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Effects of Human Recombinant Luteinizing Hormone and Follicle-Stimulating Hormone in Patients with Acquired Hypogonadotropic Hypogonadism: Study of Sertoli and Leydig Cell Secretions and Interactions

Service d’Endocrinologie et des Maladies de la Reproduction (J.Y., B.C., P.C., G.S.) and Laboratoire d’hormonologie (S.B.), Hôpital Bicêtre, 94275 Kremlin Bicêtre, France; and ARES Serono (E.L.), CH-1211 Geneva, Switzerland.

Address correspondence and requests for reprints to: Gilbert Schaison, M.D., Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, 94275 Kremlin Bicêtre cedex, France. E-mail: gilbert.schaison{at}bct.ap-hop-paris.fr

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Experimental data suggest that FSH-stimulated Sertoli cells can enhance LH-induced Leydig cell testosterone (T) production. The function of Leydig and Sertoli cells can be selectively studied by using recombinant human LH (rhLH) and recombinant human FSH (rhFSH) in patients with complete gonadotropin deficiency. The aim of the present study was to assess the secretion of testicular T, estradiol (E₂), and inhibin B and the physiological relevance of the Sertoli-Leydig cell interaction in man. For that purpose, six patients with acquired complete hypogonadotropic hypogonadism received the following treatments for three periods of 1 month in a random order: 1) rhLH, 900 IU/day sc; 2) rhFSH, 150 IU/day sc; and 3) combined rhLH/rhFSH treatments. Each treatment period was separated by a washout period of 15 days. Plasma LH, FSH, T, E₂, and inhibin B were measured before and every 10 days during each treatment. During rhLH administration, mean plasma LH levels rose significantly from 0.4 ± 0.2 IU/L to 11.7 ± 1.2 IU/L (P < 0.01) and plasma FSH levels did not change. rhFSH administration induced a significant increase in plasma FSH levels (from 0.5 ± 0.4 to 12.1 ± 1.4 IU/L; P < 0.01), whereas mean plasma LH levels remained low. Mean plasma E₂ levels were unchanged during rhFSH treatment, but they increased significantly during rhLH from 22 ± 4 to 54 ± 8 pmol/L (P < 0.01) and during rhLH plus rhFSH administration. rhFSH treatment induced a sustained elevation of mean plasma inhibin B levels from 58 ± 13 to 175 ± 25 pg/mL (P < 0.01), similar to the increase occurring during rhFSH plus rhLH administration. In contrast, mean plasma inhibin B levels did not increase during rhLH administration. Finally, a similar and significant increase in mean plasma T levels occurred during both rhLH and rhLH plus rhFSH treatment from 0.9 ± 0.3 to 5.4 ± 0.7 nmol/L (P < 0.01) and from 1.0 ± 0.4 to 6.0 ± 0.9 nmol/L (P < 0.01), respectively. In contrast, during rhFSH treatment mean plasma T levels remained unchanged when compared with baseline. In conclusion: 1) the increase of plasma E₂ induced by rhLH and the absence of effect of rhFSH confirm that Leydig cells are the major site of testicular E₂ production in man; 2) the secretion of inhibin B is increased by rhFSH and not by rhLH, and, thus, Sertoli cells seem to be the main source of inhibin B production; and 3) the increase of plasma T induced by rhLH is not enhanced by rhFSH. These results suggest that the stimulatory effect of FSH on Leydig cell steroidogenesis by a Sertoli cell paracrine factor does not seem to play a major physiologic role in man.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
THE PITUITARY gonadotropins LH and FSH are the main regulators of testicular hormonal secretion. In addition, experimental data obtained in vitro and in vivo in rats and pigs suggest that FSH-stimulated Sertoli cells can enhance LHinduced Leydig cell testosterone (T) production (1). The specific functions of testicular cells and the paracrine regulation of Leydig cells by Sertoli cells are difficult to study in vivo in man. Complete hypogonadotropic hypogonadism (HH) characterized by the absence of secretion of endogenous gonadotropins is a convenient model to assess the respective effects of LH and FSH on gonadal function (2, 3, 4). Furthermore, because the Leydig cells contain only receptors for LH and the Sertoli cells contain only receptors for FSH, the use of recombinant human LH (rhLH) and recombinant human FSH (rhFSH) enables the functions of both Leydig and Sertoli cells to be studied selectively. Recently, rhFSH has been available for therapeutic use, and its efficacy has been demonstrated in humans (5, 6, 7, 8, 9). More recently, rhLH has been produced, and its clinical pharmacology and efficacy assessed in women (7, 9, 10, 11). However, the effects of rhLH on testicular steroid secretion in men have not yet been reported.

