Spermatogenesis Stimulation

The induction of spermatogenesis in patients with hypogonadotropic hypogonadism requires testicular stimulation with GnRH or gonadotropins. Various preparations are available (see Table 1) to reach this goal, each with advantages and disadvantages. Because the maturation of spermatogonia to mature sperm takes approx 70 d, the first sperm usually do not appear in the ejaculate for at least 3 mo, but it may take 2 yr for patients with congenital hypogonadotropic hypogonadism to become sperm positive. The huge variation in individuals can be explained by the diversity of hypogonadotropic hypogonadism and depends on whether spermatogenesis previously progressed to full maturation. There are several other factors that influence the success of stimulation therapy in patients with hypogonadotropic hypogonadism which are discussed later in this chapter.

Pulsatile GnRH Therapy

Pulsatile GnRH therapy can be used to stimulate spermatogenesis in men with GnRH deficiency and normal pituitary function (10), whereas continuous stimulation with GnRH is unsuccessful because it downregulates GnRH receptors and disrupts GnRH-R signal transduction, leading to a decrease in gonadotropin synthesis and secretion and gonadal suppression (11).

The pulsatile application of GnRH using a portable minipump most closely simulates normal physiology. The pump needle is usually placed in the subcutaneous tissue of the abdomen and is changed regularly (every 2 d). The pump is programmed to deliver a small bolus of GnRH every 120 min, because this frequency was most effective (12). A starting dose of 4 |g per pulse is often selected, with increases of 2 |g every 2 wk if LH secretion does not rise. Maximum doses are 20 |g per pulse. The dose of GnRH that is required to achieve testosterone levels in the normal adult male range and to stimulate spermatogenesis varies considerably in men with hypogo-nadotropic hypogonadism ranging from 5 to 20 ^g/120 min or 25-600 ng/kg per bolus. The therapeutic dose correlates positively with body weight and negatively with pretreatment testicular size (12). Serum testosterone levels usually normalize within 1-2 mo, and the testes increase in size within 3-6 mo after therapy begins. For adjustments, serum testosterone, gonadotropins, and testicular volume should be monitored closely at 2- to 4-wk intervals. Most patients should be treated for up to 2 yr to maximize testicular growth and achieve spermatogenesis, because it has been shown that the time until appearance of sperm in the ejaculate is quite variable, ranging from 2 to 22 mo of therapy (7).

GnRH is not an appropriate treatment for patients with pituitary disease and will be ineffective in men with CHH resulting from GnRH receptor mutations. These mutations produce a variable degree of resistance to GnRH. According to our experience, GnRH-R mutations are rare, and we found none in approx 50 patients diagnosed as IHH or Kallmann syndrome (data unpublished). However, a few cases have been described (13-15) (see Chapter 5). Because these cases are rare, PCR testing of the GnRH receptor gene sequence is recommended only if a patient fails to respond to pulsatile GnRH treatment. In our view, screening before beginning pulsatile GnRH treatment is not currently necessary. Gordon Holmes spinocerebellar ataxia and X-linked adrenohypoplasia congenita are two other forms of inherited HH in which responsiveness to GnRH is impaired (16). The formation of antibodies to GnRH or its receptor seldom occurs but can lead to a failure of pulsatile GnRH therapy (17,18). These patients should be treated with gonadotropins to induce spermatogenesis rather than with pulsatile GnRH.

Gonadotropin Therapy

Gonadotropin therapy is generally effective in achieving fertility in cases of pituitary insufficiency or GnRH resistance but is also an option for patients with hypothalamic disorders. Since the 1960s, hCG and human menopausal gonadotropin (hMG) that are purified from the urine of pregnant and menopausal women, respectively, have proven to be an effective treatment for spermatogenesis stimulation (5,7,19-21). hCG is used as the source of LH activity, because both hormones have structurally similar subunits and activate the same Leydig cell receptor. hMG has been used as the source of FSH, but it also contains LH activity. However, the LH activity is too low to maintain Leydig cell function, so a combination of hMG with hCG is required to achieve fertility (12). In the early 1980s, a purified preparation of urinary FSH (uFSH) and a highly purified preparation of urinary FSH (uFSH-HP), both from the urine of menopausal women, which are practically devoid of LH activity, were produced. uFSH-HP is prepared using specific anti- FSH monoclonal antibodies. Although in the original preparations of FSH the gonadotropin content represented less than 5% of the total protein, increased purity of more than 95% is achieved with uFSH-HP, with a 60-fold increase in specific activity (22). Recently, recombinant preparations of human FSH, hCG, and LH, which represent the purest gonadotropin preparations, have become available. These preparations are compared in detail in the following paragraphs.

