Gonadotropin Replacement Research Articles

Clomiphene citrate treatment for acquired hypogonadotropin hypogonadism

Objective: Pituitary dysfunction due to acquired hypogonadotropin hypogonadism (HH) is an uncommon, but potentially treatable cause of male infertility or sexual dysfunction. Classically, congenital HH (Kallmann syndrome) is treated with gonadotropin replacement. In a cohort of symptomatic men with acquired HH, we hypothesize that pituitary replacement may be possible with clomiphene citrate (CC). Materials and Methods: Over a three year period, seven patients presented with infertility (n= 3) or sexual dysfunction (n=4) and were diagnosed with partial HH. All patients had a history, physical exam and hormone evaluation performed; the hormone evaluation revealed low testosterone and gonadotropins in each case. Genetic testing was performed when indicated. Pituitary imaging was also performed when indicated. Because of negative past medical history and recent onset of symptoms, these cases were deemed acquired HH. After evaluation, daily oral treatment with 12.5 mg CC was initiated and assessed with serial testosterone, gonadotropin and semen evaluations. CC dose was optimized for testosterone levels and relief of symptoms. Assessed outcomes included changes in semen quality, fertility, and sexual function. Results: Partial HH was due to prolactinoma resection (n = 1), pituitary Rathke’s cleft cyst (n = 1), and idiopathic (n=5). No genetic etiology was identified. Pre- and post-treatment hormone levels are reported below. Among infertile patients, all three exhibited improved semen quality and one conceived naturally. In the sexual dysfunction group, normal erections and libido were observed in all patients (n = 4). No side effects of therapy were observed. Tabled 1 Conclusions: In unusual cases of acquired HH, clomiphene citrate may benefit patients with infertility or sexual dysfunction. Traditionally, CC has been used empirically, but in this condition, its use may be more rational and effective. Based upon this pilot study, further investigation of this treatment indication is warranted.

Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism

Objective: To evaluate the clinical and hormonal responses of adolescent males with hypogonadotropic hypogonadism (HH) in response to gonadotropin replacement with the use of long-term combined hCG and FSH therapy. Design: Prospective clinical study. Setting: Clinical pediatric department providing tertiary care. Patient(s): Seven prepubertal males with isolated HH with a mean (±SD) age of 15.44 ± 1.97 years and seven prepubertal males with panhypopituitarism-associated HH with a mean (±SD) age of 18.1 ± 3.24 years were studied. Intervention(s): Human chorionic gonadotropin (1,000–1,500 IU IM) and FSH (75–100 IU SC) were administered every alternate day of the week until the total induction of puberty and spermatogenesis was achieved. Main Outcome Measure(s): Serum testosterone levels, testicular volume, penis length, and sperm count were evaluated after the administration of hCG and FSH. Result(s): All patients achieved normal sexual maturation and normal or nearly normal adult male levels of testosterone. The increase in testicular size was significant in both groups. Positive sperm production was assessed in four of five patients with isolated HH and in three of three patients with panhypopituitarism-associated HH. Conclusion(s): Long-term combined hCG and FSH therapy is effective in inducing puberty, increasing testicular volume, and stimulating spermatogenesis in adolescent males with isolated HH and panhypopituitarism-associated HH.

Gonadotropin therapy in males with hypogonadotropic hypogonadism: factors affecting induction of spermatogenesis after gonadotropin replacement.

Sixteen patients with hypogonadotropic hypogonadism received gonadotropin replacement therapy. Two patients treated with HCG alone showed induction of spermatogenesis 2 and 12 months after the start of treatment. Three subjects receiving combination therapy showed sperm appearance 6-28 months after treatment. The patients showing sperm appearance, whose testicular volume was > or = 4 ml, showed a higher sperm count and impregnated their partners, although no relationship was found between pretreatment testicular volume and sperm appearance. The response to HCG test correlated with sperm appearance after gonadotropin therapy. Sperm appearance was not observed in any subject except for one who showed no response to luteinizing hormone-releasing hormone (LH-RH) test and none of the patients without response of FSH to LH-RH demonstrated any induction of spermatogenesis. In conclusion, the responses to LH-RH test and possibly to HCG test could predict the induction of spermatogenesis after gonadotropin replacement therapy, and a large testicular volume is associated with post-treatment fertility.

The Reversibility of Anabolic Steroid-Induced Azoospermia

Anabolic steroid associated male infertility is a little known but potentially treatable form of drug related infertility. We report on a bodybuilder with a 5-year history of steroid use who was azoospermic. He underwent successful gonadotropin replacement and conception was achieved 3 months after therapy was initiated. Important diagnostic and therapeutic considerations in steroid-induced infertility are discussed.

