The Effect of Varicocelectomy on Serum Testosterone Levels in Infertile Men with Varicoceles
Li-Ming Su, Marc Goldstein, Peter N. Schlegel
Division of Male Reproductive Medicine and Microsurgery, James Buchanan Brady Foundation, Department of Urology, New York Hospital-Cornell Medical Center and Center for Biomedical Research, Population Council, New York, New York.
Accepted 7 April 1995.
Abstract Full Text PDF Images References
We evaluated the effect of varicocelectomy on serum testosterone.
Materials and Methods
We retrospectively reviewed the effect of varicocelectomy on serum testosterone levels in 53 infertile men with varicoceles.
Mean serum testosterone increased from a preoperative level of 319 plus/minus 12 to 409 plus/minus 23 ng./dl. postoperatively (p less than 0.0004). Men with at least 1 firm testis preoperatively had a greater increase in serum testosterone (p less than 0.005). An inverse correlation was noted between preoperative testosterone levels and change in testosterone after varicocelectomy (r = −0.34, p less than 0.013).
Varicocelectomy can increase serum testosterone for infertile men with varicoceles. Although improvement in serum testosterone does not necessarily cause a direct improvement in semen quality, varicocelectomy may improve hormonal and spermatogenic function.
Factors in nonuniform induction of azoospermia by testosterone enanthate in normal men. World Health Organization Task Force on Methods for the Regulation of Male Fertility.
Handelsman DJ, Farley TM, Peregoudov A, Waites GM
Department of Medicine, University of Sydney, New South Wales, Australia.
Fertility and Sterility [1995, 63(1):125-33]
Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, U.S. Gov't, Non-P.H.S.
Abstract Highlight Terms
Gene Ontology(1) Diseases(1) Chemicals(1)
OBJECTIVE: To identify factors differentiating men becoming azoospermic from those remaining oligozoospermic within 6 months of T treatment.
DESIGN: Prospective, open, noncomparative contraceptive efficacy study.
SETTING: International multicenter study of 271 men in 10 centers in seven countries.
PATIENTS: Data from 157 achieving azoospermia and 68 remaining oligozoospermic after 6 months of treatment were analyzed. The remaining 46 men were excluded as having unclassifiable suppression status due to discontinuation before completion of suppression.
INTERVENTIONS: Weekly IM injections of 200 mg T enanthate.
MAIN OUTCOME MEASURES: Anthropometric, seminal, hormonal, and biochemical data obtained before, during, and after treatment as potential predictors of consistent azoospermia.
RESULTS: Azoospermic men had  faster rates of fall in sperm output and, after a delay of 75 +/- 4 days (mean +/- SE) for sperm to reappear in the ejaculate, exhibited a faster rate of recovery of sperm output;  higher pretreatment levels of FSH (mean +/- SE; 3.7 +/- 0.3 versus 2.7 +/- 0.4 mIU/mL [conversion factor to SI units, 1.00]); and  (if treated for > 15 months) a prolonged after treatment rebound in gonadotropins compared with nonazoospermic men. There were no other differences in pretreatment variables or plasma T levels and changes in androgen-sensitive markers during treatment. None of the variables explained the higher rates of azoospermia among men in Chinese (91%, n = 3) compared with non-Chinese centers (60%, n = 7).
CONCLUSION: Nonuniformity of T-induced azoospermia among healthy fertile men is not due to anthropometric or ethnic differences, to variations in androgen effects, or to poor compliance with treatment. The heterogeneity in individual susceptibility to T-induced azoospermia is most consistent with quantitative differences in the hormonal regulation of spermatogenesis and is likely to be evident with other hormonal methods for male contraception.
Clinical trial with testosterone undecanoate for male fertility control
E. Nieschlag, H. Hoogen, M. Bölk, H. Schuster, E.J. Wickings
Abteilung Experimentelle Endokrinologie Universitäts-Frauenklinik Westring 11 4400 Münster, F.R. Germany
Accepted 21 November 1978.
Abstract Abstract + References PDF References
The newly available orally effective testosterone undecanoate (TU) was investigated as a possible means for male fertility control. One of 7 normal volunteers exposed to 80 mg TU three times a day for 10–12 weeks became azoospermic, the remaining showed slightly suppressed or unaffected sperm counts. The insufficient suppression of spermatogenesis in 6 out of 7 subjects may be due to the fact that testosterone levels are only sufficiently high to suppress gonadotropins for some hours after ingestion of the drug.
Fertil Steril. 1972 Jul;23(7):498-504.
The testosterone rebound phenomenon in the treatment of male infertility.
Rowley MJ, Heller CG.