In the present study, the functions of Leydig and Sertoli cells have been selectively studied in vivo by using rhLH and rhFSH in patients with complete acquired gonadotropin deficiency. This pathological model also provided the opportunity to assess the physiological relevance in man of the paracrine regulation of Leydig cells by Sertoli cells.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Subjects

Six men with complete postpubertal acquired HH and dissociated hypopituitarism, but normal GH secretion, were studied. These patients were selected to avoid the confounding effects of GH deficiency on the testicular response to gonadotropins (12, 13). The gonadotropin deficiency was the consequence of hypothalamic or pituitary infiltrative and tumoral processes (Table 1). In all patients pituitary function was assessed before replacement therapy. Plasma cortisol and ACTH were low and unresponsive to ovine CRH, 100 µg iv. Mean (±SD) plasma-free T₄ levels were 6.3 ± 2.0 pmol/L (normal range, 11.0–24 pmol/L). Mean plasma basal and TRH (200 µg iv)-stimulated TSH levels were 0.15 ± 0.13 µU/mL and 2.3 ± 1.4 µU/mL. In all patients plasma PRL levels were not increased. Plasma GH levels were above 10 ng/mL after GHRH, 100 µg iv and insulin-induced hypoglycemia. Plasma insulin-like growth factor I (IGF-I) levels were normal. The complete gonadotropin deficiency was confirmed by the association of low plasma T and inhibin B levels with low basal and stimulated (GnRH, 100 µg iv) LH and FSH levels (Table 1). In addition, studies of pulsatile LH secretion (every 10 min for 8 h) showed no detectable LH pulses. The six patients received replacement T, T₄, and hydrocortisone therapy. None of the patients had previously received gonadotropin replacement therapy.

All the patients were studied after withdrawal of T for at least 2 months. Hydrocortisone, 20 mg/day, and thyroid hormone replacement therapy were maintained. Each patient received the following treatments for three periods of 1 month in a random order: 1) rhLH (Laboratoires Serono, Aubonne, Switzerland), 450 IU twice daily sc at 0800 and 2000 h; 2) rhFSH (Laboratoires Serono), 150 IU/day sc at 0800 h; and 3) combined rhLH, 900 IU, plus rhFSH, 150 IU. Each treatment period was separated by a washout period of 15 days. Blood samples were drawn before and every 10 days at 1000 h during the three treatment periods.

To compare the relative effects of rhLH and human CG (hCG) on testicular T secretion, all patients received, after a washout period of 2 months, for 1 month, in a random order, hCG (1500 IU) im twice a week alone or hCG (1500 IU) im twice a week plus rhFSH (150 IU/day) sc at 0800 h. Blood samples were drawn before and every 10 days (48 h after the last hCG injection) at 1000 h during each treatment.

All subjects gave informed consent for participation in this study, which was approved by the local human investigation committee.

Assays

Plasma LH and FSH were measured by immunofluorometric assay (Cis-Bio, Gif-sur-Yvette, France). The intra- and interassay coefficients of variation were 1.5% and 5.2% for LH and 2.6% and 4% for FSH, respectively. The limit of detection of both assays was 0.15 IU/L. Plasma T and estradiol (E₂) levels were measured by RIA after chromatography on a celite column, as described previously (14, 15). The detection limit for T and E₂ was 0.17 nmol/L and 18.3 pmol/L, respectively. Inter- and intra-assay precision coefficients of variation for these plasma steroid RIAs were 6.0% and 5.8% for T and 8.5% and 5.1% for E₂. Plasma inhibin B levels were measured by a commercially available enzyme-linked immunoabsorbent assay (manufactured by Serotec, Kidlington, Oxford, UK), which has previously been described (16, 17); the lower limit of detection was 10 pg/mL, and the inter- and intra-assay coefficients of variation were 15% and 6%, respectively.

Statistical analyses

The data are presented as the mean ± SE. Statistical significance was considered at P < 0.05. ANOVA was performed to detect between-treatment and time-related differences. The Wilcoxon rank order paired test was used after ANOVA for comparison between treatments and with baseline levels (18).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Plasma gonadotropins

In patients with acquired HH, mean plasma levels of both gonadotropin levels were low. Mean plasma LH levels rose significantly during rhLH (from 0.4 ± 0.2 IU/L to 11.7 ± 1.2 IU/L; P < 0.01) and during rhLH plus rhFSH (from 0.8 ± 0.3 IU/L to 12.0 ± 1.5; P < 0.01) treatments. This increase was similar during both treatments (Fig. 1A). In contrast, mean plasma LH levels remained unchanged when rhFSH was administered alone (Fig. 1A).

View larger version (14K): [in this window] [in a new window]   Figure 1. A, Mean (±SE) plasma LH levels in patients with acquired HH treated with rhLH, rhFSH, or both treatments administered simultaneously. *P < 0.01 and °P < 0.01 when compared with baseline and FSH-treated patients, respectively. B, Mean (±SE) plasma FSH levels in patients with acquired HH treated with rhLH, rhFSH, or both treatments administered simultaneously. *P < 0.01 and °P < 0.01 compared with baseline and LH-treated patients.