Cellular pattern of insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in the developing and mature ovarian follicle.

We have employed in situ hybridization histochemistry to map the cellular pattern of insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in developing rat ovaries from the time of birth through adulthood, and in response to hypophysectomy and gonadotropin replacement. From the early postnatal period, both IGF-I and IGF-I receptor messenger RNAs (mRNAs) were highly abundant and evenly distributed in granulosa cells of small, growing follicles. In large follicles, however, IGF-I gene expression was heterogeneous. IGF-I mRNA was most abundant in granulosa cells lining the antrum and surrounding the oocyte, but was low or undetectable in mural granulosa cells of Graafian follicles, and was also undetectable in luteinized granulosa cells of corpora lutea. IGF-I receptor mRNA was evenly distributed in developing and mature follicles and was highly abundant in the luteinized granulosa cells of corpora lutea. IGF-I receptor but not IGF-I mRNA was detected in growing oocytes. Hypophysectomy resulted in a decrease and treatment with PMSG resulted in an increase in follicular IGF-I receptor mRNA levels, whereas there was no change in IGF-I mRNA levels in the same protocol. In summary, high levels of both IGF-I and IGF-I receptor gene expression occur in the granulosa cells of actively growing follicles, suggesting that granulosa cell IGF-I may have a role in follicular or oocyte growth. IGF-I gene expression is lost concomitant with follicular enlargement and granulosa cell differentiation, whereas IGF-I receptor gene expression continues at high levels in luteinized granulosa cells, suggesting that IGF effects on differentiated granulosa cell function are due to circulating, not local, hormone. Finally, granulosa cell IGF-I receptor gene expression appears to be regulated by the gonadotropin present in pregnant mare serum.

Subcutaneous gonadotropin therapy in male patients with hypogonadotropic hypogonadism

The response to subcutaneous (SC) gonadotropin replacement therapy, using human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) or hCG alone, was evaluated in male hypothalamic hypogonadism. Sixteen patients with hypothalamic hypogonadism were treated with gonadotropins for induction of puberty and normalization of spermatogenesis. The results were analyzed retrospectively. The study was carried out in a clinical endocrinology department providing tertiary care and in private practices of endocrinology. Eight patients with idiopathic hypogonadotropic hypogonadism and eight patients with Kallmann's syndrome in prepubertal or early pubertal stages. Human chorionic gonadotropin and hMG were administered SC in individual dosages. Increase of serum testosterone (T), testicular volume, semen volume, and sperm count were evaluated. Normalization of serum T and complete sexual maturation was achieved in all patients. Spermatogenesis was induced in all but two patients. Seven patients showed normal findings in semen volume and sperm count, and two patients had semen quality close to normal. In five patients sperm count remained less than 10 x 10(6)/mL. The results obtained by SC gonadotropin replacement prove this mode of administration to be effective in stimulating steroidogenesis and spermatogenesis in hypogonadotropic males.

Growth hormone response following growth hormone releasing hormone injection in thalassemia major: influence of pubertal development

Thirty-five patients with thalassemia major, aged 7 to 21 years, were studied to define the relationship between the pubertal development and the growth-hormone (GH) secretion during sleep, after administration of GH-releasing factor (hpGRF 1-44), and betaxolol-glucagon or arginin-insulin. Pubertal development was classified as being appropriate or delayed for chronological age. GH response to pharmacological stimuli and during sleep was not linked to the pubertal development according to the chronological age. The peak of GH secretion after GHRH injection was significantly delayed in thalassemic patients with retarded puberty. The integrated secretion of GH during the 120-min test was slightly but not significantly reduced in these patients. The prepubertal pattern of GHRH response was restored in the patients receiving substitutive therapy by HCG or testosterone. The alteration of GH response to GHRH in thalassemic patients is likely to be only due to delayed puberty and decreased endogeneous GHRH secretion since it is corrected by androgen or gonadotropin replacement.