PMID: 5036597 [PubMed - indexed for MEDLINE]
Large doses of testosterone were used to cause degeneration of the testicular germinal epithelium and a subsequent rebound of spermatogenesis, to produce improved seminal fluid. A 29% pregnancy rate was obtained by 131 patients treated for idiopathic oligospermia, and an 8% pregnancy rate was obtained by 12 patients treated for azoospermia. The seminal fluid of three patients (2%) was permanently damaged by the therapy.
PMID: 1168591 [PubMed - indexed for MEDLINE]
Asian J Androl. 2010 Jul;12(4):480-9. Epub 2010 Jun 7.
Obesity: modern man's fertility nemesis.
Cabler S, Agarwal A, Flint M, du Plessis SS.
Center for Reproductive Medicine, The Cleveland Clinic, Cleveland, OH 44195, USA.
The obesity pandemic has grown to concerning proportions in recent years, not only in the Western World, but in developing countries as well. The corresponding decrease in male fertility and fecundity may be explained in parallel to obesity, and obesity should be considered as an etiology of male fertility. Studies show that obesity contributes to infertility by reducing semen quality, changing sperm proteomes, contributing to erectile dysfunction, and inducing other physical problems related to obesity. Mechanisms for explaining the effect of obesity on male infertility include abnormal reproductive hormone levels, an increased release of adipose-derived hormones and adipokines associated with obesity, and other physical problems including sleep apnea and increased scrotal temperatures. Recently, genetic factors and markers for an obesity-related infertility have been discovered and may explain the difference between fertile obese and infertile obese men. Treatments are available for not only infertility related to obesity, but also as a treatment for the other comorbidities arising from obesity. Natural weight loss, as well as bariatric surgery are options for obese patients and have shown promising results in restoring fertility and normal hormonal profiles. Therapeutic interventions including aromatase inhibitors, exogenous testosterone replacement therapy and maintenance and regulation of adipose-derived hormones, particularly leptin, may also be able to restore fertility in obese males. Because of the relative unawareness and lack of research in this area, controlled studies should be undertaken and more focus should be given to obesity as an etiolgy of male infertility.
PMID: 20531281 [PubMed - indexed for MEDLINE]
Philos Trans R Soc Lond B Biol Sci. 2010 May 27;365(1546):1557-69.
Non-classical actions of testosterone and spermatogenesis.
Department of Cell Biology and Physiology, Magee Women's Research Institute, University of Pittsburgh, 204 Craft Avenue, Room B305, Pittsburgh, PA 15261, USA. firstname.lastname@example.org
Testosterone is essential to maintain spermatogenesis and male fertility. In the absence of testosterone stimulation, spermatogenesis does not proceed beyond the meiosis stage. After withdrawal of testosterone, germ cells that have progressed beyond meiosis detach from supporting Sertoli cells and die, whereas mature sperm cannot be released from Sertoli cells resulting in infertility. The classical mechanism of testosterone action in which testosterone activates gene transcription by causing the androgen receptor to translocate to and bind specific DNA regulatory elements does not appear to fully explain testosterone regulation of spermatogenesis. This review discusses two non-classical testosterone signalling pathways in Sertoli cells and their potential effects on spermatogenesis. Specifically, testosterone-mediated activation of phospholipase C and calcium influx into Sertoli cells is described. Also, testosterone activation of Src, EGF receptor and ERK kinases as well as the activation of the CREB transcription factor and CREB-mediated transcription is reviewed. Regulation of germ cell adhesion to Sertoli cells and release of mature sperm from Sertoli cells by kinases regulated by the non-classical testosterone pathway is discussed. The evidence accumulated suggests that classical and non-classical testosterone signalling contribute to the maintenance of spermatogenesis and male fertility.
PMID: 20403869 [PubMed - indexed for MEDLINE] PMCID: PMC2871922
Reprod Biol. 2010 Mar;10(1):19-35.
Cryptorchidism and long-term consequences.
Kurpisz M, Havryluk A, Nakonechnyj A, Chopyak V, Kamieniczna M.
Institute of Human Genetics, Polish Academy of Sciences, Department of Reproductive Biology and Stem Cells, Strzeszynska 32, 60-479 Poznan, Poland. email@example.com
Cryptorchidism has been on the rise for several decades and can be observed with frequency of 1-2% of males within the first year of age. It may appear as an isolated disorder or can be a consequence of genetic and endocrine abnormalities connected with somatic anomalies. Its genetic background still seems to be unclear although a range of genes can be responsible for the development of this syndrome. Cryptorchidism can be associated with serum testosterone level although the often co-existing hypogonadotropic hypogonadism may also indicate the involvement of pituitary hormones. Recently, environmental factors have been blamed for cryptorchidism induction. Autoimmune reactions in conjunction with steroid hormones regulating immune response can be also partly responsible for cryptorchidism etiology. The appearance of antisperm antibodies can be considered as a marker or a serious side-effect of uncorrected cryptorchidism. If so, it could be implied that early surgery (orchidopexy) should be beneficial since it may prevent antisperm antibodies induction or at least eliminate them in the post-operative period.
