Pulsatile Gnrh Or Human Chorionic Gonadotropin/Human Menopausal Gonadotropin As Effective Treatment for Men with Hypogonadotropic Hypogonadism: a Review of 42 Cases

European Journal of Endocrinology (1998) 139 298–303 ISSN 0804-4643

Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases

Dorothee Bu¨chter, Hermann M Behre, Sabine Kliesch and Eberhard Nieschlag Institute of Reproductive Medicine of the University, D-48149 Mu¨nster, Germany (Correspondence should be addressed to E Nieschlag, Institute of Reproductive Medicine of the University, Domagkstrasse 11, D-48149 Mu¨nster, Germany)

Abstract Stimulatory therapy with either GnRH or gonadotropins is an effective treatment to induce spermatogenesis and achieve paternity in men with secondary hypogonadism. However, there is still uncertainty about the optimal treatment modality and schedule, the duration of treatment necessary and the influence of interfering factors such as maldescended testes. We have extended our previous series of men treated for secondary hypogonadism and now present our therapeutic experience with 42 cases. Twenty-one patients with hypothalamic disorders (11 with idiopathic hypogonadotropic hypogonadism (IHH) and 10 with Kallmann syndrome (KalS)) were treated with GnRH (group Ia) or human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) (group Ib), and 21 patients with hypopituitarism (group II) were treated with hCG/hMG. A total of 57 treatment courses were initiated for induction of spermatogenesis, 36 of these for the purpose of induction of pregnancy in the female partner. Bilateral testicular volumes doubled within 5–12 months of therapy. Sperma- togenesis as evidenced by the appearance of sperm in the ejaculate was induced in 54/57 courses. Pregnancies occurred in 26/36 courses. Unilaterally maldescended testes did not preclude patients with IHH or KalS from gaining fertility under therapy and spermatogenesis could be successfully initiated even in some individuals with bilateral maldescended testes. In general there was a tendency for a longer duration of therapy until induction of spermatogenesis in patients with a history of bilateral cryptorchidism. However, this did not reach statistical significance. In patients with IHH or KalS treated with either hCG/hMG or GnRH there were no statistically significant differences in terms of duration to appearance of sperm or pregnancy rates. Even in KalS patients as old as 43 years spermatogenesis could be induced. In repeatedly treated patients stimulation of spermatogenesis tended to be faster while time until induction of pregnancy was significantly shorter in the second treatment course. In conclusion, GnRH or hCG/hMG are effective therapeutic modalities for patients with IHH or KalS. It remains to be determined whether highly purified urinary gonadotropin preparations or recombinant LH and FSH will provide therapeutic advantages.

European Journal of Endocrinology 139 298–303

Introduction found it timely to summarize our experience with the conventional treatment in order to provide a basis of It is well known that in men with secondary hypogo- standard therapy. We have therefore extended our nadism spermatogenesis and fertility can be induced previous series and now present our therapeutic by gonadotropin or gonadotropin-releasing hormone experience with 42 cases, including the previously (GnRH) therapy. In hypothalamic disorders (idiopathic published 26 cases (1). hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KalS)) pulsatile GnRH or gonadotropins can be used alternatively, while male patients with pituitary insufficiency can only be treated with gonadotropins. Subjects and methods However, there is still uncertainty with regard to the optimal treatment modality and schedule, the necessary Patients duration of treatment and the influence of interfering Forty-two adult hypogonadal men received 57 courses factors such as maldescended testes. of GnRH or gonadotropin treatment in order to induce As treatment with urinary human menopausal spermatogenesis. From the total of 57 courses, 36 were gonadotropin (hMG) may be replaced by highly purified initiated with the intention of inducing a pregnancy in urinary preparations or by recombinant follicle- the female partner. These patients formed three groups stimulating hormone (FSH) in the near future we according to diagnosis and/or treatment.

