Hypogonadotropic Hypogonadism Men Research Articles

Reversible hypogonadotropic hypogonadism in men with the fertile eunuch/Pasqualini syndrome: A single-center natural history study.

Congenital hypogonadotropic hypogonadism (HH) is a heterogeneous genetic disorder characterized by disrupted puberty and infertility. In most cases, HH is abiding yet 10-15% undergo reversal. Men with HH and absent and partial puberty (i.e., testicular volume <4mL and >4mL respectively) have been well-studied, but the rare fertile eunuch (FE) variant remains poorly characterized. This natural history study of 240 men with HH delineates the clinical presentation, neuroendocrine profile, rate of reversal and genetics of the FE variant. We compared three HH groups: FE (n=38), absent puberty (n=139), and partial puberty (n=63). The FE group had no history of micropenis and 2/38 (5%) had cryptorchidism (p<0.0001 vs. other groups). The FE group exhibited higher rates of detectable gonadotropins, higher mean LH/FSH levels, and higher serum inhibin B levels (all p<0.0001). Neuroendocrine profiling showed pulsatile LH secretion in 30/38 (79%) of FE men (p<0.0001) and 16/36 (44%) FE men underwent spontaneous reversal of HH (p<0.001). The FE group was enriched for protein-truncating variants (PTVs) in GNRHR and FGFR1 and 4/30 (13%) exhibited oligogenic PTVs. Findings suggest men with the FE variant exhibit the mildest neuroendocrine defects of HH men and the FE sub-type represents the first identified phenotypic predictor for reversible HH.

Reproductive outcomes of microdissection testicular sperm extraction in hypogonadotropic hypogonadal azoospermic men after gonadotropin therapy.

Male infertility caused by hypogonadotropic hypogonadism (HH) is not common. The main treatment is gonadotropins for 12 months or longer. If the patient is still azoospermic, conventional or microdissection testicular sperm extraction (mTESE) may further help in sperm retrieval. We aimed to analyze the fertility outcomes of HH men treated at our institute. From 2008 to 2020, infertile men with hormone profile showing HH were enrolled. Gonadotropin therapy was prescribed if parenthood was being considered. Assisted reproductive technology was available to help patients attain fertility depending on the results of sperm analysis. Patient outcomes, including sperm retrieval, pregnancy and live birth rates, were analyzed. Seventeen initially azoospermic patients were administered gonadotropins for an average of 11.1 months, and sperm was subsequently found in the ejaculate of seven patients (41%). mTESE was performed on the other ten (59%) who were still azoospermic. For these 10 patients, they had collectively undergone an average 12.1 months (range 6-23 months) of gonadotropin therapy. Sperm was retrieved in nine (90.0%) cases. After 11 cycles of TESE-ICSI, six (54.5%) successful pregnancies were recorded, resulting in five (55.6%) cases with live-born babies, including two sets of twins, and one case of missed abortion at 9 weeks of gestation. Gonadotropin therapy reversed azoospermia in a portion of the HH male patients studied. Of men who were still azoospermic after gonadotropin treatment, a majority could still have testicular sperm retrieved by mTESE for use in assisted reproductive technology, subsequently resulting in live births.

Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men

Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men

Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults.