PMID: 20349021 [PubMed - indexed for MEDLINE]
J Endocrinol. 2010 May;205(2):117-31. Epub 2010 Feb 9.
Hormonal regulation of male germ cell development.
Ruwanpura SM, McLachlan RI, Meachem SJ.
Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia.
Over the past five decades, intense research using various animal models, innovative technologies notably genetically modified mice and wider use of stereological methods, unique agents to modulate hormones, genomic and proteomic techniques, have identified the cellular sites of spermatogenesis, that are regulated by FSH and testosterone. It has been established that testosterone is essential for spermatogenesis, and also FSH plays a valuable role. Therefore understanding the basic mechanisms by which hormones govern germ cell progression are important steps towards improved understating of fertility regulation in health diseases.
PMID: 20144980 [PubMed - indexed for MEDLINE]
Hum Reprod Update. 2010 May-Jun;16(3):293-311. Epub 2009 Nov 4.
The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis.
MacDonald AA, Herbison GP, Showell M, Farquhar CM.
School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
It has been suggested that body mass index (BMI), especially obesity, is associated with subfertility in men. Semen parameters are central to male fertility and reproductive hormones also play a role in spermatogenesis. This review aimed to investigate the association of BMI with semen parameters and reproductive hormones in men of reproductive age.
MEDLINE, EMBASE, Biological Abstracts, PsycINFO and CINAHL databases and references from relevant articles were searched in January and February 2009. Outcomes included for semen parameters were sperm concentration, total sperm count, semen volume, motility and morphology. Reproductive hormones included were testosterone, free testosterone, estradiol, FSH, LH, inhibin B and sex hormone binding globulin (SHBG). A meta-analysis was conducted to investigate sperm concentration and total sperm count.
In total, 31 studies were included. Five studies were suitable for pooling and the meta-analysis found no evidence for a relationship between BMI and sperm concentration or total sperm count. Overall review of all studies similarly revealed little evidence for a relationship with semen parameters and increased BMI. There was strong evidence of a negative relationship for testosterone, SHBG and free testosterone with increased BMI.
This systematic review with meta-analysis has not found evidence of an association between increased BMI and semen parameters. The main limitation of this review is that data from most studies could not be aggregated for meta-analysis. Population-based studies with larger sample sizes and longitudinal studies are required.
PMID: 19889752 [PubMed - indexed for MEDLINE]
Endocr Rev. 2009 Apr;30(2):119-32. Epub 2009 Jan 27.
Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice.
Wang RS, Yeh S, Tzeng CR, Chang C.
Department of Pathology and Urology, George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
Androgens are critical steroid hormones that determine the expression of the male phenotype, including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis. Their actions are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. AR functions as a ligand-dependent transcription factor, regulating expression of an array of androgen-responsive genes. Androgen and the AR play important roles in male spermatogenesis and fertility. The recent generation and characterization of male total and conditional AR knockout mice from different laboratories demonstrated the necessity of AR signaling for both external and internal male phenotype development. As expected, the male total AR knockout mice exhibited female-typical external appearance (including a vagina with a blind end and a clitoris-like phallus), the testis was located abdominally, and germ cell development was severely disrupted, which was similar to a human complete androgen insensitivity syndrome or testicular feminization mouse. However, the process of spermatogenesis is highly dependent on autocrine and paracrine communication among testicular cell types, and the disruption of AR throughout an experimental animal cannot answer the question about how AR in each type of testicular cell can play roles in the process of spermatogenesis. In this review, we provide new insights by comparing the results of cell-specific AR knockout in germ cells, peritubular myoid cells, Leydig cells, and Sertoli cells mouse models that were generated by different laboratories to see the consequent defects in spermatogenesis due to AR loss in different testicular cell types in spermatogenesis. Briefly, this review summarizes these results as follows: 1) the impact of lacking AR in Sertoli cells mainly affects Sertoli cell functions to support and nurture germ cells, leading to spermatogenesis arrest at the diplotene primary spermatocyte stage prior to the accomplishment of first meiotic division; 2) the impact of lacking AR in Leydig cells mainly affects steroidogenic functions leading to arrest of spermatogenesis at the round spermatid stage; 3) the impact of lacking AR in the smooth muscle cells and peritubular myoid cells in mice results in similar fertility despite decreased sperm output as compared to wild-type controls; and 4) the deletion of AR gene in mouse germ cells does not affect spermatogenesis and male fertility. This review tries to clarify the useful information regarding how androgen/AR functions in individual cells of the testis. The future studies of detailed molecular mechanisms in these in vivo animals with cell-specific AR knockout could possibly lead to useful insights for improvements in the treatment of male infertility, hypogonadism, and testicular dysgenesis syndrome, and in attempts to create safe as well as effective male contraceptive methods.