Initiation of Gonadotropin Therapy With Human Chorionic Gonadotropin. Therapy is initiated by administration of hCG, which stimulates testicular testos terone production and the synthesis of other Leydig cell products that are required for spermatogenesis and testicular growth. With a dose of 1000-2500 IU twice per week (e.g., Monday and Friday), serum testosterone levels usually normalizes within 1-2 mo, otherwise, the dose is increased. Higher doses of hCG also increase plasma estradiol levels, however, and may cause gynecomastia. The development of anti-hCG antibodies is rare but may be considered if there is resistance to GnRH therapy (23). Both intramuscular and sc adminstration of hCG are effective. Intramuscular administration is often more painful and may require medical/paramedical assistance for injections. Compliance is greater when the sc route of administration is chosen, as this can be done by self-injection comparable to insulin injection in patients with diabetes.

In patients with adult-onset (acquired) hypogonadism or incomplete congenital gonadotropin deficiency, spermatogenesis may be induced with hCG alone (19,20,24), probably because of sufficient endogenous production of FSH. Responsiveness to hCG alone may be predicted by the presence of testes that exceed prepubertal size (4 mL and larger) before therapy is initiated (20).

In patients with congenital complete forms of hypogonadotropic hypogonadism the addition of an FSH-containing preparation is usually necessary to stimulate spermatogenesis, and, therefore, the induction phase with hCG alone is followed by coadministration of an FSH-containing preparation after 8-12 wk. This regimen is also advisable for patients with hypogonadotropic hypogonadism in whom spermatogenesis had been successfully induced with hCG alone, because the addition of an FSH-containing preparation to hCG increased testicular volume, sperm concentration, and pregnancy outcome (5,24).

Alternatives to hCG: Recombinant hCG (rhCG) or LH (rhLH). Recombinant preparations of hCG and LH might be advantageous over the existing products derived from urine because they have higher purity and consistency. However, there are no data so far available concerning the efficiency of rhLH or rhCG for stimulation of spermatogenesis in patients with hypogonadotropic hypogonadism. The administration of rhCG to older men with age-related androgen deficiency produced androgenic effects on hormones and muscle mass (25). In women undergoing in vitro fertilization, rhLH and rhCG were well tolerated and as effective as urinary hCG in inducing final follicular maturation and ovulation (26,27).

Treatment With hCG and Human Menopausal Gonadotropin. hMG is purified from the urine of menopausal women. The usual starting dose is 75 IU three times weekly (e.g., Monday, Wednesday, and Friday), intramuscularly or subcutaneously, in combination with 1000-2500 IU hCG twice weekly subcutaneously. To minimize the number of injections, hCG and hMG can be mixed in the same syringe. The treatment is generally well tolerated, but because hMG preparations contain LH activity in addition to FSH activity, increased Leydig cell stimulation may occur, leading to higher plasma levels of testosterone and increased conversion to estradiol, compared with treatment with hCG alone. As a result, patients may develop gynecomastia, which is usually reversible if the dose of hCG is reduced, but may be permanent. On average, sperm appear in the ejaculate after 5 mo of therapy, and maximum sperm counts are achieved after approx 2 yr (28). Sperm quality (motility and morphology) is usually normal during treatment with hCG/hMG. If azoospermia persists beyond 6 mo of combination treatment, the hMG dose can be increased to 150 IU three times a week, with the hCG dose remaining unchanged. Approximately 10% of patients fail to produce sperm in the ejaculate (7,28).

Therapy With hCG/Urinary or Highly Purified Urinary Human FSH. Urinary FSH, as well as the highly purified preparation, are effective alternatives to hMG for the initiation and maintenance of spermatogenesis in patients with hypogonadotropic hypogonadism. In comparison to hMG, uFSH-HP has enhanced specific activity (10,000 IU/mg of protein vs 150 IU/mg of protein for hMG) and negligible LH activity (<0.1 IU LH/1000 IU FSH). Administration of 75-150 IU uFSH or uFSH-HP three times weekly, in combination with 1000-2500 IU hCG twice weekly (both subcuta-neously), increases testicular size, and spermatogenesis is usually induced after 5-9 mo. These preparations are generally well tolerated, and no antibody to FSH has so far been detected during or after therapy (29-32).

