see 'Initial treatment: hCG' below). In comparison, only one of eight males 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 follicle-stimulating hormone (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 [2,8,9]. In one report, as an example, only one of the seven males 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 used for its FSH but also containing luteinizing hormone [LH]) [2].

●In one report, the time to achieve spermatogenesis with gonadotropin therapy was longer in patients who had previously been treated with testosterone [6]. However, a subsequent meta-analysis did not show an effect of prior testosterone treatment [10].

Gonadotropin treatment of males 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 assisted reproductive technology (ART), such as in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) [11]. (See "In vitro fertilization: Overview of clinical issues and questions" and "Intracytoplasmic sperm injection".)

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 (algorithm 1). Testosterone replacement will not restore spermatogenesis.

Initial treatment: hCG — 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 males who have secondary hypogonadism and desire to become fertile.

LH, by the use of its substitute hormone hCG, is always replaced before FSH for three reasons (algorithm 1):

●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 [12].

●hCG preparations are considerably less expensive than exogenous FSH preparations, in particular, recombinant FSH.

Both recombinant hCG and recombinant LH preparations are available, but we do not recommend either. 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. Recombinant hCG is used as an ovulatory trigger for ovulation induction but has no advantage for stimulation of spermatogenesis.

Dosing and regimen — After stopping testosterone therapy, hCG is administered according to the following regimen (algorithm 1):

●Patients are taught to self-administer hCG. We use hCG given intramuscularly or subcutaneously in the thigh at an initial dose of 2000 units three times a week, always on the same three days (eg, Mondays, Wednesdays, and Fridays). The vial of hCG contains 5000 or 10,000 units of hCG powder; dissolving the powder with 2.5 mL or 5 mL yields 2000 units/mL. The patient is instructed to inject 1 mL. Although urinary hCG is not approved for subcutaneous administration by the US Food and Drug Administration (FDA), many clinicians prefer this route because it is easier and better tolerated by patients [13].

●Adverse effects of hCG therapy are few and generally similar to those of testosterone. (See "Testosterone treatment of male hypogonadism".)

Monitoring — The serum testosterone concentration is measured every one to two months and, if it is not between 400 and 800 ng/dL (13.87 to 27.7 nmol/L) within two to three months, the dose is increased by using lower volumes of diluent (algorithm 1). Some patients require as much as 10,000 units per dose. On rare occasions, the serum testosterone concentration fails to respond to hCG, even to 10,000 units three times a week. This problem is thought to be due to antibodies to hCG [14,15]. Males with a history of cryptorchidism also often have a poor response. Gonadotropin therapy will therefore not be successful in these patients, and they may wish to consider in vitro fertilization (IVF) with donor semen or adoption. (See "In vitro fertilization: Overview of clinical issues and questions".)

Less often, the serum testosterone will be higher than normal in response to the initial dose of 2000 units three times a week, so the dose is decreased by dissolving the powder in larger volumes of diluent.

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 (algorithm 1). An increase in testicular volume is usually associated with an increase in sperm count.

Adding FSH

●Human menopausal gonadotropins (hMG) – If the sperm count has not reached 5 to 10 million/mL and/or pregnancy has not occurred six months after serum testosterone is 400 to 800 ng/dL (13.87 to 27.7 nmol/L), we add hMG (a preparation used for its FSH but also contains LH) (algorithm 1). Although most patients have a sperm count in the 5 to 10 million/mL range by six months, others require 12 to 24 months (if only hCG is used) [3]. As mentioned above, males with a prepubertal onset of hypogonadism are unlikely to respond to hCG alone, particularly if the hypogonadism is accompanied by cryptorchidism [2]. (See 'Which patients are likely to respond?' above.)

hMG contains purified extracts of FSH and LH and is the pharmaceutical preparation we recommend replacing FSH in stimulating spermatogenesis in males who are infertile due to secondary hypogonadism whose sperm counts have not responded to hCG alone. The effect of FSH is exerted via the Sertoli cells of the seminiferous tubules. FSH is necessary for the initiation of spermatogenesis, but not for its maintenance or reinitiation [2].

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 (algorithm 1):

The initial dose is 75 units (the contents of one vial) three times a week; it is most conveniently administered subcutaneously (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 5 to 10 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 [15]. 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.

●Recombinant human follicle-stimulating hormone (rhFSH) – rhFSH 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, rhFSH has been tested in males with hypogonadotropic hypogonadism and is commercially available. One report describes 100 males 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. Following hCG pretreatment for three to six months, the addition of rhFSH to hCG (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 [16].

rhFSH has not been compared directly with hMG in men, but its efficacy when added to hCG in stimulating spermatogenesis in males with hypogonadotropic hypogonadism seems similar [10]. Because the improved purity of rhFSH is not necessary in men, the increased cost of rhFSH (almost double that of hMG) does not seem warranted.

