Edition 76 - November 2019 / Subject Review

Subject Review – Ed. 76

Marco A. Rivarola and Alicia Belgorosky.

Hospital de Pediatria Garrahan, Buenos Aires, Argentina.

For this issue Subject Review Section, we have selected the following publication:



Clinical Endocrinology. 2019;91:237–244.

Establishing reproductive potential and advances in fertility preservation techniques for XY individuals with differences in sex development.

Rumana Islam1, Sheila Lane2, Suzannah A. Williams3, Christian M. Becker4, Gerard S. Conway5, y Sarah M. Creighton6

1Department of Reproductive Medicine, John Radcliffe Hospital, Oxford University

Hospitals, Oxford, UK; 2Department of Paediatric Oncology and Haematology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK; 3Nuffield Department of Women’s and Reproductive Health, Women’s Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK; 4Nuffield Department of Women’s and Reproductive Health, Oxford Endometriosis CaRe Centre, Women’s Centre, John

Radcliffe Hospital University of Oxford, Oxford, UK; 5Department of Endocrinology, University College London Hospitals, London, UK; 6Elizabeth Garrett Anderson UCL Institute of Women’s Health, University College, London Hospitals, London, UK.


BACKGROUND: Discordance between gonadal type and gender identity has often led to an assumption of infertility in patients with differences in sex development (DSD). However, there is now greater recognition of fertility as being an important issue for this group of patients. Currently, gonadal tissue that may have fertility potential is not being stored for individuals with DSD and, while gonadectomy forms part of management, gonads are often discarded. The area of fertility preservation has been predominantly driven by onco-fertility which is a field dedicated to preserving the fertility of patients undergoing gonadotoxic cancer treatment. The use of fertility preservation techniques could be expanded to include individuals with DSD where functioning gonads are present.

METHODS: This is a systematic literature review evaluating original research articles and relevant reviews between 1974 and 2018 addressing DSD and fertility, in vitro maturation of sperm, and histological/ultrastructural assessment of gonadal tissue in the following conditions: complete and partial androgen insensitivity syndrome, in 17β‐hydroxysteroid dehydrogenase type 3 and 5α‐reductase deficiency.

CONCLUSION: Successful clinical outcomes of ovarian tissue cryopreservation are paving the way for similar research being conducted using testicular tissue and sperm. There have been promising results from both animal and human studies, leading to cryopreservation of testicular tissue now being offered to boys, prior to cancer treatment. Although data are limited, there is evidence to suggest the presence of reproductive potential in the gonads of some individuals with DSD. Larger, more detailed studies are required, but if these continue to be encouraging, individuals with DSD should be given the same information, opportunities, and access to fertility preservation, as other patient groups.

Excerpts selected from this article:


Fertility is often affected by DSD, due to gonadal and endocrine disturbances, or direct anatomical reasons inherent to the DSD. Recently, there has been a greater recognition that fertility is an important aspect of care for this group of patients. The 2016 update of the International Consensus Conference on intersex disorders addressed polarizing topics, which included a reference to the importance of fertility, but with the recognition that evidence about the best fertility-preserving options remains inadequate.

Societal perceptions towards nontraditional family structures have expanded significantly in recent years, such that having a biological child is now possible for a significant proportion of adults with DSD. Although technology is still evolving, promising research using animal models leads to an expectation that primordial oocytes and sperm cells will soon be able to be matured in vitro and used with assisted reproductive technologies to produce a biological child.

Several types of DSD can affect fertility, as summarized as follows:

Complete Androgen Insensitivity.

In complete androgen insensitivity syndrome (CAIS), an X-linked DSD where affected individuals have an XY karyotype and intraabdominal/inguinal testes but are phenotypically female, with normally developed female external genitalia. The condition is caused by inactivating mutations of the androgen receptor (AR) gene, rendering AR insensitive to androgen stimulation. The normal functioning testes produce androgens as well as antimullerian hormone (AMH) which inhibits the formation of the uterus in utero. At pubertal age, individuals with CAIS typically present with primary amenorrhea, but earlier diagnosis can be suspected (45,XY karyotype along with female external genitalia) or if an inguinal hernia is found to contain a testis. Pubic and axillary hair growth is sparse in these patients, but breast development occurs at the expected time of puberty, due to increased levels of estrogens from the aromatization of excessive substrate from the testes. The risk of gonadal tumor development in CAIS patients is thought to increase with age in patients who retain their testes into adulthood or late adulthood. Therefore, current best practice is to recommend a gonadectomy in adolescence after completion of spontaneous puberty (with the patient’s own estrogen stimulation). Fertility issues in these patients are complex, including maturation of competent germ cells and individual psychological acceptance.

Partial Androgen Insensitivity Syndrome.          

Unlike CAIS, the decision about whether to raise the child as male or female in PAIS is not straightforward. The clinical presentation depends on the degree of responsiveness of the external genitalia to androgens. The typical phenotype is a micropenis, severe hypospadias (perineal-scrotal) and a bifid scrotum that might contain gonads. Androgen supplementation might be needed at puberty in patients with androgen resistance. Surgery is usually performed during the second to the third year of life to repair hypospadias and bring undescended testes into the scrotum. The risk of germ cell tumors is higher in partial than in CAIS. Patients reared male to undergo external genital reconstruction and orchiopexy for possible fertility preservation, with close monitoring and regular testicular self‐examination. Males with mild androgen insensitivity syndrome have oligo or azoospermia and are subfertile.