PMID: 19176467 [PubMed - indexed for MEDLINE] PMCID: PMC2662628
Eur J Endocrinol. 2008 Dec;159 Suppl 1:S9-15. Epub 2008 Sep 16.
Delemarre EM, Felius B, Delemarre-van de Waal HA.
Medical School Leiden Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Puberty is the result of increasing pulsatile secretion of the hypothalamic gonadotropin releasing hormone (GnRH), which stimulates the release of gonadotropins and in turn gonadal activity. In general in females, development of secondary sex characteristics due to the activity of the gonadal axis, i.e., the growth of breasts, is the result of exposure to estrogens, while in boys testicular growth is dependent on gonadotropins and virilization on androgens. Hypogonadotropic hypogonadism is a rare disease. More common is the clinical picture of delayed puberty, often associated with a delay of growth and more often familial occurring. Especially, boys are referred because of the delay of growth and puberty. A short course (3-6 months) of androgens may help these boys to overcome the psychosocial repercussions, and during this period an increase in the velocity of height growth and some virilization will occur. Hypogonadotropic hypogonadism may present in a congenital form caused by developmental disorders, some of which are related to a genetic disorder, or secondary to hypothalamic-pituitary dysfunction due to, among others, a cerebral tumor. In hypogonadotropic hypogonadism puberty can be initiated by the use of pulsatile GnRH, gonadotropins, and sex steroids. Sex steroids will induce development of the secondary sex characteristics alone, while combined administration of gonadotropins and GnRH may induce gonadal development including fertility.
PMID: 18796540 [PubMed - indexed for MEDLINE]
Reproduction. 2008 Dec;136(6):691-701. Epub 2008 May 30.
Hormonal suppression for fertility preservation in males and females.
Meistrich ML, Shetty G.
Department of Experimental Radiation Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.
Methods to restore fertility of men and women sterilized by medical treatments and environmental toxicant exposures are under investigation. Rendering spermatogenesis and ovarian follicular development kinetically quiescent by suppression of gonadotropins has been proposed to protect them from damage by cytotoxic therapy. Although the method fails to protect the fertility of male mice and monkeys, gonadotropin and testosterone suppression in rats before or after cytotoxic therapy do enhance the recovery of spermatogenesis. However, the mechanism involves not the induction of quiescence but rather the reversal, by suppression of testosterone, of a block in differentiation of surviving spermatogonia caused by damage to the somatic environment. In men, only one of eight clinical trials was successful in protecting or restoring spermatogenesis after cytotoxic therapy. In women, protection of primordial follicles in several species from damage by cytotoxic agents using GnRH analogs has been claimed; however, only two studies in mice appear convincing. The protection cannot involve the induction of quiescence in the already dormant primordial follicle but may involve direct effects of GnRH analogs or indirect effects of gonadotropin suppression on the whole ovary. Although numerous studies in female patients undergoing chemotherapy indicate that GnRH analogs might be protective of ovarian function, none of the studies showing protection were prospective randomized clinical trials and thus they are inconclusive. Considering interspecies differences and similarities in the gonadal sensitivity to cytotoxic agents and hormones, mechanistic studies are needed to identify the specific beneficial effects of hormonal suppression in select animal models that may be applicable to humans.
PMID: 18515310 [PubMed - indexed for MEDLINE] PMCID: PMC2605202
Curr Opin Endocrinol Diabetes Obes. 2008 Jun;15(3):255-60.
Progress and prospects in male hormonal contraception.
Center for Research in Reproduction and Contraception, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. firstname.lastname@example.org
PURPOSE OF REVIEW:
Testosterone functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary. Low concentrations of these hormones deprive the testes of the signals required for spermatogenesis and results in markedly decreased sperm concentrations and effective contraception in a majority of men. Male hormonal contraception is well tolerated and acceptable to most men. Unfortunately, testosterone-alone regimens fail to completely suppress spermatogenesis in all men, meaning that in some the potential for fertility remains.