●Corifollitropin alfa is a recombinant gonadotropin of the common glycoprotein alpha subunit and a beta subunit that is a hybrid of the beta subunit of human FSH and the carboxy terminus of the beta subunit of hCG that is approved for ovulation induction in some countries. In a trial in 18 males with hypogonadotropic who remained azoospermic after treatment with hCG alone, treatment with combined hCG and corifollitropin alfa for one year increased the sperm count to ≥1 x 10⁶/mL in 14 males and to a mean sperm count of 5.2 x 10⁶/mL [17].

Clinical outcomes

Sperm concentration — The sperm produced by an hCG and FSH regimen are qualitatively normal; thus, less than a normal number of sperm is usually sufficient to restore fertility (figure 1) [18].

Timing of response — Males treated with both hCG and hMG achieve sperm in approximately 6 to 10 months, but the time to pregnancy is longer. In one study of 75 males 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 males who became fathers was 28.2 months (95% CI 21.6-38.5). In a second series, the only significant predictor of success (achieving pregnancy) was testicular size [19].

Pregnancy not achieved — If pregnancy does not occur spontaneously within 12 to 24 months of achieving any sperm in the ejaculate, we suggest assisted reproductive technologies (ART), such as intrauterine insemination (IUI), IVF, and, as a last resort, intracytoplasmic sperm injection (ICSI) (algorithm 1) [20]. (See "In vitro fertilization: Overview of clinical issues and questions" and "Intracytoplasmic sperm injection".)

Pregnancy achieved — hMG should be discontinued at the end of the first trimester 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 (algorithm 1). 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 (algorithm 1). (See "Testosterone treatment of male hypogonadism".)

ROLE OF PULSATILE GnRH — Spermatogenesis can also be stimulated in males who have secondary hypogonadism by gonadotropin-releasing hormone (GnRH) if the hypogonadism is the result of hypothalamic and not pituitary disease. Some studies comparing gonadotropin with pulsatile GnRH treatment showed similar stimulation of spermatogenesis with both therapies [21,22], but a more recent study demonstrated that pulsatile GnRH increased sperm production to a greater degree and more rapidly [23].

This therapy is limited by the need for a subcutaneous infusion pump, as well as its cost and limited availability. GnRH is currently unavailable in the United States but is used in some specialized centers in other countries.

The rationale for pulsatile GnRH 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".)

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 approximately 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 [24]. 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 "Isolated 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 males 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 [24]. 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 [25].

CLOMIPHENE CITRATE — Clomiphene citrate has been used off-label to attempt to increase sperm density in males with oligospermia or azoospermia and normal to mildly-low serum testosterone concentrations.

Clomiphene is a weak estrogen receptor antagonist that stimulates gonadotropin secretion in females and males with normal pituitary function. Clomiphene studies have had variable results, but a few reports describe the use of clomiphene in males who have unequivocal secondary hypogonadism due to hypothalamic disease. One report described three males 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 [26].

Clomiphene has not been reported to improve sperm density in males 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 males. (See "Treatments for male infertility".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Male infertility or hypogonadism".)

SUMMARY AND RECOMMENDATIONS

●Candidates – The diagnosis of secondary hypogonadism must be firmly established before considering induction of spermatogenesis therapy. We recommend treatment with gonadotropins for most males desiring fertility who have secondary hypogonadism due to either hypothalamic or pituitary disease who wish to become fertile. (See 'Pretreatment evaluation' above.)

●Gonadotropin therapy – For males with secondary hypogonadism due to hypothalamic or pituitary disease who are seeking fertility, we recommend gonadotropin therapy (Grade 1B). Pulsatile gonadotropin-releasing hormone (GnRH) has similar efficacy but is not widely available (see 'Gonadotropin therapy' above and 'Role of pulsatile GnRH' above). We do not use clomiphene citrate in these patients. (See 'Clomiphene citrate' above.)

•Initial therapy with hCG – Induction of spermatogenesis human chorionic gonadotropin (hCG) is used to replace luteinizing hormone (LH). 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. For some patients, hCG alone is sufficient for stimulation of spermatogenesis.

•Addition of FSH – If hCG administration alone does not increase the sperm count to at least 5 to 10 million/mL and/or if pregnancy has not occurred six months after serum testosterone is 400 to 800 ng/dL (13.87 to 27.7 nmol/L), we add human menopausal gonadotropin (hMG), a preparation that contains follicle-stimulating hormone (FSH) (algorithm 1). Although most patients have a sperm count that is at least 5 to 10 million/mL by six months, males with small testes at baseline may require 12 to 24 months. (See 'Adding FSH' above.)

•Assisted reproductive technology – If sperm have appeared in the ejaculate but pregnancy has not occurred spontaneously after 12 to 24 months of combined treatment, we suggest assisted reproductive technology (ART) using the patient's semen (algorithm 1). (See 'Pregnancy not achieved' above.)

●Subsequent management – Management once pregnancy has been achieved depends upon whether the couple is planning another pregnancy in the near future (algorithm 1). (See 'Pregnancy achieved' above.)