Androgen Synthesis Disorders

Androgen synthesis defects, such as 17β‐hydroxysteroid dehydrogenase type 3, and the 5α‐reductase deficiency (5ARD), result in varying degrees of under‐masculinization depending on the enzyme deficiency. Individuals with these deficiencies have often been brought up as a female, but if testes are retained, they experience variable virilization during puberty. Affected individuals may be infertile due to the lack of spermatogenesis. However, fertility is likely in those with milder phenotypes.

5-Alpha-Reductase Deficiency.

Five-alpha‐reductase deficiency (5ARD) results from the impaired conversion of testosterone to dihydrotestosterone (DHT). Mutation of the SRD5A2 (steroid 5 alpha-reductase 2) gene leads to an autosomal recessive disorder affecting sexual differentiation in individuals with 46,XY karyotype; their phenotype ranging from almost normal female structures to a distinct male phenotype when older, with ambiguous genitalia at birth. Given the severe defect of the external genitalia, most newborns are raised as females. Patients exhibit virilization at puberty without breast development, which can be accompanied by a gender identity change from female to male.

In most instances, the testes are located in the inguinal region. Testicular descent through the inguinal canal is generally arrested in 46,XY individuals with 5ARD. Semen abnormalities in this situation include oligozoospermia with reduced volume. While spontaneous paternity in men with 5ARD is extremely rare due to azoospermia or oligo-astheno-terato-zoospermia, following bilateral orchidopexy and male genital reconstruction, there are case reports of successful pregnancies and live births using intrauterine insemination and IVF with ICSI. The increasing efficacy of these techniques, including testicular sperm extraction and cryopreservation of testicular tissue in cases of azoospermia, makes biological parenthood a future possibility for the most severely affected men with this enzyme defect.

17-beta Hydroxysteroid Dehydrogenase 3 (HSD17B3) Deficiency

17‐beta hydroxysteroid dehydrogenase 3 (17βHSD‐3) is primarily expressed in the testes and converts androstenedione to testosterone, which is necessary for normal masculinization of external genitalia in utero. The condition is autosomal recessive with mutations in the HSD17B3 gene. The majority of affected individuals are born with female or with ambiguous external genitalia. While some individuals may be diagnosed in infancy after evaluation for ambiguous genitalia or inguinal hernia, many are not diagnosed until puberty, when they present with virilization. Virilization at puberty may be due to residual activity of 17βHSD‐3 in the presence

of increased androstenedione, as well as activity of extragonadal 17βHSD isoenzymes. Gender reassignment from female to male has been reported in 39%‐64% in patients who were initially raised as girls (Cohen-Kettenis PT et al. Arch Sex Behav, 2005).

For patients raised males, with retention of testes, spontaneous fertility is unlikely. Examination of testicular histology reveals arrested spermatogenesis. It is unknown whether early orchidopexy will result in a more favorable outcome.


Cryopreservation of mature sperm is routinely used for fertility preservation for men and some post-pubertal boys, but cryopreservation of postpubertal testicular tissue can also be used for azoospermic patients having orchidectomy or patients too ill to produce a semen sample before starting cancer treatment.

Cryopreservation of immature testicular tissue containing spermatogonial stem cells (SSCs) and spermatogonial cells is the only option that can be offered to pre-pubertal patients to date. Cryopreservation of mature sperm is routinely used for fertility preservation for men and some post-pubertal boys, but cryopreservation

of post-pubertal testicular tissue can also be used for azoospermic patients having orchiectomy or patients too ill to produce a semen sample before starting cancer treatment. Cryopreservation of immature testicular tissue containing spermatogonial stem cells (SSCs) and spermatogonial cells is the only option that can be offered to prepubertal patients to date.

Human Fertilisation and Embryology Authority (HFEA, UK Government) storage regulations allow gametes to be stored for longer than the 10‐year standard period if a registered medical practitioner gives a written opinion that the individual whose gametes are being stored is likely to become prematurely infertile. Gonadal tissue must be stored in a Centre that has HFEA accreditation. This means that gonadal tissue can be cryopreserved in childhood, and stored for future use well into middle or late adulthood.

Ovarian tissue cryopreservation was proposed over 50 years ago with the storage and preservation of testicular tissue being available for about the last 20 years. Progress of this research has mainly focused on ovarian cortex cryopreservation with the view to either future re-implantation of tissue or culture and production of mature oocytes by in vitro maturation (IVM) with the hopes of restoring fertility in those deemed at high risk of premature ovarian insufficiency. In vitro development of follicles with IVM of oocytes isolated from cryopreserved ovarian cortex has not yet resulted in pregnancy; however, IVM from isolated immature oocytes and orthotopic auto-transplantation of cryopreserved ovarian tissue has yielded pregnancies


There is evidence to suggest reproductive potential in the testicular tissue removed from individuals with XY DSD in terms of the presence of germ cells. Larger confirmatory studies and studies looking into the reproductive development of these germ cells in vitro and in xenografting experiments are required. However, based on current research findings, patients without DSD who face infertility, and are unable to bank semen, are being offered testicular tissue cryopreservation as a way to try to safeguard fertility potential. Therefore, the same options and opportunities in terms of fertility preservation should be offered to DSD patients as to other patient groups.

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