Because of this, novel combinations of testosterone and progestins, which synergistically suppress gonadotropins, have been studied. Two recently published testosterone/progestin trials are particularly noteworthy. In the first, a long-acting injectable testosterone ester, testosterone decanoate, was combined with etonogestrel implants and resulted in 80-90% of subjects achieving a fewer than 1 million sperm per milliliter. In the second, a daily testosterone gel was combined with 3-monthly injections of depot medroxyprogesterone acetate producing similar results.
Testosterone-based hormone combinations are able to reversibly suppress human spermatogenesis; however, a uniformly effective regimen has remained elusive. Nevertheless, improvements, such as the use of injectable testosterone undecanoate, may lead to a safe, reversible and effective male contraceptive.
PMID: 18438174 [PubMed - indexed for MEDLINE] PMCID: PMC2664382
J Clin Endocrinol Metab. 2007 May;92(5):1659-65. Epub 2007 Feb 13.
The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men.
Amory JK, Wang C, Swerdloff RS, Anawalt BD, Matsumoto AM, Bremner WJ, Walker SE, Haberer LJ, Clark RV.
Department of Medicine, Veterans Affairs-Puget Sound Health Care System, University of Washington, Seattle, WA 98195, USA.
J Clin Endocrinol Metab. 2007 Nov;92(11):4379.
Dutasteride and finasteride are 5alpha-reductase inhibitors (5ARIs) that dramatically reduce serum levels of dihydrotestosterone (DHT).
Because androgens are essential for fertility, we sought to determine the impact of 5ARI administration on serum testosterone (T), DHT, and spermatogenesis. DESIGN, SETTING, SUBJECTS, AND INTERVENTION: We conducted a randomized, double-blinded, placebo-controlled trial in 99 healthy men randomly assigned to receive dutasteride (D; 0.5 mg) (n = 33), finasteride (F; 5 mg) (n = 34), or placebo (n = 32) once daily for 1 yr.
MAIN OUTCOME MEASURES:
Blood and semen samples were collected at baseline and 26 and 52 wk of treatment and 24 wk after treatment and were assessed for T, DHT, and semen parameters.
D and F significantly (P < 0.001) suppressed serum DHT, compared with placebo (D, 94%; F, 73%) and transiently increased serum T. In both treatment groups, total sperm count, compared with baseline, was significantly decreased at 26 wk (D, -28.6%; F, -34.3%) but not at 52 wk (D, -24.9%; F, -16.2%) or the 24-wk follow-up (D, -23.3%; F, -6.2%). At 52 wk, semen volume was decreased (D, -29.7%; F, -14.5%, significantly for D) as was sperm concentration (D, -3.2%; [corrected] F, -7.4%, neither significant). There was a significant reduction of -6 to 12% in sperm motility during treatment with both D and F and at follow-up. Neither treatment had any effect on sperm morphology.
This study demonstrates that the decrease in DHT induced by 5ARIs is associated with mild decreases in semen parameters that appear reversible after discontinuation.
PMID: 17299062 [PubMed - indexed for MEDLINE]
Hum Reprod Update. 2007 Mar-Apr;13(2):163-74. Epub 2006 Nov 11.
The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility.
Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP.
Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Current treatments of subfertile couples are usually empiric, as the true cause of subfertility often remains unknown. Therefore, we outline the role of nutritional and biochemical factors in reproduction and subfertility. A literature search was performed using MEDLINE, Science Direct and bibliographies of published work with both positive and negative results. The studies showed that folate has a role in spermatogenesis. In female reproduction, folate is also important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development. Zinc has also been implicated in testicular development, sperm maturation and testosterone synthesis. In females, zinc plays a role in sexual development, ovulation and the menstrual cycle. Both folate and zinc have antioxidant properties that counteract reactive oxygen species (ROS). Thiols, such as glutathione, balance the levels of ROS produced by spermatozoa and influence DNA compaction and the stability and motility of spermatozoa. Oocyte maturation, ovulation, luteolysis and follicle atresia are also affected by ROS. After fertilization, glutathione is important for sperm nucleus decondensation and pronucleus formation. Folate, zinc, ROS and thiols affect apoptosis, which is important for sperm release, regulation of follicle atresia, degeneration of the corpus luteum and endometrial shedding. Therefore, the concentrations of these nutrients may have substantial effects on reproduction. In conclusion, nutritional and biochemical factors affect biological processes in male and female reproduction. Further research should identify pathways that may lead to improvements in care and treatment of subfertility.
PMID: 17099205 [PubMed - indexed for MEDLINE]