Journal of Reproductive Medicine Gynaecology & Obstetrics Category: Medical Type: Review Article
Fertility in Disorders of Sex Development: Evidence and Uncertainties
- Nastaran Foyouzi1*, David E Sandberg2
- 1 Department Of Obstetrics And Gynecology, Division Of Reproductive Endocrinology & Infertility, University Of Michigan, Ann Arbor, MI, 48104, Michigan, United States
- 2 Department Of Pediatrics And Communicable Diseases, Division Of Pediatric Psychology And The Child Health Evaluation & Research (CHEAR) Unit, University Of Michigan, Ann Arbor, Michigan, United States
*Corresponding Author:Nastaran Foyouzi
Department Of Obstetrics And Gynecology, Division Of Reproductive Endocrinology & Infertility, University Of Michigan, Ann Arbor, MI, 48104, Michigan, United States
Received Date: Jan 04, 2019 Accepted Date: Jan 28, 2019 Published Date: Feb 11, 2019
Recent developments in the field of medicine, genetics and biotechnology have led to a rethinking of optimal management in Disorders of Sex Development (DSD). In parallel, advancement in Assisted Reproductive Technologies (ART) has dramatically changed the fertility expectation of DSD patients and their families. Even though our knowledge remains incomplete, our understanding of fertility potential has improved significantly. Consequently, care providers are in a stronger position to advice patients affected by DSD (and their surrogates) in the decision-making process around fertility. Therefore, sharing of this knowledge with parents of the affected child and ongoing counseling by an infertility specialist should be considered an essential part of the interdisciplinary team approach.
Objective and Rationale
This review examines the current evidence in fertility potential and treatment options for these rare disorders and highlights the areas of uncertainty to elucidate the importance and need for targeted research in this area of medicine.
This review benefits from a PubMed literature review on fertility potential and treatment options available for DSD. The review is meant to be comprehensive, but not exhaustive of the relevant literature.
The intended audiences for this review are health care professionals who provide care to pediatric patients with DSD, including family medicine, primary care specialists, behavioral/mental health (psychology, social work and psychiatry), geneticists and genetic counselors, obstetricians/gynecologist, pediatric urologists and nurses. Nonetheless, we expect health professional students, educators, parents of children with DSD and adults with DSD will also read and benefit from this review.
The purpose of this review is to assist health care professionals in delivering sexual-wellbeing education, fertility potential and available treatment options, initially to the parents and, subsequently, to the patient following a staged and developmentally-sensitive schedule. This review reflects a comprehensive, but necessarily selective, literature review on fertility potential and treatment options for individuals with DSD, designed to address the substantial evidentiary gaps in the medical literature on DSD treatment.
DISORDERS OF SEX DEVELOPMENT CLASSIFICATION
Among women with TS and ovarian failure, IVF, using donated oocytes has resulted in a pregnancy rate similar to those using donated oocytes for other indications (56.6% success rate) . Studies on obstetric and perinatal outcomes in TS oocyte donor pregnancies are few, but there is an exceptionally high risk of complications, including pregnancy-induced hypertensive disorders, preeclampsia, gestational diabetes, preterm labor, multiple gestation, low birth weight, sex chromosome abnormalities, spontaneous abortion or an inherent endometrial abnormality possibly associated with a deficiency of X-linked genes that regulate endometrial receptivity [14-16]. Additionally, the risk of death during pregnancy is increased as much as 100-fold, primarily due to complications of aortic dissection or rupture [17,18]. This risk is the greatest for those patients with pre-existing abnormalities such as a bicuspid aortic valve or a dilated aortic root, but all patients are subject to risk of death due to aortic dissection . Consequently, TS should be regarded as a relative contraindication to pregnancy. Those who express serious interest in oocyte donation must receive thorough evaluation and counseling, and those having any significant cardiac abnormality should be strongly discouraged or offered surrogacy or gestational carrier cycles . Preconception counseling should include screening for associated medical conditions, particularly the cardiovascular system by cardiology consultation. Thyroid status, renal function test, fasting blood glucose and oral glucose tolerance test should be assessed. The American Society for Reproductive Medicine (ASRM) practice committee recommends that any significant echocardiographic abnormality be considered an absolute contraindication of pregnancy in patients with TS . The National Institute of Child Health and Human Development Guidelines further define this group as those with a history of bicuspid aortic valve, aortic dilation, or aortic coarctation . An additional risk factor for cardiac complications includes the presence of multiple gestations. Therefore, in an IVF setting, with or without oocyte donation, a single embryo transfer should be considered, although monozygotic twinning may still occur (0.9-1.64% compared to 0.4% in general population). The possibility of selective reduction should be discussed . The patient should be followed during the pregnancy by an interdisciplinary team of specialists, including the maternal fetal medicine expert, a cardiologist and an endocrinologist.
