Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Hypogonadotropic hypogonadism (HH) is characterized by abnormally low endogenous gonadotropin levels, and negligible testosterone activity caused by either a lack or inadequate secretion of gonadotropin-releasing hormone (GnRH), or insufficient production of two pituitary gonadotropins and result in impairment of spermatogenesis [1]. It is an uncommon cause of male infertility, and this disorder can be broadly classified as being congenital or acquired based on etiology, with an estimated prevalence between 1/4000 and 1/10,000 in men [2]. To date, a genetic basis for congenital HH can be identified in roughly 50% of affected cases, and is notable for its highly variable expressivity and penetrance owing not only to classic Mendelian inheritance (autosomal recessive, autosomal dominant, X-link recessive transmission) but also to the oligogenic inheritance genetic model involved [3].
The hormonal regulation of spermatogenesis involves complex paracrine and endocrine interactions among the various structural elements of the testis and the endocrine system [4]. Without sufficient gonadotropins to stimulate and maintain testicular function, azoospermia is the most commonly manifested semen phenotype evident in HH men [5]. While most cases of male infertility are caused by unexplained defects in spermatogenesis for which specific treatment may be lacking, hypogonadotropic hypogonadism is an exception in that effective treatments for the condition are available, and in fact most affected individuals respond well to such treatment. Arguably, exogenous gonadotropin is the recommended fertility-inducing treatment of choice for HH men who wish to attain fertility. Various gonadotropin preparations are used to induce spermatogenesis and generally, fertility can be restored in up to 80% of HH men with a reported median time for the appearance of sperm in semen in 7 months after initiation of therapy with human chorionic gonadotropin (hCG) alone or in combination with human menopausal gonadotropin (hMG) [6]. The dosage of hCG/hMG is typically titrated according to quarterly assessed individual responses in semen parameters and testosterone levels. With adequate treatment duration, one series even reported spermatogenesis achieved in 88% of patients [7].
Ideally, a treatment course of 12–18 months may help HH men attain maximal sperm count and impregnate their partners through natural conception. However, regardless of etiology, smaller testicular volume, particularly in those cases <4 ml, portends a poor prognosis for the use of gonadotropin treatment to induce successful spermatogenesis [6, 8, 9]. For those with persistent azoospermia who are unresponsive to gonadotropin therapy, or those cases of azoospermic men with female partners whose evaluations reveal diminished ovarian reserve, early use of assisted reproductive technology (ART) to surgically retrieve sperm from testes may provide favorable fertility outcomes. However, there are as yet few studies available on the reproductive outcomes of HH men after receiving sperm-induction treatments, with few prior results reporting on fertilization and pregnancy outcomes of intracytoplasmic sperm injection (ICSI) for azoospermic HH men using testicular sperm extraction (TESE) [5, 10, 11]. In view of this, the present study was undertaken to investigate the cycle characteristics and fertility outcomes after ICSI using surgically retrieved sperm.
Materials and methods
Patients
Between 2008 and 2020, azoospermic men presenting with primary infertility and a diagnosis of HH were selected for this study. All subjects underwent a standard complete infertility evaluation, including a detailed medical history regarding the type of infertility and a thorough general physical examination. The basic hormone diagnostic workup consists of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, prolactin and estradiol (E2); HH was defined by the findings of inadequate (low) serum levels of FSH, LH and testosterone. This study was approved by the Taipei Veterans General Hospital Institutional Review Board (IRB: 2020-04-004BC).
Treatment protocol
Therapy was initiated by administration of human chorionic gonadotropin (hCG) 3000 IU (Pregnyl, MSD Pharmaceuticals), which was given subcutaneously twice per week for a period of 24 weeks. Once treatment commenced, each patient was advised to submit their semen specimen once every 3 months thereafter. The ejaculates were obtained by masturbation after 3 days of sexual abstinence. Highly purified human menopausal gonadotropin (hMG) (Menopur, Ferring Pharmaceuticals), in doses of 75 IU 2 times per week, was added to the regimens of those HH men who did not recover spermatogenesis through hCG alone. During the gonadotropin therapy period, the frequency of hCG and the dosage of hMG were gradually adjusted as necessary based on regularly evaluated serum hormone profile and performed until adequate response was achieved. All patients were informed that the appearance of spermatozoa in semen typically required a gonadotropin treatment course of up to 6 to 12 months.
