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Male Hypogonadotropic Hypogonadism: Factors Influencing Response to Human Chorionic Gonadotropin and Human Menopausal Gonadotropin, Including Prior Exogenous Androgens* (1985)
ABSTRACT
Although testosterone (T) therapy is sufficient for maturation and maintenance of secondary sex characteristics in hypogonadal men, gonadotropins are required for stimulation of spermatogenesis. Thirteen men with hypogonadotropic hypogonadism received treatment with hCG, followed in 12 by the addition of human menopausal gonadotropin (hMG). All initially had undetectable serum LH and FSH and low T levels and were azoospermic with small testes. During therapy, all achieved normal male levels of T. Twelve of 13 had marked and continuous increase in testicular volume. Three men had sperm in the ejaculate with hCG treatment alone. All but 1 patient developed sperm in their seminal fluid during combined hCG and hMG therapy. Two men achieved three pregnancies, and 2 more had semen that produced hamster oocyte penetration assays in the fertile range during the protocol period. Four of 5 who achieved sperm densities greater than 1 million/ml while receiving combined therapy maintained or increased sperm production while receiving continued hCG therapy after hMG was withdrawn
We examined the response to gonadotropin therapy of men who had received previous T therapy and those who had not. There were no differences in rapidity or degree of response, as assessed by rising in serum T, increase in testis volume, or maximal sperm density achieved. Multiple pituitary deficits and cryptorchidism were negative prognostic factors.
In summary, the prognosis for successful stimulation of spermatogenesis in men with hypogonadotropic hypogonadism treated with hCG/hMG is good and not adversely affected by prior androgen treatment. Despite undetectable serum FSH levels, hCG treatment was sufficient to both initiate and maintain spermatogenesis in some patients. (J Clin Endocrinol Metab 6 1 : 746,1985)
Treatment of hypogonadotropic hypogonadism in men is directed at two goals. The first is the restoration of a normal androgen milieu, allowing successful virilization. The second is the induction of fertility. Adult serum testosterone (T) levels may be achieved by either exogenously administered T or stimulation of endogenous T production with hCG. The long-acting T-esters have several advantages in this regard. Firstly, they are significantly less expensive than an equally effective dose of hCG. Secondly, normal virilization and potency can be maintained with biweekly or less frequent injections of T enanthate or T cypionate, whereas hCG is usually administered two or three times a week.
When fertility is desired, however, testicular stimulation with gonadotropins is necessary, and exogenous T is no longer sufficient. Several investigators have treated men with hypogonadotropic hypogonadism with gonadotropins (1-6) and LHRH (7-9). We had the opportunity to study a group of hypogonadotropic men prospectively with a standard protocol. This allowed us to assess not only the likelihood of response but also the importance of several factors that may have prognostic significance.
*Cost and convenience factors favor the T-esters, and they are the preferred mode of therapy in hypogonadotropic men until fertility becomes a goal. The major use for either hCG/hMG or pulsatile LHRH is the induction of fertility. Although both therapies are effective, their relative efficacies have not been directly compared. A recent report suggests that response rates are similar (9). LHRH treatment requires that patients wear an infusion pump throughout the day. Because hCG/hMG therapy requires only three or fewer injections a week, gonadotropin therapy is likely to be preferred by many patients. As it is probable that even lower doses of hCG (28, 29) and hMG (6) may be effective, further studies designed to optimize dose and injection schedules may further increase this advantage.
In summary, hypogonadotropic men can be treated effectively and safely with T-esters until they desire fertility. We then recommend hCG alone; an early response to this medication probably has prognostic value. From our results and those of others, it seems prudent to treat with hCG alone for 1 yr, or until the testicular volume reaches a plateau. Then hMG should be added. Cryptorchidism and prepubertally acquired multiple pituitary defects were negative prognostic factors, whereas patients with gonadotropin deficiency acquired postpubertally responded quickly and dramatically. Androgen pretreatment did not have a negative effect on the outcome. As long as testicular volume continues to increase, therapy should be continued. In some patients, induction of fertility may occur in a matter of months. In others, increased sperm counts may not be obtained for 1-2 yr or longer.