For some, oocyte donation may not be acceptable for personal, religious or legal reasons. In such cases, fertility preservation has been considered for selected women with TS. This approach is only applicable in patients with a mosaic karyotype, presence of ovarian follicles and a slower rate of germ cell loss [22,23]. Fertility preservation in adolescent girls with TS has recently been reported, but there is limited experience in using the preserved cells. The pregnancy success rate is unknown and the procedure is considered experimental.
To date, more than 100 healthy children have been born after ICSI with testicular sperm from non-mosaic KS men. An initial success rate of 40-50% by TESE has been reported in a small series in adult males with 47,XXY . A new technique, microdissection TESE (or Micro TESE), has shown significantly better sperm recovery rates (70%) compared to conventional TESE. Therefore, this technique should be favored over traditional TESE . The only predictive factor for successful sperm recovery in KS seems to be testicular histopathology, but even without sperm in histological sections, TESE has proven successful. Live birth rates of 20-46% have been reported once sperm are obtained . Neither testicular ultrasonography, extensive chromosome analysis, degree of virilization, testicular volume, nor serum testosterone, FSH, LH, or inhibin B levels are predictive of TESE outcomes. Even patients with unmeasurable inhibin B levels have undergone successful TESE . In boys with KS, the markedly reduced number of adult spermatogonia indicates severely impaired fertility potential, even before puberty . Cryopreservation of semen samples from KS boys in early puberty is a possible option and should be offered to appropriate patients before the start of testosterone supplementation . The expected success rate is exceedingly low, since the onset of puberty initiates a marked acceleration in germ cell depletion and one must also take into account the limited ability of boys to provide semen samples during early puberty.
Other options for sperm cryopreservation in young boys who are unable to ejaculate are penile vibro-stimulation or rectal electro-stimulation under general anesthesia or TESE . Studies have shown a successful sperm retrieval with TESE in KS boys despite a presence of decreased AMH and inhibin B and increased FSH [38,40,41]. However, the testis may contain spermatogonia and non-completely differentiated germ cells-spermatocytes and elongated spermatids. Nevertheless, these cryopreserved testicular samples containing immature spermatogonia would require in vitro maturation of spermatogonia into mature spermatozoa, or at least into late/elongated spermatids. Recent studies indicate that human testicular tissue can be cultured for at least 3 weeks without essential loss of spermatogonia, yielding normal spermatids with some fertilization potential [42,43]. However, at present this option for fertility preservation in pre-pubertal boys remains entirely experimental. It is important to counsel these patients and their parents about the fertility preservation options and procedures over a period of time beginning after the onset of puberty, when it is feasible to collect a semen sample, or when the patient is mature enough to consider alternative options and to accept the failure of germ cell retrieval [38,44].
Men with 47,XYY syndrome and normal sperm counts can potentially impregnate their partners. For those appearing to be infertile due to the high prevalence of oligospermia and abnormal sperm chromosomal constitution, IVF - with or without ICSI - may be an option . These patients and their partners should receive genetic counseling to understand the potential risks to their offspring and be offered Preimplantation Genetic Diagnosis (PGD) . Affected men with symptoms of hypogonadism or low total testosterone levels may benefit from empiric medical therapy such as clomiphene citrate or anastrozole to alleviate symptoms of hypogonadism and maximize intratesticular testosterone and spermatogenesis. There is no universal pattern for evaluation or identifying the ideal patient for such therapy . Because there is no consensus on the optimal medication, along with considerable uncertainty on the efficacy of these therapies, this treatment is considered investigational.