᭧ 1998 Society of the European Journal of Endocrinology

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The patients with hypothalamic disorders (group I) intramuscular or subcutaneous doses of 1000–2500 IU chose either GnRH or human chorionic gonadotropin hCG applied twice a week (Monday and Friday) and 75– (hCG)/hMG therapy according to their own predilection 150 IU hMG applied three times a week (Monday, and formed groups Ia or Ib: group Ia consisted of six Wednesday and Friday) (2). Alternatively, patients patients with IHH (n ¼ 4) or KalS (n ¼ 2) and was given with hypothalamic disorders were administered 5– pulsatile GnRH treatment (Lutrelef, Ferring, Kiel, Ger- 20 mg GnRH every 120 min subcutaneously using a many) in seven courses. Group Ib consisted of 18 patients Zyklomat pulse pump (Ferring). The butterfly needle with IHH (n ¼ 9) and KalS (n ¼ 9) and received hCG was placed in the abdominal wall subcutaneously and (Pregnesin, Serono, Unterschleissheim, Germany) and changed every second day. hMG (Pergonal, Serono) in combination in 20 courses. During the course of treatment control examinations Group II consisted of 21 patients with hypopituitarism were performed every 3 to 6 months between 0800 h treated with hCG/hMG in 30 therapy cycles. and 1200 h at which time a physical and clinical Some patients were treated with more than one examination was performed. Blood samples were drawn treatment course (five of the patients of groups Ia and Ib, for hormone measurements as well as hematology and and six of group II). Each cycle was considered clinical chemistry (data not shown). Testicular volume separately. Three patients with IHH/KalS changed was measured regularly by palpation or ultrasonogra- their treatment regimen from one cycle to another phy (3). Results are recorded as total testicular volume and are therefore represented in group Ia and in group of right and left testes. Semen parameters were analyzed Ib. Again each course was considered separately. according to WHO guidelines (4). Treatment continued until sperm appeared in the ejaculate, until pregnancy occurred or until the patient Statistics opted for termination of therapy. For the analysis of the pregnancy rates only those patients who had been Regression analysis was applied where appropriate. treated for at least 12 months and had not terminated Results are given as mean Ϯ S.D. or as median and range. therapy early were included. Differences between groups were tested by Student’s Some patients had a history of treated unilateral or t-test, Mann–Whitney rank sum test or Kruskal–Wallis bilateral maldescended testes: three patients of group Ia, test. Contingency tables were tested by Chi-square test and eight of group Ib and one of group II. One of these Fisher exact test where appropriate. P values <0.05 were patients had a unilateral maldescended testis located in considered significant. Computations were performed the inguinal canal. One patient had experienced using the statistical software package Sigma Stat 2.0 testicular torsion with consecutive testicular atrophy (Jandel, Erkrath, Germany). of the right testis at the age of 18 years (1). Two patients had bilateral cryptorchidism until adolescence (age 17 and 22 years). Results At the beginning of treatment, mean age of the The treatment was tolerated well by all patients and patients of group Ia was 30.1 Ϯ 5.0 years (19–35 none discontinued treatment because of medical years), in group Ib mean age was 29.1 Ϯ 7.2 years (21– reasons. 43 years), while in group II patients had a mean age of 34.1 Ϯ 6.1 years (23–48 years). Testosterone substitution was terminated at least 4 weeks before GnRH Testicular size or hCG/hMG treatment. It consisted of either testos- After 5–12 months of therapy bilateral testicular terone enanthate (250 mg/14–21 days intramuscu- volumes increased from an initial mean of 6.8 Ϯ 2.2 ml larly) (Testoviron Depot 250 mg, Schering, Berlin, (group Ia), 4.4 Ϯ 2.86 ml (group Ib) and 14.0 Ϯ 8.7 ml Germany), transdermal testosterone (10–15 mg/day (group II) to 14.9 Ϯ 3.2 (Ia), 15.3 Ϯ 7.4 (Ib) and 28.3 Ϯ perscrotal) (Testoderm, Alza, Palo Alto, CA, USA) or 10.9 ml (II) respectively. In patients with maldescended testosterone undecanoate (2–3 × 40 mg/day orally) testes an increase of testicular volumes also occurred (Andriol, Organon, Oberschleissheim, Germany). (Fig. 1). There was a clear relation between the initial Previous GnRH or gonadotropin treatment had been testicular volume and the duration of therapy until first terminated at least 6 months before initiation of a new appearance of sperm in the ejaculate (Fig. 2). GnRH or hCG/hMG treatment with the exception of one patient (patient number 8, see results), whose gonadotropin pretreatment was immediately followed by GnRH Induction of spermatogenesis therapy (1). Spermatogenesis as evidenced by the appearance of sperm in the ejaculate was induced in 54/57 therapy cycles. In group Ia sperm appeared in six of seven GnRH Methods therapy cycles (85.7%). In group Ib gonadotropin Treatment of patients with hypopituitarism or with therapy led to achievement of sperm in 18/20 therapy hypothalamic disorders consisted of a combination of cycles (90%). In patients of group II 30 therapy cycles