Sperm retrieval with microdissection testicular sperm extraction (mTESE)
The mTESE procedure was performed under general anesthesia and was modified by the maneuver originally described by Schlegel [12]. In brief, a 3-cm median raphe incision was made in the scrotum, followed by delivery of the testis. Tunica albuginea was opened vertically, and microdissection was carried out to search for seminiferous tubules with a larger diameter under optical magnification (20–25×) using an operating microscope. The area containing dilated tubules could thereby be clearly distinguished; after the selected seminiferous tubules were meticulously excised, tissue was transferred to the Eppendorf containing sperm culture media. These samples were subsequently sent to the in vitro fertilization (IVF) lab for examination of viable sperm by an embryologist. When no sperm was obtained on ipsilateral search, the procedure was repeated on the contralateral testicle in the same manner. If mature testicular sperm was recovered, intracytoplasmic sperm injection (ICSI) was subsequently performed.
Controlled ovarian stimulation and embryo transfer
To increase the opportunities for fertilization, we performed one or more cycles of controlled ovarian stimulation collecting fresh ± cryopreserved eggs to be subsequently fertilized with the limited surgically retrieved fresh spermatozoa. The detailed protocol, from controlled ovarian stimulation to embryo transfer and fetal heartbeat detection, was previously described by Huang et al. [13]. Most patients started controlled ovarian stimulation with gonadotropin during the early follicular phase after checking the antral follicle count (AFC) and serum hormone (estradiol, LH, progesterone) levels. On stimulation day 5, sonography and serum hormone levels were checked, and daily GnRH antagonist administration was initiated to prevent LH surge. On stimulation day 8, we repeated sonography and serum hormone monitoring to decide the timing of trigger (by hCG or GnRH agonist or a combination of both). Since early 2017, progestin-primed ovarian stimulation (PPOS) with long-acting FSH, an extremely patient-friendly protocol, has been used at our institution when deemed feasible and the efficacy was thereafter validated in the literature [14]: A single injection of corifollitropin alfa (Elonva, MSD Pharmaceuticals) was given in the early follicular phase, followed by oral medroxyprogesterone acetate (MPA) (Provera, Pfizer Pharmaceuticals) 5 mg twice daily. One week later, serum hormone levels were checked, and follicle development was monitored via sonography, and the timing of trigger was decided.
After oocyte retrieval
Oocytes were retrieved on the same day as sperm-retrieval surgery, which was about 36 h after triggering. Cryopreserved oocytes from the same patient were thawed for ICSI on the day of sperm retrieval. Embryos were vitrified at pronuclear stage, or on day 2, 3 or 5 after fertilization with fresh spermatozoa. Frozen-thawed embryo transfer was performed after endometrial preparation. Serum beta hCG levels were measured about 2 weeks later (biochemical pregnancy). Ten days after biochemical pregnancy was determined, we used transvaginal sonography to confirm gestational sacs (clinical pregnancy).
Statistical analysis
The nonparametric test and Fisher’s exact test were performed to compare continuous and categorical variables in patients with or without sperm detected in semen after gonadotropin treatment. A value of p < 0.05 was considered to be statistically significant. All statistical analyses were performed using the SAS software, V9.2 (SAS Institute, NC, USA).
Results
Profile of HH patients
The analysis included 17 infertile men with HH whose baseline characteristics are shown in Table 1. The identified causes of HH in these men included the following: 3 (17.6%) due to acquired HH (pituitary tumor), 4 (23.5%) due to Kallmann syndrome, and 10 (58.8%) due to normosmic idiopathic HH. The average patient age was 36.1 ± 3.5 years and basal serum levels of FSH, LH, testosterone, prolactin and estradiol were 0.7 ± 1.0 (mIU/ml), 0.4 ± 0.3 (mIU/ml), 0.7 ± 0.5 (ng/ml), 8.9 ± 4.7 (ng/ml), 17.5 ± 9.7 (pg/ml), respectively.