Germ cell and Sertoli cell proliferation and maturation in human testes occur in three main waves, during the late fetal and early neonatal period and at early puberty. They are triggered by periods of increased activity of the hypothalamic-pituitary-gonadal (HPG) axis. In hypogonadotropic hypogonadism (HH), these processes are variably disturbed. The objective of this study was to explore whether success of gonadotropin replacement in HH men is predictable by the origin of HH, indicating time of onset and severity of GnRH/gonadotropin deficiency. The data of 51 adult HH patients who had undergone one cycle of hCG/FSH treatment were reviewed. Five groups were established, according to the underlying HH origin. Therapeutic success by final bi-testicular volumes (BTVs) final sperm concentrations (SC) and conception rates were compared and related to baseline parameters, indicative of the degree of HPG-axis disruption. Overall, BTVs rose from 13 ± 15 to 27 ± 15 mL, spermatogenesis was induced in 98%, with mean SCs of 15 ± 30 mill/mL, spontaneous pregnancies in 37% and additional 18% via intracytoplasmic sperm injection. Kallmann syndrome patients had the poorest responses (BTV: 16.9 ± 10 mL; SC: 3.5 ± 5.6 mill/mL), followed by patients with congenital/infancy-acquired multiple pituitary hormone deficiencies (MPHD) and patients with HH+absent puberty (BTV: 21 ± 14/24 ± 9 mL; SC: 5.5 ± 6.5/ 14.5 ± 23.8 mill/mL). HH men with pubertal arrest and with post-pubertally acquired MPHD had the best results (BTV: 36 ± 14/38 ± 16 mL; SC: 25.4 ± 34.2/29.9 ± 50.5 mill/mL). Earlier conception after 20.3 ± 11.5 months (vs. 43.1 ± 43.8; p = 0.047) of gonadotropin treatment with higher pregnancy rates (62% vs. 42%) was achieved in the two post-pubertally acquired HH subgroups, compared to the three pre-pubertally acquired. Therapeutic success was higher in patients without previously undescended testes, with higher baseline BTVs (pre- vs. post-pubertal HH: 5 ± 4 mL vs. 26 ± 16 mL; p < 0.0001) and higher baseline inhibinB levels (pre- vs. post-pubertal HH: 16.6 vs. 144.5 pg/mL; p = 0.0004). The cause of HH is a valuable predictor of outcome of gonadotropin replacement in adults.

PD24-08 WHICH IS THE BEST TREATMENT FOR HYPOGONADOTROPIC HYPOGONADISM AZOOSPERMIC MEN IN JAPAN?

You have accessJournal of UrologyInfertility: Therapy1 Apr 2014PD24-08 WHICH IS THE BEST TREATMENT FOR HYPOGONADOTROPIC HYPOGONADISM AZOOSPERMIC MEN IN JAPAN? Yoshitomo Kobori, Shigeyuki Ota, Takeshi Shin, Masashi Iijima, Hiroshi Yagi, Gaku Arai, Shigehiro Soh, and Hiroshi Okada Yoshitomo KoboriYoshitomo Kobori More articles by this author , Shigeyuki OtaShigeyuki Ota More articles by this author , Takeshi ShinTakeshi Shin More articles by this author , Masashi IijimaMasashi Iijima More articles by this author , Hiroshi YagiHiroshi Yagi More articles by this author , Gaku AraiGaku Arai More articles by this author , Shigehiro SohShigehiro Soh More articles by this author , and Hiroshi OkadaHiroshi Okada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1999AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The standard treatment for male hypogonadotropic hypogonadism (HH) has not yet been determined. The objective of this study is to compare the efficacy and safety of recombinant human follicle-stimulating hormone (r-hFSH), human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) treatment for HH in Japanese men and to identify characteristics predictive of spermatogenesis. A multicenter, open-label, retrospective study was performed with combined rhFSH, hMG and hCG treatment to induce spermatogenesis in each idiopathic, acquired and adult onset MHH patients. METHODS Total 137 HH patients were enrolled. Seventy-nine patients with pre-pubertal onset idiopathic HH, forty-two patients with acquired HH and sixteen patients with adult onset idiopathic HH were considered for this study (19-44 years old). All of them were azoospermia before treatment. They received only hCG treatment, hCG + hMG treatment, or hCG +rhFSH treatment. Semen analyses were performed periodically, and pubertal advancement and long-term safety and tolerability were also evaluated. If patients with hCG or hCG + hMG treatment could not succeed in induction of spermatogenesis, hCG + rhFSH was started. RESULTS Spermatozoa with ejaculation was achieved by 16 of 55 (29%) with hCG treatment alone, 7 of 14 (50%) with hGC + hMG treatment, 31 of 35 (89%) with hCG + rhFSH treatment. The group of using rhFSH obtained spermatogenesis in significantly higher rate (p<0.05). Even if sperm was not retrieved with treatment of hCG or hCG + hMG, most patients (over 90%) could achieve spermatogenesis with adding rhFSH. The mean duration to achieve appearance of sperm in the ejaculates were 11.1 months with hCG treatment, 27.2 months with hCG +hMG treatment and 10.7 months with hCG +rhFSH treatment. The most effective doses were 5000 IU of hCG two times weekly and 150 IU of rhFSH two or three times weekly. CONCLUSIONS Long-term treatment of azoospermic HH men using rhFSH, hMG and hCG was effective for stimulating spermatogenesis and is well-tolerated. The combined use of hCG and rhFSH was the most useful in spermatogenesis for male HH patients. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e733 Peer Review Report Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yoshitomo Kobori More articles by this author Shigeyuki Ota More articles by this author Takeshi Shin More articles by this author Masashi Iijima More articles by this author Hiroshi Yagi More articles by this author Gaku Arai More articles by this author Shigehiro Soh More articles by this author Hiroshi Okada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Clinical efficacy, safety and tolerability of recombinant human chorionic gonadotropin to restore spermatogenesis and androgen production of hypogonadotropic hypogonadal men