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In the subgroup of patients treated by more than one treatment course mean duration until appearance of sperm was 5.5 Ϯ 4.0 months in the first and 3.3 Ϯ 1.34 months for the second course. This difference is not statistically significant (P ¼ 0.256). Duration until induction of pregnancy was significantly shorter in the second than in the first treatment course (6.4 Ϯ 3.6 vs 12.9 Ϯ 7.2 months, P ¼ 0.038). Most pregnancies occurred with sperm counts far below the normal range: group Ia median 1.65 × 106/ml (1.2–15.3 × 106/ml); group Ib 1.2 × 106/ml (0.1–9.0 × 106/ml) and group II 8.1 × 106/ml (0.1–180 × 106/ml) (Fig. 4).

Pregnancy rates Thirty-six of 57 cycles (24 different patients) had been Figure 1 Pretreatment values of total testicular volume and increase of total testicular volume under GnRH or hCG/hMG initiated for the induction of pregnancy in the female therapy for 5–12 months. (A) Courses of GnRH treatment (n ¼ 6) partner. Pregnancies occurred in 26/36 cycles (72%) for IHH/KalS patients. (X) Courses of hCG/hMG treatment (n ¼ 16) (16 different patients). for IHH/KalS patients. (O) Courses of hCG/hMG treatment (n ¼ 14) In group Ia four out of five therapy cycles (80%) led to a for hypopituitarism patients. pregnancy (three patients), in group Ib five out of ten (50%) cycles led to a pregnancy (three patients) and in group II the pregnancy rate per therapy cycle was 17/ with hCG/hMG were initiated and all were successful in 21 (81%) (12 patients). (Two patients achieved paternity induction of spermatogenesis. both after gonadotropin and after GnRH therapy). In each Duration of therapy until first appearance of sperm in group there were patients with successful induction of the ejaculate lasted on average 4 months (2–22 pregnancy who were older than 30 years or, in single months) for patients of group Ia, 6 months (1–18 cases, even older than 40 years at the beginning of months) for group Ib and 4 months (2–16 months) for therapy. Fig. 5 shows the efficacy of induction of group II. Furthermore the duration of time until spermatogenesis and induction of pregnancy per therapy induction of pregnancy was on average 6.5 months cycle. Four of the 16 described pregnancies were achieved (3–21 months) for group Ia, 8.0 (1–15 months) for with the aid of techniques of assisted reproduction (one by group Ib and 10 months (2–46 months) for patients intrauterine insemination, three by intracytoplasmic with hypopituitarism (group II) (Fig. 3). sperm injection (ICSI)). Altogether one of these ICSI pregnancies and three naturally achieved pregnancies ended prematurely in an abortion. Seven patients had a history of unilateral maldescent: one of group Ia (IHH), five of group Ib (two IHH, three KaLS) and one of group II (pituitary malformation). Spermatogenesis could be successfully induced in all seven of them. Four of these patients desired offspring and pregnancy occurred in two of their wives. Five patients had a history of bilaterally maldescended testes: two of group Ia (one IHH, one KalS) and three of group Ib (one IHH, two KalS). Spermatogenesis could be initiated in three of these five cases. Two failed, of whom one had had bilateral cryptorchidism up until the age of 22 years and the other until the age of 17 years. (The last one was patient number 8 who changed from gonadotropin therapy directly to therapy with the GnRH pump but both therapy regimens failed.) Two of five patients with a history of bilateral maldescent intended to achieve paternity, but no pregnancy Figure 2 Relation between initial testicular volume and duration of occurred. therapy until first appearance of sperm in the ejaculate. (A) Courses Duration until induction of spermatogenesis was 5 of GnRH treatment (n ¼ 6) for IHH/KalS patients. (X) Courses of hCG/hMG treatment (n ¼ 17) for IHH/KalS patients. (O) Courses of months (1–16 months) in the group of all patients with hCG/hMG treatment (n ¼ 14) for hypopituitarism patients. unilateral maldescent and 13 months (12–22 months)