Sperm was found in the ejaculate for seven (41.2%) of the 17 HH patients who received gonadotropin treatment. For these 7 men, a median treatment period of 5 months (range 1–37 months) was required for the appearance of first sperm in the ejaculate. Four of these seven men who received hCG alone have their sperm presence in their ejaculate within 6 months. Six of those 17 (35.3%, 6/17) men attained a sperm concentration of more than 1 × 106/ml after hCG/hMG administration, and four (23.5%, 4/17) men further reached a normal sperm concentration (>15 × 106/ml). Notably, treatment with gonadotropin stimulation resulted in sperm production for 16.7% (1/6) of patients with smaller testes (<4 ml) and 54.5% (6/11) of patients with relatively larger testes (≥4 ml), though the observed difference did not reach significant levels (p = 0.32). Moreover, statistical analysis revealed no significant differences between the 2 groups of patients (i.e., those with sperm present vs. those with sperm absent from the ejaculate after gonadotropin treatment) in terms of testis size, BMI, hormone levels (FSH, LH, Testosterone, prolactin, E2), history of exogenous testosterone administration and underlying etiology (Table 1).
Among the gonadotropin-responsive patients, those who produce a faster response rates (less than 5 months, N = 4), have comparable circulating hormone level to the only patient who received 37 months of gonadotropin injections. For those who failed gonadotropin treatment, 8 out of 10 patients have reported increased hair growth as well as libido.
mTESE results
Ten patients who remained azoospermic after a mean treatment duration of 12.1 months with gonadotropins further underwent mTESE; sperm retrieval was successful for 9 (90%) of those patients and unsuccessful for one (10%). For the one unsuccessful case, the testis histopathology demonstrated Sertoli-cell only pattern, and the histopathological slide demonstrated absence of spermatogonia, which was confirmed by further staining of spermatogonia cell surface receptor GFRα1.
Reproductive outcomes
Three of the seven men (42.9%) with sperm presence in semen successfully impregnated their partner, with one case resulting in a twin pregnancy and two cases in singletons. All pregnancies resulted in safe childbirth.
With respect to ART, mTESE-ICSI was performed on 9 couples, with at least one mature oocyte injected with fresh testicular sperm. After a total of 11 mTESE-ICSI cycles, including 2 cycles for 2 couples, eight (88.9% = 8/9) successful biochemical pregnancies (positive hCG) and six (66.7%, 6/9) successful clinical pregnancies were recorded. One of the six pregnancies had a missed abortion at 9 weeks of gestation, and the other five cases had live-born babies, including three singletons and two sets of twins, resulting in a cumulative live-birth rate of 55.6% (5/9). In total, there were 7 newborns, all with no malformations or defects. For those couples who delivered, the mean number ICSI cycles needed to obtain a delivery was 1.2. (Table 2)
Discussion
Our findings suggest that a proportion of HH men may be successfully treated with gonadotropins to induce spermatogenesis, while other HH men who are unresponsive to exogenous gonadotropin therapy and exhibit persistent azoospermia may nevertheless have a good chance to obtain spermatozoa from the testis for ICSI using mTESE. In fact, the ICSI outcomes in such cases were comparable to those achieved by couples with non-male factor infertility, as measured by fertilization rate, pregnancy rate and the live birth rate [15].