Gonadotropin therapy, in the form of human chorionic gonadotropin (hCG) and/or human menopausal gonadotropin (hMG), is indicated to restore spermatogenesis in hypogonadotropic hypogonadal (hypo-hypo) males. Recently, recombinant hCG (rec-hCG) become available, but data is limited on its effectiveness to treat men with hypo-hypo. We present the clinical efficacy, safety and tolerability of rec-hCG to restore spermatogenesis and androgenic status in a group of men with hypo-hypo seeking fertility. Case-series. Eleven men with adult-onset hypo-hypo seeking fertility restoration was treated with a single weekly subcutaneous (SC) injection of rec-hCG for a minimum of 12 weeks. All patients presented with clinical signs of hypoandrogenism and were azoospermic. Testis biopsy results revealed peritubular fibrosis and maturation arrest. Mean baseline FSH, LH and testosterone levels were 0.46 ± 0.28 mUI/mL, 0.39 ± 0.32 mUI/mL and 41.3 ± 26.9 ng/dL. All but one man restored spermatogenesis after a mean of 12 treatment weeks. Total motile sperm count at the completion of treatment was 39x106 (range 0.0-156.9x106). Testosterone levels at the 12th treatment weeks were 647.5 ± 219.0 ng/dL, respectively. A marked improvement in virilization, libido and erectile function was also observed. Mean combined testis volume increased from 24 mL before to 33 mL posttreatment. Headache, gynecomastia and increased estradiol levels were observed in one man who did not recover spermatogenesis. All patients reported hCG SC self-administration with mininmal or no local side effects and/or discomfort. In our series, a single weekly injection of rec-hCG was effective to restore spermatogenesis and androgen production in most adult-onset hypo-hypo males. In view of the favorable efficacy, safety and tolerability profile of rec-hCG, it may be considered as an alternative to intramuscular urinary-derived hCG administration to hypo-hypo men seeking fertility.

Efficacy of recombinant human follicle stimulating hormone at low doses in inducing spermatogenesis and fertility in hypogonadotropic hypogonadism

Recombinant-FSH (rFSH) added to hCG at dose of 450 IU weekly is effective in inducing spermatogenesis in patients with hypogonadotropic hypogonadism (HH), but there are no data on the use of lower doses. This observational retrospective study evaluated whether 150-225 IU of rFSH weekly were able to induce spermatogenesis in HH men who failed to start it with hCG alone. Thirty-four patients with pre-pubertal onset HH (20-44 yr old) without adverse fertility factors were considered for this study. After hCG pre-treatment they received also either rFSH (Group 1) or highly purified urinary FSH (hpFSH) (Group 2) 75 IU sc 2 or 3 times weekly. Semen analysis was performed every 3 months during pre-treatment and the 1st yr of combined therapy. Patients were also invited to refer pregnancies in their partners during the subsequent 12 months. Total sperm count/ejaculate did not show significant difference between 2 groups, while a significantly higher forward motility was observed in Group 1 (p<0.05). The median times to achieve sperm output thresholds (first sperm appearance, sperm concentration >1.5 or >5 mil/ml) were significantly lower in Group 1 (p<0.04, 0.03, and 0.001, respectively). A tendency to a shorter time to pregnancy was shown in partners of Group 1. Our data indicate that lower rFSH week dose than that so far used was able to induce potentially fertilizing sperm output in HH men previously treated with hCG. The rFSH effects are comparable to those of hpFSH but with a trend to a faster outcome achievement.

Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f®): long-term treatment in azoospermic men with hypogonadotropic hypogonadism

To demonstrate the efficacy and safety of follitropin alfa administered with hCG on spermatogenesis in adult male hypogonadotropic hypogonadism (HH) patients. Phase III, multicenter, open-label, noncomparative. Seven US medical centers. A total of 36 adult males with severe HH. A total of 1,000 U hCG on alternate days for 3 to 6 months, with dose adjustments after 2 months, if necessary, to normalize T levels, followed by follitropin alfa 150 U and hCG on the same alternate days for 18 months, with dose adjustments as necessary. Proportion of patients with sperm density > or =1.5 x 10(6)/mL. Pubertal advancement and long-term safety and tolerability were also evaluated. In total, 22 of 29 patients (75.9%) who received > or =1 dose of follitropin alfa and 20 of 25 patients (80%) who completed 18 months of hCG + follitropin alfa treatments achieved a sperm concentration > or =1.5 x 10(6)/mL. A sperm concentration >20 x 10(6)/mL was achieved by 8 of 29 men (27.5%). Median sperm concentration at 18 months was 5.2 x 10(6)/mL. Pubertal development continued during the study, and testis volumes increased. Five clinical pregnancies were achieved. Acne (52% of patients) was the most common side effect, and gynecomastia was reported in 10% of patients. Long-term treatment of azoospermic HH men using follitropin alfa and hCG is effective for stimulating spermatogenesis and is well-tolerated.

Rescue of spermatogenesis arrest in azoospermic men after long-term gonadotropin treatment

Several studies have shown that FSH treatment can improve sperm production quantitatively and increase the spermatogonial population in oligozoospermic men with normal hormonal profiles. In this study, we describe the results of long-term gonadotropin therapy of normogonadotropic patients with nonobstructive azoospermia.

Advancing towards a male contraceptive: a novel approach from an unexpected direction

The development of an effective, reversible and safe male contraceptive has been the focus of research around the world for more than 30 years. There are numerous challenges in the development of a male contraceptive. Unlike women, who produce one functional gamete per month, men produce ∼100 million sperm every day. Based on animal studies and clinical results from treating hypogonadotropic hypogonadal men, a contraceptive agent that would functionally suppress either the formation or maturation of spermatozoa with a 90% efficacy would probably have little or no effect on fertility. Several non-hormonal avenues for male contraception are being developed, and a recent study provides an exciting novel approach to male contraception by administration of a drug that modifies the biosynthesis of glycosphingolipids.

Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone.

It is generally accepted that both gonadotropins LH and FSH are necessary for initiation and maintenance of spermatogenesis. We investigated the relative importance of FSH for the maintenance of spermatogenesis in hypogonadotropic men. 13 patients with gonadotropin deficiency due to idiopathic hypogonadotropic hypogonadism (IHH), Kallmann syndrome or pituitary insufficiency were analyzed retrospectively. They had been treated with gonadotropin-releasing hormone (GnRH) (n=1) or human chorionic gonadotropin/human menopausal gonadotropin (hCG/hMG) (n=12) for induction of spermatogenesis. After successful induction of spermatogenesis they were treated with hCG alone for maintenance of secondary sex characteristics and in order to check whether sperm production could be maintained by hCG alone. Serum LH, FSH and testosterone levels, semen parameters and testicular Volume were determined every three to six Months. After spermatogenesis had been successfully induced by treatment with GnRH or hCG/hMG, hCG treatment alone continued for 3-24 Months. After 12 Months under hCG alone, sperm counts decreased gradually but remained present in all patients except one who became azoospermic. Testicular Volume decreased only slightly and reached 87% of the Volume achieved with hCG/hMG. During treatment with hCG alone, FSH and LH levels were suppressed to below the detection limit of the assay. Once spermatogenesis is induced in patients with secondary hypogonadism by GnRH or hCG/hMG treatment, it can be maintained in most of the patients qualitatively by hCG alone, in the absence of FSH, for extended periods. However, the decreasing sperm counts indicate that FSH is essential for maintenance of quantitatively normal spermatogenesis.