Plasma E₂

Mean plasma E₂ levels were unchanged during rhFSH treatment (24 ± 3 vs. 26 ± 5 pmol/L), but they increased significantly during rhLH (from 22 ± 4 to 54 ± 8 pmol/L; P < 0.01) and rhLH plus rhFSH (from 26 ± 3 to 53 ± 8 pmol/L; P < 0.01) administration (Fig. 2).

View larger version (13K): [in this window] [in a new window]   Figure 2. Mean (±SE) plasma E2 levels. Patients and protocol are the same as in the legend to Fig. 1. *P < 0.01, rhLH treatment compared with baseline and rhFSH-treated patients. °P < 0.0, rhLH treatment compared with baseline and rhFSH-treated patients.

rhFSH administration induced a sustained elevation of mean plasma inhibin B levels from 58 ± 13 to 175 ± 25 pg/mL (P < 0.01), similar to the increase occurring during rhFSH plus rhLH administration (from 43 ± 9 to 185 ± 18 pg/mL) (Fig. 3). In contrast, mean plasma inhibin B levels did not change during rhLH administration (47 ± 10 vs. 53 ± 13 pg/mL) (Fig. 3).

View larger version (12K): [in this window] [in a new window]   Figure 3. Mean (±SE) plasma inhibin B levels. Patients and protocol are the same as in the legend to Fig. 1. *P < 0.01, rhFSH treatment compared with baseline and rhLH-treated patients. °P < 0.01, rhFSH plus rhLH treatment compared with baseline and rhLH-treated patients.

A similar and significant increase in mean plasma T levels occurred during both rhLH and rhLH plus rhFSH treatment from 0.9 ± 0.3 to 5.4 ± 0.7 nmol/L (P < 0.01) and from 1.0 ± 0.4 to 6.0 ± 0.9 nmol/L (P < 0.01), respectively (Fig. 4A). In contrast, during rhFSH treatment, mean plasma T levels remained unchanged when compared with baseline (0.9 ± 0.3 vs. 1.2 ± 0.4 nmol/L) (Fig. 4A).

View larger version (15K): [in this window] [in a new window]   Figure 4. A, Mean (±SE) plasma T levels. Patients and protocol are the same as in the legend to Fig. 1. *P < 0.01, rhLH treatment compared with baseline and rhFSH-treated patients. °P < 0.01, rhLH plus rhFSH treatment compared with baseline and rhFSH-treated patients. B, Mean (±SE) plasma T levels in patients with acquired HH treated with hCG alone or in association with rhFSH. *P < 0.01, hCG treatment compared with baseline. °P < 0.01, hCG plus rhFSH treatment compared with baseline.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The specific physiological functions of testicular cells and the paracrine regulation of Leydig cells by Sertoli cells are difficult to study in vivo in normal man. Therefore, complete HH characterized by the absence of secretion of endogenous gonadotropins is a convenient model to assess the respective effects of LH and FSH on gonadal function. Because the Leydig cells contain only receptors for LH and the Sertoli cells contain only receptors for FSH, the use of rhLH and rhFSH enables the functions of both Leydig and Sertoli cells to be studied selectively. In the present study, using recombinant human gonadotropins, endocrine testicular function was assessed in adult men with acquired HH and hypopituitarism, but normal GH secretion. This pathological model was convenient to evaluate the specific roles of rhLH and rhFSH on Leydig and Sertoli cell function and to assess the physiological relevance of the concept that FSH can enhance testicular T production induced by LH in humans. Men with acquired HH were selected, and subjects with congenital HH or GH deficiency were excluded. In congenital HH, the absence of fetal or neonatal gonadotropin secretion may impair the development of Sertoli cells and their response to short-term FSH administration (19, 20). In patients with GH and IGF-I deficiency, testicular LH receptors and steroidogenic responsiveness may be decreased (12, 13).

The administration of rhLH (900 IU/day) alone or in association with rhFSH increased plasma LH levels similarly, to the levels observed in normal men. During rhLH treatment, low plasma FSH levels remained unchanged, as expected, with the LH recombinant preparation used in this study. During rhFSH (150 IU/day), plasma FSH levels increased but plasma LH levels did not change.

In patients with acquired HH, mean plasma E₂ levels were almost undetectable. A significant and similar increase was observed during isolated rhLH treatment or combined rhLH plus rhFSH treatment. In contrast, plasma E₂ levels remained low when rhFSH was administered alone. These results confirm that, in contrast to rat testis (21), the human testicular aromatase is localized within Leydig cells and not in Sertoli cells. This conclusion is in agreement with previous immunohistochemical and enzymatic studies showing that immunoreactive aromatase and aromatase activity were present only in the Leydig cells and absent from the Sertoli cells in normal adult human testes (22).