Since congenital HH is most often diagnosed after the age of puberty, the main therapeutic goal for these adolescents or young men is to restore a physical appearance and behavior close to normal. To achieve this goal, several therapeutic options exist, including administering exogenous testosterone, gonadotropins or pulsatile GnRH using a portable pump [16]. For HH men who aim at restoring spermatogenesis and improving fertility potential, no particular protocol or preparations has demonstrated its superiority in restoring spermatogenesis according to reported clinical trials [17,18,19]. Nevertheless, despite the absence of established protocol, exogenous gonadotropin supplement is currently the most widely used approach due to its convenience and relatively lower cost compared to pulsatile GnRH administration [20]. Based on the current recommendations of the European Association of Urology, one to two years of gonadotropin administration may be required before the appearance of sperm in the ejaculate [21]. A phase III multicenter trial had shown effectiveness and safety of long-term gonadotropin usage, for up to 18 months [22]. However, according to a few clinical studies, observation of sperm production can be expected after an average treatment period of 6 months in the majority of patients [6, 23]. In those cases, parenthood was observed in less than half of cases without using assisted reproductive technology, despite sperm concentration that are lower than standard, according to WHO 2010 criteria (i.e., <15 mil/ml) [6]. This is probably due to the existence of good fertilizing capacity of sperm in HH men treated with gonadotropins. In our series, 7 out of 17 patients (41%) treated with gonadotropin showed a resulting appearance of spermatozoa in their semen specimens, but only 3 patients (3/7, 43%) achieved fatherhood. Accordingly, the live birth rates we observed from gonadotropin treatment alone were lower than those described in the aforementioned study. These lower live birth rates can be attributed to the fact that, rather than indefinitely continue to undergo gonadotropin treatment, which is a self-paid treatment option under the Taiwanese National Health Insurance system, a number of our patients chose to undergo mTESE/ICSI instead. The patients also made this decision based on the female spouses’ age or due to the uncertainty of fertility outcome after prolonged treatment.
In our clinic, HH men desiring paternity were counseled prior to commencing treatment regarding the general underlying characteristics that determine the outcome of gonadotropin therapy. Extensive review of literature revealed that testis size determined chances for successful induction of spermatogenesis [6, 23]. In particular, smaller testicular volume (<4 ml) presaged a lower likelihood for spermatozoa to appear in the ejaculate; moreover, patients with smaller volume generally require longer time to induce spermatogenesis than those with larger baseline testicular volume [17]. In addition, other studies reported Kallmann syndrome [24] and previous treatment with exogenous testosterone as being adverse prognostic factors [6]. However, the aforementioned factors were not demonstrated to confer bad prognoses in our study, and this is likely due to our relatively small cohort size which limited its usefulness in finding statistically significant risk factors.
According to a meta-analytic review [19], it has been shown that using combination treatment with hCG and FSH offer a higher success rate in achieving spermatogenesis comparing to hCG triggering alone. Notably, applying different preparations of FSH product (purified, urine-derived or recombinant) is associated with similar treatment outcomes. Concerning the treatment duration required for the induction of spermatogenesis using combined gonadotropin therapy, a median of 7–9 months is considered requisite for the appearance of sperm in semen, but the time span may range from 3 to 19 months [6, 20, 23]. Although no consensus has been reached regarding the duration of spermatogenesis induction, most studies reported their reproductive outcome and spermatogenesis results with gonadotropin usage within 24 months, and recommend delaying assisted reproductive technology intervention until optimal testicular development and maximal sperm production have been achieved [7, 10, 25]. In our cohort, the duration of treatment seems excessive (mean 12.1 months, range 6–23 months) for gonadotropin non-responsive men, before they underwent mTESE-ICSI. Two patients received 23 months and one patient received 18 months of gonadotropin treatment until they proceed with surgical sperm retrieval. This may be due, in part, to the observation of progressive testicular growth in these three men after prolonged gonadotropin administration, and their individual decision to extend treatment, despite the option of assisted conception was offered for these persistent azoospermic HH men after 9 months of treatment.
Assisted reproductive technology, employing testis-derived spermatozoa procured via TESE followed with subsequent IVF-ICSI treatment, increases the chances for pregnancy in infertile couples. Prior studies have reported their experiences in treating HH couples using TESE and ICSI. In 2004, Meseguer et al. [26] reported a 30-year-old man with idiopathic HH who unsuccessfully underwent 12 months of gonadotropins therapy, but then successfully achieved fertilization using cryopreserved spermatozoa retrieved by conventional TESE. While the resulting pregnancy failed in that particular case, the report clearly demonstrated the potential of using assisted reproduction techniques with TESE-ICSI to treat these patients. In another study, Fahmy et al. [5] reported that sperm was successfully retrieved in 11 (73%) of 15 azoospermic HH patients using conventional TESE, but disclosed a suboptimal fertility outcome of 41.7% fertilization rate and 17.6% pregnancy rate per cycle. Moreover, two smaller case studies demonstrated good sperm retrieval rates (100%) using mTESE in two and four HH men who remained azoospermic despite adequate medical treatment [10, 11]. In one of the two studies, Akarsu et al. [11] recorded three clinical pregnancies in six mTESE-ICSI cycles, resulting in two live births using fresh and thawed sperm in 4 couples. The authors reported different fertility outcomes with fresh and cryopreserved spermatozoa, and a better fertilization rate was observed for fresh (58%) compared to thawed (19%) sperm [11]. In the present study, we used fresh spermatozoa in all cases and found a similar fertilization rate (60.1%), pregnancy rate per mTESE/ICSI cycle (54.5%), and live-birth rate (55.6%). The comparison of the reproductive outcomes of our present study with those reported in previous literature is presented in Table 3.