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Figure 3 Duration of treatment (months as median) until appearance of ﬁrst sperm and induction of pregnancy. Left column of each set: courses of GnRH treatment for IHH/KalS patients. Centre column: courses of hCG/hMG treatment for IHH/KalS patients. Right column: courses of hCG/hMG treatment for hypopituitarism patients.

in the patients with bilateral maldescent. In comparison Several trials have been performed using only one of to that a group of all patients without uni- or bilateral the pituitary gonadotropins to assess the initiation and maldescent needed 4.5 months (2–18 months). The maintenance of spermatogenesis. Burris et al. (5) differences between these three conditions were not classified their IHH patients according to testicular statistically significant. Duration until induction of volume and considered volumes of less than 4 ml as a pregnancy was 9 months (1–21 months) for patients sign of complete gonadotropin deficiency and a volume with a history of unilateral cryptorchidism. Neither of above 4 ml as a sign of partial gonadotropin deficiency. the two patients with a history of bilateral cryptorchid- When treatment consisted of hCG only they failed to ism who wanted to father a child was successful in this induce spermatogenesis in 5/11 men in the small testis goal. Duration until pregnancy for all patients without group but could successfully achieve fertility by hCG history of uni- or bilateral cryptorchidism (independent alone in 9/11 patients in the large testis group. Vicari et al. of diagnosis and treatment regimen) was 8 months (2– (6) were able to initiate spermatogenesis in patients with 46 months). This difference was not statistically IHH by administration of hCG alone, but found an significant. increasing testicular volume and a higher sperm output in some patients after additional treatment with hMG and Discussion concluded that the combined treatment with hCG/hMG should be the method of choice for patients with the wish Treatment of hypogonadotropic hypogonadism may be for pregnancy. initiated for two purposes, androgenization and fertility. When comparing the administration of FSH in While the first goal can be reached by testosterone combination with testosterone to hCG/hMG therapy substitution, the second can only be achieved by Schaison et al. (7) concluded that the combined treatment is gonadotropins or with pulsatile GnRH treatment. necessary since neither testosterone alone nor testosterone

Figure 4 Development of sperm concentrations until induction of pregnancy. (A) Courses of GnRH treatment (n ¼ 4) for IHH/KalS patients. (X) Courses of hCG/hMG treatment (n ¼ 5) for IHH/KalS patients. (O) Courses of hCG/hMG treatment (n ¼ 17) for hypopituitarism patients.