hCG/Human Recombinant FSH Therapy. Human recombinant FSH (rhFSH) is prepared using DNA technology from Chinese Hamster Ovary (CHO) cells that are transfected with FSH subunit genes. The two preparations available contain different iso-forms, follitropin a (Gonal-F) and follitropin P (Follistim). Although there are minor differences between these isoforms, they are equivalent for clinical purposes (33). rhFSH has a high specific activity and contains no LH activity. It is well tolerated, and no serum antibodies to FSH or CHO proteins have yet been detected (34,35). A dose of 150 IU rhFSH three times weekly (e.g., Monday, Wednesday, and Friday) or 225 IU twice weekly in combination with 1000-2500 IU hCG twice weekly (both subcutaneously) was sufficient to induce testicular growth and spermatogenesis after 6-9 mo. This regimen was successful in inducing spermatogenesis in approx 90% of patients with hypogonadotropic hypogonadism. However, if azoospermia persists, the dose of rhFSH may be increased to a maximum dose of 300 IU three times a week (34-37). Testosterone levels usually show only a minor increase after rhFSH has been added to hCG. Likewise, estradiol and SHBG levels remain constant, whereas inhibin B levels increase to values typical of normozoospermic men (34).

Outlook: Long-Acting rhFSH. Because of the short half-life of currently available FSH preparations, multiple injections (usually three times weekly) are necessary to produce sufficient FSH concentrations for induction of spermatogenesis in patients with hypogonadotropic hypogonadism. FSH-CTP is a long-acting recombinant FSH-like substance produced by CHO-cells transfected with the genes of the alpha subunit of human FSH and a hybrid beta subunit. In a clinical study in patients with hypogo-nadotropic hypogonadism, the half-life of FSH-CTP was increased two to three times compared with rhFSH. A clear rise in serum inhibin B levels was observed, and no FSH antibodies were detected. Therefore, FSH-CTP might represent a new convenient FSH preparation for the treatment of male infertility resulting from hyogonadotropic hypogonadism in the future (38).

Impact of Baseline Testicular Volume

As a result of GnRH or gonadotropin therapy, testicular volume increases, with the final testicular size depending on the initial testicular size. The testicular volume at the beginning of therapy was also a good predictor for the length of treatment necessary until spermatogenesis is induced (7,34), i.e., length of treatment is inversely correlated with testicular volume. During therapy, testicular volume should be monitored carefully by ultrasonography, because an increase precedes the first appearance of sperm and the patient can be apprised of the potential for success of treatment (39). Patients with a testicular volume of less than 4 mL have been classified as completely gonadotropin deficient and respond less well to stimulation therapy than do those men with a testicular volume above 4 mL as a sign of partial gonadotropin deficiency (28,40). However, spermatogenesis can be induced even in patients with a testicular volume of less than 3 mL, but this may require treatment for 18-24 mo (7,28).

Impact of Maldescended Testes

Another predictive indicator of response to hCG/hMG or GnRH is a history of maldescended testes, because the patients often remain below the normal adult testicular volume during stimulation therapy and need extended therapy until spermatogenesis is induced. The average time of treatment for induction of spermatogenesis in patients with hypogonadotropic hypogonadism with bilateral maldescent was 13 mo compared with 4.5 mo in patients with hypogonadotropic hypogonadism with no history of maldescent (7). This difference can probably be explained by damage to testicular tissue resulting from maldescent, as judged by histological evaluation (21,41). Nevertheless, cryptorchidism does not preclude patients from gaining fertility, especially if it is unilateral (7).

Monitoring Testicular Volume and Laboratory Parameters

To optimize the potential for success, as well as to achieve sufficient androgen substitution and safe treatment with minimum side effects, regular examination of the testes and selected laboratory parameters is mandatory. Because the duration of treatment with GnRH or gonadotropins necessary to induce spermatogenesis is dependent on the initial testicular size, and as an increase in testicular volume may precede sperm appearance, testicular size should be monitored by palpation or ultrasonography every 3-6 mo. Furthermore, increased echodensity, indicative of increased tissue density, results from stimulated sperm production and is, therefore, a favorable sign. Testicular volume should also be monitored regularly if a pregnancy has occurred, and spermato-genesis should be maintained with hCG alone until delivery. If spermatogenesis can be maintained with hCG alone, testicular volume decreases only slightly (9) (see Fig. 2).