Although our current study is limited by its retrospective design, relatively limited number of patients, and the fact that a majority of HH men underwent mTESE before the maximum gonadotropin response achieved, we nevertheless found evidence that even with shorter periods of spermatogenesis induction treatment, testicular sperm can be obtained in most azoospermic HH men using mTESE with optimal reproductive outcomes.
In conclusion, gonadotropin therapy can reverse azoospermic status in certain HH male patients. In men who are still azoospermic after gonadotropin treatment, testicular sperm can still be retrieved by mTESE in almost all patients for use in assisted reproductive technology to achieve live births.
Data availability
Not applicable
References
Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009;5(10):569–76. https://doi.org/10.1038/nrendo.2009.177.
Fromantin M, Gineste J, Didier A, Rouvier J. Impuberism and hypogonadism at induction into military service. Statistical study. Probl Actuels Endocrinol Nutr. 1973;16:179–99.
Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, Bouligand J, et al. Genetics in endocrinology: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178(3):R55–80. https://doi.org/10.1530/EJE-17-0749.
Huleihel M, Lunenfeld E. Regulation of spermatogenesis by paracrine/autocrine testicular factors. Asian J Androl. 2004;6(3):259–68.
Fahmy I, Kamal A, Shamloul R, Mansour R, Serour G, Aboulghar M. ICSI using testicular sperm in male hypogonadotrophic hypogonadism unresponsive to gonadotrophin therapy. Hum Reprod. 2004;19(7):1558–61. https://doi.org/10.1093/humrep/deh243.
Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab. 2009;94(3):801–8. https://doi.org/10.1210/jc.2008-1648.
Morris GC, Lloyd-Evans E, Cahill DJ. Induction of spermatogenesis in men with hypogonadotropic hypogonadism. J Assist Reprod Genet. 2021;38:803–7. https://doi.org/10.1007/s10815-020-02058-0.
Pitteloud N, Hayes FJ, Boepple PA, DeCruz S, Seminara SB, MacLaughlin DT, et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002;87(1):152–60. https://doi.org/10.1210/jcem.87.1.8131.
Miyagawa Y, Tsujimura A, Matsumiya K, Takao T, Tohda A, Koga M, et al. Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: a 30-year retrospective study. J Urol. 2005;173(6):2072–5. https://doi.org/10.1097/01.ju.0000158133.09197.f4.
Bakircioglu ME, Erden HF, Ciray HN, Bayazit N, Bahçeci M. Gonadotrophin therapy in combination with ICSI in men with hypogonadotrophic hypogonadism. Reprod Biomed Online. 2007;15(2):156–60. https://doi.org/10.1016/s1472-6483(10)60703-1.
Akarsu C, Caglar G, Vicdan K, Isik AZ, Tuncay G. Pregnancies achieved by testicular sperm recovery in male hypogonadotrophic hypogonadism with persistent azoospermia. Reprod Biomed Online. 2009;18(4):455–9. https://doi.org/10.1016/s1472-6483(10)60119-8.
Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod. 1999;14(1):131–5.
Huang CY, Chen GY, Shieh ML, Li HY. An extremely patient-friendly and efficient stimulation protocol for assisted reproductive technology in normal and high responders. Reprod Biol Endocrinol. 2018;16(1):18. https://doi.org/10.1186/s12958-018-0335-0.
Huang C-Y, Chen G-Y, Shieh M-L, Li H-Y. Validating the use of Corifollitropin alfa in progestin-primed ovarian stimulation protocol on normal and high responders by comparing with conventional antagonist protocol: a retrospective study. Life (Basel). 2020;10(6):90. https://doi.org/10.3390/life10060090.
Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, Jamieson DJ. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA. 2015;313(3):255–63. https://doi.org/10.1001/jama.2014.17985.
Howles CM, Tanaka T, Matsuda T. Management of male hypogonadotrophic hypogonadism. Endocr J. 2007;54(2):177–90. https://doi.org/10.1507/endocrj.02-kr-98.
Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol. 1998;139(3):298–303. https://doi.org/10.1530/eje.0.1390298.
Liu L, Banks SM, Barnes KM, Sherins RJ. Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 1988;67(6):1140–5. https://doi.org/10.1210/jcem-67-6-1140.
Rastrelli G, Corona G, Mannucci E, Maggi M. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study. Andrology. 2014;2(6):794–808. https://doi.org/10.1111/andr.262.
Prior M, Stewart J, McEleny K, Dwyer AA, Quinton R. Fertility induction in hypogonadotropic hypogonadal men. Clin Endocrinol (Oxf). 2018;89(6):712–8. https://doi.org/10.1111/cen.13850.
Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, et al. European Association of Urology guidelines on male infertility: the 2012 update. Eur Urol. 2012;62(2):324–32. https://doi.org/10.1016/j.eururo.2012.04.048.
Matsumoto AM, Snyder PJ, Bhasin S, Martin K, Weber T, Winters S, et al. Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f): long-term treatment in azoospermic men with hypogonadotropic hypogonadism. Fertil Steril. 2009;92(3):979–90. https://doi.org/10.1016/j.fertnstert.2008.07.1742.
Warne DW, Decosterd G, Okada H, Yano Y, Koide N, Howles CM. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril. 2009;92(2):594–604. https://doi.org/10.1016/j.fertnstert.2008.07.1720.
Rohayem J, Sinthofen N, Nieschlag E, Kliesch S, Zitzmann M. Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults. Andrology. 2016;4(1):87–94. https://doi.org/10.1111/andr.12128.
Dwyer AA, Raivio T, Pitteloud N. Gonadotrophin replacement for induction of fertility in hypogonadal men. Best Practice & Research Clinical Endocrinology & Metabolism. 2015;29(1):91–103. https://doi.org/10.1016/j.beem.2014.10.005.
Meseguer M, Garrido N, Remohí J, Pellicer A, Gil-Salom M. Testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) in hypogonadotropic hypogonadism with persistent azoospermia after hormonal therapy. J Assist Reprod Genet. 2004;21(3):91–4. https://doi.org/10.1023/b:jarg.0000027021.66435.02.
Acknowledgements
The authors thank the Taipei Veterans General Hospital for grants support (VGH-109-C-132). We also gratefully acknowledge Dr. Guan-Yeu Chen for his support regarding data collection in TESE-ICSI cycles.
Code availability
Not applicable
Funding
This study was supported by the Taipei Veterans General Hospital for grants support (VGH-109-C-132).
Author information
Authors and Affiliations
Contributions
Yu-Kuang Chen and I-Shen Huang contributed equally to this article.
Wei-Jen Chen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Wei-Jen Chen.
Acquisition of data: Yu-Kuang Chen.
Analysis and interpretation of data: Yu-Kuang Chen.
Drafting of the manuscript: Yu-Kuang Chen, I-Shen Huang, Wei-Jen Chen.
Critical revision of the manuscript for important intellectual content: Wei-Jen Chen, I-Shen Huang, Chen-Yu Huang.
Statistical analysis: Yu-Kuang Chen.
Obtaining funding: None.
Administrative, technical, or material support: Chi-Hong Ho, Eric Yi-Hsiu Huang
Supervision: William J. Huang
Other: None.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Taipei Veterans General Hospital Institutional Review Board (IRB: 2020-04-004BC).
Consent for publication
Not applicable
Conflict of interest
The authors declare that there is no potential conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Chen, YK., Huang, IS., Chen, WJ. et al. Reproductive outcomes of microdissection testicular sperm extraction in hypogonadotropic hypogonadal azoospermic men after gonadotropin therapy. J Assist Reprod Genet 38, 2601–2608 (2021). https://doi.org/10.1007/s10815-021-02211-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-021-02211-3