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Figure 5 Effectiveness of therapy in terms of induction of spermatogenesis and pregnancy rates. Left column of each set: courses of GnRH treatment for IHH/KalS patients. Centre column: courses of hCG/hMG treatment for IHH/KalS patients. Right column: courses of hCG/hMG treatment for hypopituitarism patients. in the presence of FSH could bring about or maintain necessary length of treatment and confirm earlier spermatogenesis. observations (13). Even in patients with very small The question of interfering factors such as previous initial testicular volume successful therapy is possible. maldescent has been discussed controversially. A Testicular volume should be monitored very carefully, history of maldescended testes is generally considered preferably by ultrasonography. Less meticulous assess- a negative prognostic factor (8, 9). In contrast, other ments may be the reason why others did not find these authors found that maldescended testes do not neces- correlations (12). sarily preclude fertility (10–12). We were able to initiate In our patients we could not find a statistically spermatogenesis in all of our patients with a history of significant difference between the two treatment forms, unilateral maldescent and achieved a pregnancy rate of GnRH or gonadotropin administration, either concern- 50% (of patients) in those who had a wish for children. ing duration of therapy or with regard to efficacy of Spermatogenesis could also be induced in patients with induction of spermatogenesis or pregnancy. In our a history of bilateral maldescent. However, two of this patients with IHH or KalS there is a tendency for higher subgroup failed to develop spermatogenesis. In both success in achieving paternity with the GnRH pump patients bilateral maldescent had persisted until adoles- than with hCG/hMG. However, our group of patients cence (ages of 17 and 22 years). Two of five patients treated with this therapy form is too small to allow a with a history of bilateral maldescent wanted to achieve valid answer and differences are not statistically fatherhood but neither was successful. One of the two significant. Previously more rapid initiation of sperma- patients was patient number 8, who changed therapy togenesis and higher testicular volumes were seen with regimen directly (gonadotropin to GnRH pump), but GnRH therapy compared with gonadotropins (14, 15) both regimens failed. Because there are only few and patients who had failed to respond to gonadotropin patients with bilateral cryptorchidism treated with treatment achieved adequate testicular stimulation by these therapies we found it useful and necessary to intravenous administration of GnRH (10). However, in a include this patient in this evaluation although he had 2-year comparison of pulsatile GnRH and hCG/hMG in changed therapy directly. Altogether we can conclude patients with IHH Liu et al. (16) showed that GnRH that unilateral maldescent does not preclude fertility therapy ‘does not accelerate or enhance testicular growth, under gonadotropin or GnRH therapy, and spermato- hasten the onset of sperm production or increase sperm genesis can even be successfully induced in some output significantly’. Thus even after three decades of patients with previous bilateral cryptorchidism. Never- hCG/hMG treatment and two decades of pulsatile GnRH theless there is a tendency for a longer duration of no preference can be given to either therapy and the patient therapy until induction of spermatogenesis in patients can decide which modality he may prefer. with a history of bilateral maldescent, but differences In comparison to the first treatment course, time until did not reach statistical significance. This might be due sperm appeared in semen and pregnancies occurred to the small number of patients but this observation was shorter in the consecutive treatment courses. This should be borne in mind when counseling patients. has important implications for the counseling of the Our data clearly show that testicular volume at the patients. We now advise patients to induce spermato- beginning of therapy is a good predictor for the genesis even if there is no immediate desire for paternity

Downloaded from Bioscientifica.com at 10/02/2021 10:33:25PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 139 Gonadotropin or GnRH treatment in hypogonadal men 303 since this first course of treatment will assure the 5 Burris AS, Rodbard HW, Winters SJ & Sherins RJ. Gonadotropin patient (and the physician) that paternity is possible and therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by if required, time to induction of pregnancy will be initial testicular size. Journal of Clinical Endocrinology and shorter. In our experience the information that fertility Metabolism 1988 66 1144–1151. can be achieved brings high psychological benefit for 6 Vicari E, Mongioi A, Calogero AE, Moncada ML, Sidoti G, Polosa P the patients with respect to self- confidence and quality & D’Agata R. Therapy with human chorionic gonadotrophin of life. alone induces spermatogenesis in men with isolated hypogonadotrophic hypogonadism – long-term follow-up. International Currently, highly purified urinary hMG preparations Journal of Andrology 1992 15 320–329. and recombinant FSH are being tested for the treatment 7 Schaison G, Young J, Pholsena M, Nahoul K & Couzinet B. Failure of hypogonadotropic hypogonadism. It appears that of combined follicle-stimulating hormone–testosterone administra- these preparations are at least as effective as conven- tion to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. JournalofClinicalEndocrinology tional hCG/hMG treatment (17, 18). However, a direct and Metabolism 1993 77 1545–1549. comparison between old and new gonadotropin treat- 8 Finkel DM, Phillips JL & Snyder PJ. 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