Sertoli-Cell-Only Syndrome

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Sertoli-cell-only (SCO) syndrome, also called germ cell aplasia or Del Castillo syndrome, describes a condition of the testes in which only Sertoli cells line the seminiferous tubules. [1] Sertoli cells help to make up the blood-testis barrier and are responsible assisting with sperm production. These cells respond to follicle-stimulating hormone (FSH) released by the hypothalamus, which helps to promote spermatogenesis. Typically, men with SCO syndrome present between age 20-40 years for evaluation of infertility and are found to be azoospermic, a term describing the absence of sperm in the ejaculate.

The physical examination findings are often unremarkable, and the diagnosis is made on the basis of testicular biopsy findings. While investigation to identify a cause of SCO syndrome is ongoing, the etiology and mechanism of this process are currently unknown. No known effective treatment exists, but these men may be able to reproduce with assisted reproductive technology.

See the image below.

Sertoli cells have in general have several functions. They provide support to the developing spermatogonia and secrete a number of substances that aid in fetal development. For example, Sertoli cells secrete anti-müllerian hormone (AMH), which helps to ensure regression of müllerian ducts as a fetus develops into a male. They also secrete inhibin and activin, which help to regulate FSH secretion by the hypothalamus. [2] Activin has a positive feedback on the hypothalamus, causing increased levels of FSH necessary for sperm production. Inhibin has a negative feedback on the hypothalamus and helps to maintain testicular homeostasis. See the image below.

Involvement of other organ systems is rare, but is secondary to the underlying condition causing SCO syndrome. As an example, Klinefelter syndrome is characterized by SCO and Leydig cell hyperplasia.

A study investigating the PRPS2 protein found that PRPS2 expression was significantly greater in patients with SCO syndrome than in those with normal spermatogenesis. In SCO syndrome mouse model, PRPS2 overexpression significantly inhibited cell apoptosis and promoted cell cycle transition in TM4 Sertoli cells. [3]

Ovol1 and Ovol2, a family of zinc finger transcription factors, are expressed in spermatocytes at the pachytene stage and are suggested to be critical regulators of pachytene progression in male germ cells. Taniguchi and colleagues reported that while hOvol1 and hOvol2 were detected by reverse transcription-polymerase chain reaction (RT-PCR) in the testes of patients capable of spermatogenesis, they were not detected in those with Sertoli cell-only syndrome. The researchers concluded that further investigation of Ovol1 and Ovol2 functions in human spermatogenesis might lead to a novel therapy. [4]

Yao and colleagues found 174 microRNAs (miRNAs) were differentially expressed in human Sertoli cells in men with SCO syndrome compared with men with obstructive azoospermia, suggesting that these miRNAs may be associated with the pathogenesis of SCO syndrome. [5]

 

Most cases of SCO syndrome are idiopathic. A congenital absence of germ cells due to failure of migration of gonocytes is theoretically possible.

A genetic basis for SCO syndrome is under intense investigation. [6]  Massive deletions in the azoospermia factor (AZF) region of the Y chromosome, specifically in AZFb/b+c, have been found in men with SCO syndrome. Five deletions arose from nonallelic homologous recombination between palindromes P5 and P1 and 2 between P4 and P1. In addition, two deletions were found at novel proximal breakpoints in the interval region between P4 and P3. [7]

Y-chromosome microdeletions are also occasionally identified as a cause of SCO syndrome. [8, 9]  As research continues, more genetic and chromosomal abnormalities associated with SCO may be found.

Expression of Fas, FasL, and active caspase-3 has been detected in Sertoli cells and hyperplastic interstitial cells. This may be associated with apoptotic elimination or altered maturation of Fas-expressing germ cells through the activation of caspase-3. [10]

Exposure to chemicals and toxins may cause SCO; however, direct cause-and-effect relationships in humans have been difficult to document.

Klinefelter syndrome, 47 XXY, results in a characteristic biopsy appearance of SCO and Leydig cell hyperplasia. [11]

Attempting to distinguish between primary (congenital) and secondary (acquired) SCO syndrome is of no prognostic significance.

The prevalence of SCO syndrome in the overall population is extremely low. Approximately 10% of US couples are affected by infertility. Of these couples, approximately 30% have a pure male factor as the underlying cause, and another 20% have a combined male and female factor. Although precise figures are difficult to obtain, less than 5%-10% of these infertile men have SCO syndrome.

SCO syndrome has no known racial predilection; however, SCO is more common in white men. In most series, most couples who present for evaluation of male infertility are white. The most common age at presentation is 20-40 years and represents most men who are trying to initiate a pregnancy.

Sertoli-cell-only (SCO) syndrome remains a stable condition with no appreciable improvement in prognosis or sperm production. Investigations have suggested that the prevalence of testicular nodules and cancer in patients with SCO syndrome is greater than that of the baseline. Initial reports show a 26% risk of nodules and a 10.5% risk of malignancy in testicles of men with pure SCO syndrome. [12]  Further studies would be helpful to support this initial report.

A number of models have been developed to predict successful sperm retrieval with testicular sperm extraction, although efficacy of these models is moderate. In general, higher patient age, higher values for serum testosterone, and lower values for serum FSH and LH were predictive for successful sperm retrieval. Idiopathic nonobstructive azoospermia and the presence of an AZFc deletion were predictive for unsuccessful sperm retrieval. [13]

Couples faced with a diagnosis of SCO syndrome should be given the options of adoption, use of donor sperm with intrauterine insemination and testicular sperm extraction with in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). See Infertility Treatments.