Proluminal Movement of 3H-Androgen across the Epididymal Epithelium in the Rat after Hypophysectomy and Gonadotropin Supplementation1

The effects of hypophysectomy and gonadotropin replacement on transepithelial movement of 3H-androgen in the rat epididymis were examined by in vivo microperifusion of 3H-testosterone followed by in vivo micropuncture to obtain peritubular and intraluminal fluid. In the caput epididymidis of normal rats, intraluminal 3H-androgen concentrations were approximately 300% of those in the interstitial space. In contrast, proluminal movement of 3H-androgen into rat caput epididymal tubules was significantly decreased 10 days after hypophysectomy. 3H-Testosterone movement across the caput epididymal epithelium was completely returned to normal by supplementation with 24 micrograms/day follicle-stimulating hormone (FSH) or 24 micrograms/day luteinizing hormone (LH). However, neither 0.12 micrograms/day FSH nor 250 micrograms/day prolactin returned proluminal androgen movement to normal. It is speculated that epididymal uptake of peritubular testosterone is mediated by androgen-binding protein, which is known to be secreted by Sertoli cells after stimulation by FSH or testosterone.

The Influence of Short Photoperiod on Testicular and Circulating Levels of Testosterone Precursors in the Adult Golden Hamster1

The in vivo effects of short photoperiod (SPP, 6L:18D) for 8 and 12 wk on plasma and testicular levels of testosterone (T) precursors in adult golden hamsters were evaluated. Plasma and testicular progesterone (P), 17 alpha-hydroxyprogesterone (17 alpha-OHP), androstenedione (A-dione), and T were measured after 5 injections of saline or human chorionic gonadotropin (hCG) (5 or 25 IU/day). The basal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) in circulation were also determined. There were significant reductions in the weight of the testes in animals exposed to SPP. After 12 wk in SPP, circulating levels and testicular content of 17 alpha-OHP, A-dione, and T were significantly reduced, suggesting that the decrease in T secretion may be associated with the impairment of synthesis and/or action of 17 alpha-steroid hydroxylase, C17-20 steroid lyase, and 17 beta-hydroxysteroid dehydrogenase enzymes in the testes. Exposure to SPP for 8 wk resulted in decreased plasma and testicular content of T. Although there were reductions in testicular content of 17 alpha-OHP and A-dione, this was not reflected in plasma levels of these steroids. After 8 and 12 wk of exposure to SPP, hCG treatment increased the total amounts of T precursors (except P at 8 wk) in the testes, but the values attained in animals exposed to 12 wk of SPP remained below those observed in hamsters kept in a long photoperiod (14L:10D), suggesting that gonadotropin replacement alone may be insufficient to normalize testicular steroidogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of sperm production by human luteinizing hormone in gonadotropin-suppressed normal men.

The relative roles of FSH and LH in the control of human spermatogenesis are not well established. We previously reported that supraphysiological doses of hCG can stimulate sperm production in gonadotropin-suppressed normal men despite prepubertal FSH levels. To determine whether more nearly physiological levels of human LH (hLH) also can stimulate spermatogenesis when FSH levels are suppressed, we administered hLH to normal men whose endogenous gonadotropin levels and sperm production were suppressed by exogenous testosterone enanthate (T). After a 3-month control period, 11 normal men received 200 mg T, im, weekly to suppress LH and FSH. T administration alone was continued for 3-4 months until 3 successive sperm concentrations (performed twice monthly) revealed azoospermia or severe oligospermia (sperm concentrations, less than 4 million/ml). Then, while continuing T, 4 of the 11 men (experimental subjects) simultaneously received 1100 IU hLH, sc, daily for 4-6 months to replace LH activity, leaving FSH activity suppressed. The effect on sperm production of the selective FSH deficiency produced by hLH plus T administration was determined. The remaining 7 men (control subjects) continued to receive T alone at the same dosage, without gonadotropin replacement, for an additional 6 months. In the four experimental subjects, sperm concentrations increased significantly from 0.7 +/- 0.7 million/ml (mean +/- SEM) during T treatment alone to 19 +/- 4 million/ml during hLH plus T administration (P less than 0.001). However, none of the men achieved sperm concentrations consistently in their own pretreatment range. Sperm motilities and morphologies were normal in all four subjects by the end of hLH plus T administration. In contrast, sperm concentrations in the seven control subjects remained suppressed (less than 3 million/ml) throughout the entire period of prolonged T administration alone. Serum LH bioactivity, determined monthly by in vitro mouse Leydig cell bioassay in all four experimental subjects, was markedly suppressed during T administration alone (120 +/- 10 ng/ml) compared to that during the control period (390 +/- 20 ng/ml; P less than 0.001). With the addition of hLH to T, LH bioactivity returned to control levels (400 +/- 40 ng/ml; P = NS compared to control value). Serum FSH levels determined monthly by RIA were reduced from 98 +/- 12 ng/ml during the control period to undetectable levels (less than 25 ng/ml) during the T alone and the hLH plus T periods (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)