At baseline, patients with acquired HH had plasma inhibin B levels markedly below those of normal men, as reported previously, in congenital HH (8, 20). The administration of rhFSH promptly restored inhibin B levels to those observed in normal men. In contrast, rhLH treatment failed to increase immunoreactive inhibin B. These results confirm the selective FSH dependence of circulating inhibin B, as reported previously, in normal men (8). Sertoli cells seem to be the main source of inhibin B production. The finding that rhFSH treatment stimulated testicular secretion of inhibin B in these patients also demonstrated the normal functional capacity of their Sertoli cells.

As expected, in patients with acquired HH mean plasma T levels were very low. A significant increase in plasma T levels was observed during rhLH treatment. This result confirmed that the rhLH preparation used in the present study was biologically active. However, in contrast to hCG (1500 IU twice weekly), rhLH at the daily dose of 900 IU failed to restore mean plasma T levels to those observed in normal adult men. This difference was probably related to the shorter half-life and lower potency of rhLH than hCG (23, 24). Therefore, in the future, higher regimen doses will be necessary to restore normal T secretion and, in association with FSH, to achieve spermatogenesis in patients with complete HH.

The use of recombinant gonadotropins in patients with acquired HH also provided an opportunity to examine the concept that FSH may enhance the responsiveness of Leydig cells to LH. Earlier studies in support of the paracrine control of Leydig cells by Sertoli cells were conducted in rodents or in in vitro models (1, 25). In hypophysectomized immature rats, FSH treatment induced Leydig cell hyperplasia, increased the number of testicular LH receptors, and increased the steroidogenic response of Leydig cells to LH (1). In vitro, coculture of Leydig cells with Sertoli cells isolated from immature pig testis enhanced hCG-stimulated T production when compared with the response of Leydig cells cultured alone. Pretreatment of cocultures with FSH further enhanced the steroidogenic capacity of Leydig cells and induced a significant increase in the number of hCG receptors (1). Several Sertoli cell-secretory products have been identified that can potentially mediate regulatory interaction between Sertoli and Leydig cells (1, 25). Some of these (e.g. IGF-I) stimulate, but others (e.g. transforming growth factor ß) inhibit Leydig cell steroidogenesis (1). In addition, the effects of these factors on Leydig cell function may be species dependent (1).

In humans, natural mutations of FSH ß-subunit and FSH receptor genes could provide new insights into the effects of FSH and steroidogenesis in Leydig cells. However, at present, case reports are rather puzzling. In one recently reported mutation of the FSH ß gene, the affected patient had delayed puberty, selective absence of FSH, and low plasma T levels with high plasma LH levels (26). In contrast, in another case of FSH ß gene mutation, the absence of FSH and azoospermia were associated with normal puberty and normal plasma T levels (27). In agreement with this latter case report, FSH deficiency has previously been reported in men with variable degrees of spermatogenesis impairment, but with normal T production and virilization (28). Similarly, men with homozygous FSH receptor-inactivating mutations reported by Tapanainen et al. (29) had variable reduction in testis size and sperm count, but all were normally masculinized and had normal plasma T levels. Thus, naturally occurring FSH ß gene and FSH receptor gene mutations in man have not clarified the putative indirect role of FSH in adult testicular Leydig cell function.

In the present study, the increase in mean plasma T levels induced by rhLH was not enhanced by the concomitant administration of rhFSH, despite the effective stimulation of Sertoli cell function, attested by the increase in plasma inhibin B. The same result was observed with a greater increase in plasma T levels after hCG and hCG plus rhFSH administration. These results are in agreement with recent studies performed in primates (30). Indeed, in juvenile rhesus monkeys receiving a pulsatile iv infusion of GnRH, the concomitant infusion of rhFSH did not affect either the mean plasma levels of T or the amplitude of pulsatile testicular T secretion. Therefore, in man as in primates, the physiological relevance of a role of FSH in LH-induced testicular steroidogenesis seems questionable.

In conclusion, complete acquired HH and the use of rhLH and rhFSH enable the functions of Leydig and Sertoli cells to be studied selectively. Apart from peripheral aromatization of testicular T, the increase of plasma E₂ induced by rhLH and the absence of an effect of rhFSH is consistent with the view that Leydig cells are the major site of testicular E₂ production in man. The secretion of inhibin B, increased by rhFSH and not by rhLH, confirms that Sertoli cells are the main source of inhibin B production. Finally, the increase in plasma T induced by rhLH or hCG was not enhanced by rhFSH. These results suggest that the stimulatory effect of FSH on Leydig cell steroidogenesis by a Sertoli cell paracrine factor does not seem to play a major physiological role in man.

Received January 26, 2000.

Revised May 19, 2000.

Accepted May 24, 2000.

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