High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men

In order to determine the efficacy of gonadotropin and gonadotropin-releasing hormone (GnRH) therapy in hypogonadotropic hypogonadal men, we performed a retrospective clinical analysis in the outpatient clinic of a University Center for Reproductive Medicine, Twenty-six men with either hypothalamic (idiopathic hypogonadotropic hypogonadism, N = 6; Kallmann syndrome, N = 8) or pituitary disorders (N = 12) were treated with gonadotropins or GnRH for induction of spermatogenesis in 33 treatment cycles and, additionally, for induction of pregnancy in the female partner in 18 out of 33 cases (12 of 26 patients). Patients were treated with a combination of 1000-2500 IE of human chorionic gonadotropin twice per week and 75-150 IE human menopausal gonadotropin three times per week intramuscularly or subcutaneously. Alternatively, GnRH was administered at doses of 5-20 micrograms every 120 min subcutaneously to men with hypothalamic disorders. Treatment lasted until sperm appeared in the ejaculate or pregnancy was induced. During therapy, testosterone levels increased into the normal range. Total testicular volumes increased significantly during therapy despite low initial testicular volumes and histories of maldescended testes. Sperm appeared in the ejaculate in 30 of 33 treated patients. Pregnancies occurred in 15 out of 18 cases even with sperm counts far below the normal range. We could not detect differences in the efficacy of gonadotropin or GnRH treatment in hypogonadotropic hypogonadism. Thus, we conclude that both gonadotropin and pulsatile GnRH therapy are most effective in the induction of spermatogenesis and pregnancies in hypogonadotropic hypogonadal men, despite maldescended testes, low initial testicular volumes or sperm concentrations below the normal limit.

Hypogonadotropic hypogonadal men respond less well to androgen substitution treatment than hypergonadotropic hypogonadal men.

This research asked whether androgen substitution therapy is as efficacious in hypogonadotropic hypogonadal men as in hypergonadotropic hypogonadal men. Erotosexual functions of two groups of six men of each diagnostic category were compared after 5-6 years of continuous androgen treatment. Treatment regimen was the same in both groups: Parenteral testosterone esters 250 mg/2 weeks. No difference was found in erectile and ejaculatory potency, but the number of sexual acts and scores of subjective quality of sexual acts, sexual excitement, and frequency of sexual thoughts and of nonsexual parameters as vigor, fatigue, anxiety were more negative in the hypogonadotropic men. The most obvious difference between the two groups is the value of LH/FSH and presumably of LHRH. Hypogonadotropic hypogonadal men may be better treated with gonadotropins (or with pulsatile LHRH, when the hypophysis is intact) than with androgens.

Hyperprolactinemic Male Infertility

Serum prolactin was studied in 25 fertile and 127 infertile men. The latter included 91 oligospermic, 27 azoospermic, and 9 hypogonadotropic hypogonadal men. The mean prolactin level in all three groups of infertile men was significantly above that of the fertile group. There was no correlation among serum levels of follicle-stimulating hormone, luteinizing hormone, sperm count, and serum prolactin values. Hyperprolactinemia was found in five patients (two oligospermic, one azoospermic, and two hypogonadotropic hypogonadal men). Bromocriptine, 2.5 mg twice daily, suppressed hyperprolactinemia. In one man with hyperprolactinemic oligospermia, treatment with bromocriptine yielded significant improvement in sperm count (to normal values).