ABSTRACT
Although testosterone (T) therapy is sufficient for maturation and maintenance of secondary sex characteristics in hypogonadal men, gonadotropins are required for stimulation of spermatogenesis. Thirteen men with hypogonadotropic hypogonadism received treatment with hCG, followed in 12 by the addition of human menopausal gonadotropin (hMG). All initially had undetectable serum LH and FSH and low T levels and were azoospermic with small testes. During therapy, all achieved normal male levels of T. Twelve of 13 had marked and continuous increase in testicular volume. Three men had sperm in the ejaculate with hCG treatment alone. All but 1 patient developed sperm in their seminal fluid during combined hCG and hMG therapy. Two men achieved three pregnancies, and 2 more had semen that produced hamster oocyte penetration assays in the fertile range during the protocol period. Four of 5 who achieved sperm densities greater than 1 million/ml while receiving combined therapy maintained or increased sperm production while receiving continued hCG therapy after hMG was withdrawn
We examined the response to gonadotropin therapy of men who had received previous T therapy and those who had not. There were no differences in rapidity or degree of response, as assessed by rising in serum T, increase in testis volume, or maximal sperm density achieved. Multiple pituitary deficits and cryptorchidism were negative prognostic factors.
In summary, the prognosis for successful stimulation of spermatogenesis in men with hypogonadotropic hypogonadism treated with hCG/hMG is good and not adversely affected by prior androgen treatment. Despite undetectable serum FSH levels, hCG treatment was sufficient to both initiate and maintain spermatogenesis in some patients. (J Clin Endocrinol Metab 6 1 : 746,1985)
Treatment of hypogonadotropic hypogonadism in men is directed at two goals. The first is the restoration of a normal androgen milieu, allowing successful virilization. The second is the induction of fertility. Adult serum testosterone (T) levels may be achieved by either exogenously administered T or stimulation of endogenous T production with hCG. The long-acting T-esters have several advantages in this regard. Firstly, they are significantly less expensive than an equally effective dose of hCG. Secondly, normal virilization and potency can be maintained with biweekly or less frequent injections of T enanthate or T cypionate, whereas hCG is usually administered two or three times a week.
When fertility is desired, however, testicular stimulation with gonadotropins is necessary, and exogenous T is no longer sufficient. Several investigators have treated men with hypogonadotropic hypogonadism with gonadotropins (1-6) and LHRH (7-9). We had the opportunity to study a group of hypogonadotropic men prospectively with a standard protocol. This allowed us to assess not only the likelihood of response but also the importance of several factors that may have prognostic significance.
*Cost and convenience factors favor the T-esters, and they are the preferred mode of therapy in hypogonadotropic men until fertility becomes a goal. The major use for either hCG/hMG or pulsatile LHRH is the induction of fertility. Although both therapies are effective, their relative efficacies have not been directly compared. A recent report suggests that response rates are similar (9). LHRH treatment requires that patients wear an infusion pump throughout the day. Because hCG/hMG therapy requires only three or fewer injections a week, gonadotropin therapy is likely to be preferred by many patients. As it is probable that even lower doses of hCG (28, 29) and hMG (6) may be effective, further studies designed to optimize dose and injection schedules may further increase this advantage.
In summary, hypogonadotropic men can be treated effectively and safely with T-esters until they desire fertility. We then recommend hCG alone; an early response to this medication probably has prognostic value. From our results and those of others, it seems prudent to treat with hCG alone for 1 yr, or until the testicular volume reaches a plateau. Then hMG should be added. Cryptorchidism and prepubertally acquired multiple pituitary defects were negative prognostic factors, whereas patients with gonadotropin deficiency acquired postpubertally responded quickly and dramatically. Androgen pretreatment did not have a negative effect on the outcome. As long as testicular volume continues to increase, therapy should be continued. In some patients, induction of fertility may occur in a matter of months. In others, increased sperm counts may not be obtained for 1-2 yr or longer.
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