To avoid androgen deficiency symptoms, such as loss of libido and potency, anemia, and osteoporosis on the one hand and side effects resulting from elevated testosterone levels, such as polycythemia on the other hand, serum testosterone levels should be checked at frequent intervals at the beginning of therapy until the correct treatment dose is identified. Subsequently, 6-12 mo for monitoring testosterone levels is usually sufficient. Serum estradiol levels should be checked at the same intervals, because elevated levels increase the risk of gynecomastia. Furthermore, hemoglobin and hematocrit should be monitored, because these parameters are dependent on testosterone levels.

Impact of Sexual Development

Patients with acquired forms of hypogonadotropic hypogonadism usually respond better to treatment than do those with congenital forms of hypogonadotropic hypogo-nadism. However, the time of onset (prepubertal vs. postpubertal) and the degree of gonadotropin deficiency (complete vs. partial) are important predictive factors. Patients with postpubertal hypogonadotropic hypogonadism have undergone spontaneous puberty with functioning tubules and spermatogenesis, and they may retain some

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Testosterone And Prenatal Development

Fig. 3. Development of sperm production in patients with secondary hypogonadism during treatment with gonadotropin-releasing hormone (GnRH) or human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) until induction of pregnancy. (Data from ref. 117.)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 duration of treatment (months)

Fig. 3. Development of sperm production in patients with secondary hypogonadism during treatment with gonadotropin-releasing hormone (GnRH) or human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) until induction of pregnancy. (Data from ref. 117.)

gonadotropin secretion, which is able to partially maintain seminiferous tubular function (19,31,32). Likewise, patients with partial congenital gonadotropin deficiency may have residual gonadotropin secretion. However, in patients with prepubertal onset of hypogonadotropic hypogonadism the degree of sexual development, as mirrored by gonadal size, may range from complete absence of sexual maturation to partial puberty. Familial cases most often have no pubertal development (95%) and a high prevalence of cryptorchidism (71%). Those men who are most severely affected are familial cases with X-linked Kallmann syndrome (42).

Fertility is restored in most patients with hypogonadotropic hypogonadism during gonadotropin or pulsatile GnRH treatment, with pregnancy rates varying between 50 and 90%. Surprisingly, these pregnancies occur with sperm concentrations as low as 1-5 million/mL (7,24,28) (see Fig. 3), which is well below the normal range (>20 million/mL). Cryptorchidism or markedly subnormal testicular volume, which predict a poorer response to treatment, do not represent absolute contraindications to therapy.

Because the sperm concentration usually remains below the normal range, evaluation, and optimization of the female partner's reproductive functions is indispensable, because the fecundity of a couple is dependent on both male and female reproductive function (43). An evaluation of the female cycle quality should be performed, and if pregnancy is not achieved after 6 mo, tubal function should be checked. Furthermore, hormonal disturbances such as polycystic ovary syndrome (PCOs), endometriosis, and other gynecological or systemic diseases can lead to female infertility (44). It is also well-known that the time span within which a couple will conceive ("time to preg-

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Responses

  • sonja
    What happened if your serum b hcg decreases?
    5 years ago
  • michael green
    Can you stimulate spermatogenesis?
    5 years ago
  • Jennifer Cribbs
    What can be done to stimulate spermogenesis?
    5 years ago
  • Daphne
    What effect do normal levels of testosterone have on spermatogenesis?
    5 years ago
  • genoveffa
    Do normal levels of testosterone stimulate or reduce spermatogenesis?
    4 years ago
  • bernice
    What affect does testosterone have on spermatogenesis?
    4 years ago
  • murray
    How to induce leydig cell production after long testosterone therapy?
    4 years ago
  • sean
    How can induction zinc deficiency practicaly on spermatogenesis?
    4 years ago
  • KATRIN PROPST
    What does testosterone depend on for spermatogenesis?
    2 years ago
  • Cailin Young
    What can be done to stimulate spermatogenesis after irradiation use?
    2 years ago
  • Jo
    How spermatogenis can be stimulated?
    12 months ago
  • hiwet
    Is there anything a doctor can to to stimulate spermatogenesis?
    10 months ago
  • Caoimhe
    How to induce spermatogenesis?
    10 months ago
  • frediana
    Is there anything doctors can do to stimulate spermatogenesis?
    9 months ago
  • mattiesko
    What happened to the stages of spermatogenesis if testosterone is sufficient?
    3 months ago
  • coby
    Do normal levels of testosterone stimulate or inhibit spermatogenesis?
    3 months ago
  • kerstin
    Does an increase in testosterone (to normal levels) stimulate or inhibit sperm production?
    3 months ago

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