Although sperm may be successfully extracted from small pockets of spermatogenesis in up to 20%-40% of men with a diagnosis of SCO syndrome, the use of these sperm for IVF/ICSI is successful in only a small percentage of patients and thus should not be offered as a standard of care.  Adoption is an effective option; however, couples must understand that adoption can be a lengthy and costly process. For intrauterine insemination, donor sperm may be obtained locally or nationally through sperm banks. 

Ramphul K, Mejias SG. Sertoli-Cell-Only Syndrome. 2018 Jan. [Medline]. [Full Text].

Sharpe RM, McKinnell C, Kivlin C, Fisher JS. Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction. 2003 Jun. 125(6):769-84. [Medline].

Lei B, Wan B, Peng J, Yang Y, Lv D, Zhou X, et al. PRPS2 Expression Correlates with Sertoli-Cell Only Syndrome and Inhibits the Apoptosis of TM4 Sertoli Cells. J Urol. 2015 Nov. 194 (5):1491-7. [Medline].

Taniguchi H, Katano T, Nishida K, Yao I, Morimoto Y, Matsuda T, et al. Expression of hOvol2 in the XY body of human spermatocytes. Andrologia. 2017 Feb. 49 (1):[Medline]. [Full Text].

Yao C, Sun M, Yuan Q, Niu M, Chen Z, Hou J, et al. MiRNA-133b promotes the proliferation of human Sertoli cells through targeting GLI3. Oncotarget. 2016 Jan 19. 7 (3):2201-19. [Medline]. [Full Text].

Miyamoto T, Koh E, Tsujimura A, Miyagawa Y, Saijo Y, Namiki M, et al. Single-nucleotide polymorphisms in the LRWD1 gene may be a genetic risk factor for Japanese patients with Sertoli cell-only syndrome. Andrologia. 2013 Feb 28. [Medline].

Yang Y, Ma MY, Xiao CY, Li L, Li SW, Zhang SZ. Massive deletion in AZFb/b+c and azoospermia with Sertoli cell only and/or maturation arrest. Int J Androl. 2008 Dec. 31(6):573-8. [Medline].

Ferlin A, Arredi B, Speltra E, Cazzadore C, Selice R, Garolla A, et al. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab. 2007 Mar. 92(3):762-70. [Medline].

Hadjkacem-Loukil L, Hadj-Kacem H, Hadj Salem I, Bahloul A, Fakhfakh F, Ayadi H. Genotyping of Tunisian azoospermic men with Sertoli cell-only and maturation arrest. Andrologia. 2011 Jul 6. [Medline].

Kim SK, Yoon YD, Park YS, Seo JT, Kim JH. Involvement of the Fas-Fas ligand system and active caspase-3 in abnormal apoptosis in human testes with maturation arrest and Sertoli cell-only syndrome. Fertil Steril. 2007 Mar. 87(3):547-53. [Medline].

Stouffs K, Gheldof A, Tournaye H, Vandermaelen D, Bonduelle M, Lissens W, et al. Sertoli Cell-Only Syndrome: Behind the Genetic Scenes. Biomed Res Int. 2016. 2016:6191307. [Medline]. [Full Text].

Mancini M, Carmignani L, Gazzano G, Sagone P, Gadda F, Bosari S, et al. High prevalence of testicular cancer in azoospermic men without spermatogenesis. Hum Reprod. 2007 Apr. 22(4):1042-6. [Medline].

Cissen M, Meijerink AM, D’Hauwers KW, Meissner A, van der Weide N, Mochtar MH, et al. Prediction model for obtaining spermatozoa with testicular sperm extraction in men with non-obstructive azoospermia. Hum Reprod. 2016 Sep. 31 (9):1934-41. [Medline]. [Full Text].

Bettella A, Ferlin A, Menegazzo M, Ferigo M, Tavolini IM, Bassi PF, et al. Testicular fine needle aspiration as a diagnostic tool in non-obstructive azoospermia. Asian J Androl. 2005 Sep. 7(3):289-94. [Medline].

Corona G, Pizzocaro A, Lanfranco F, Garolla A, Pelliccione F, Vignozzi L, et al. Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2017 May 1. 23 (3):265-275. [Medline].

Edward David Kim, MD, FACS Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center

Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, Sexual Medicine Society of North America, Tennessee Medical Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Endo, Avadel.

Joe D Mobley, III, MD, MPH Urologist, Kentucky Lake Urology Clinic

Joe D Mobley, III, MD, MPH is a member of the following medical societies: American College of Surgeons, American Medical Association, American Urological Association, Endourological Society, Tennessee Medical Association

Disclosure: Nothing to disclose.

Adam F Stewart, MD Resident Physician, Department of Surgery, Division of Urology, University of Tennessee Medical Center, University of Tennessee Graduate School of Medicine

Disclosure: Nothing to disclose.

Jared Moss, MD Resident Physician, Division of Urology, University of Tennessee Graduate School of Medicine

Jared Moss, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Bradley Fields Schwartz, DO, FACS Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine

Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, Society of University Urologists

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical; Olympus.

Erik T Goluboff, MD Professor, Department of Urology, College of Physicians and Surgeons, Columbia University College of Physicians and Surgeons; Director of Urology, Allen Pavilion, New York Presbyterian Hospital

Erik T Goluboff, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Urological Association, Medical Society of the State of New York, New York Academy of Medicine, Phi Beta Kappa, Society for Basic Urologic Research

Disclosure: Nothing to disclose.

Sertoli-Cell-Only Syndrome

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