Reports of fertility in these patients are limited. In a recent case series of 20 patients with MGD, none were fertile; 45% developed testicular failure necessitating testosterone replacement and 63% had Y chromosomal rearrangements with severely impaired fertility . There are a few case reports on individuals with 45 X/46X(r) Y karyotype with oligozoospermia or oligoasthenoteratozoospermia who were able to conceive naturally or through ART/ ICSI [54,55]. Despite the fact that most patients with MGD are infertile, with very few reports of spermatogonia in semen and even fewer reports of successful conception, it is reasonable to consider TESE (or Micro TESE) and ICSI as a fertility option . However, the risk of karyotypic abnormalities in the offspring necessitates genetic counseling or PGD.
Complete gonadal dysgenesis (Swyer syndrome)
Testicular regression syndrome
Disorders in androgen synthesis
17β-Hydroxysteroid dehydrogenase deficiencies
17β-Hydroxysteroid Dehydrogenase Deficiency (HSD17B; also called 17-ketosteroid reductase deficiency) is a rare cause of 46,XY DSD . It is inherited in an autosomal recessive pattern. Individuals with HSD17B present with testes and male Wolffian duct derived urogenital structures, but their external genitalia are undervirilized therefore they present as a female phenotype leading to a female gender announcement and gender of rearing. Puberty is associated with masculinization and 39-64% of cases reared as girls subsequently change their gender status due to extra testicular conversion of androstenedione to testosterone by unaffected HSD17B isoenzymes in peripheral tissues . Early orchiectomy appears to be associated with stability of a female gender identity . However, Phenotype may vary from mild forms with micropenis or hypospadias; undervirilization of external genitalia with or without clitoromegaly and/or labial fusion, to complete female external genitalia with testes situated in the abdomen, inguinal channels or in the labia major based on the enzyme activity .
Reports on fertility and sexual function in those affected by HSD17B are relatively limited. The histologic features of the testes may be normal in pediatric patients, but with age there is a progressive degeneration that includes atrophic Sertoli cells with basal membrane thickening, fibrosis and eventually, azoospermia . A report of a patient with 17-ketosteroid reductase deficiency did not demonstrate the presence of spermatogenesis, despite early orchiopexy and normal serum testosterone . Currently, there are no reports on fertility preservation or pregnancy in 17BHSD. It may be prudent to consider testicular biopsy and sperm cryopreservation in selected individuals followed by IVF/ICSI and PGD counseling. However, due to accelerated testicular fibrosis and evolving azoospermia, the application of this approach is entirely experimental and the expected success rate is low.
5α-Reductase type 2 deficiency
5α-reductase type 2 deficiency is a 46,XY autosomal recessive disorder characterized by impaired virilization during embryogenesis secondary to impaired conversion of testosterone to Dihydrotestosterone (DHT). Fertility ranges from a complete lack of to normal spermatogenesis . Currently, only 2 cases of spontaneous paternity have been documented in this syndrome . A more severe enzyme defect precludes spontaneous parenthood and sperm recovery in the ejaculate (i.e., azoospermia). In these cases of unknown prevalence, the only fertility therapeutic possibility is TESE, which has been used as a successful strategy in a number of patients with non-obstructive azoospermia of various origins, including those with cryptorchidism . TESE is also a reliable technique in providing information on the presence of spermatozoa in the testis for cryopreservation and future fertility preservation. Patients who desire imminent fertility may benefit from genetic counseling; the lack of a phenotype/genotype relationship makes it difficult, however, to reliably predict offspring phenotype.
Defects in androgen action
There are limited case reports of paternity after pharmacological restoration of AR function with testosterone in men with minimal AIS, but it is rarely used and is usually unsuccessful . There is a recent case report of successful pregnancy by TESE and ICSI in an azoospermic man with mild AIS . Therefore, TESE may be an effective option followed by IVF/ICSI. The couple should receive genetic counseling and PGD is advised whenever possible . The parents should be informed that their offspring will appear typical, but that daughters will carry the father's mutation and, subsequently, might transmit AIS to their sons . Because of uncertainty about the genotype-phenotype correlation in mild forms of AIS, the phenotypic consequences of the mutation in offspring cannot be reliably predicted .
Luteinizing hormone receptor defects
Disorders of AMH and AMH receptor (Persistent Müllerian Duct Syndrome)
Fertility options in PMDS patients vary based on the cause of infertility. For example TESE is a viable option followed by IVF/ICSI in individuals with germ cell hypoplasia, whereas in obstructive cases due to structural abnormality or damage to vas deferens, the option could be Microsurgical Epididymal Sperm Aspiration (MESA), Percutaneous Epididymal Sperm Aspiration (PESA) or even TESE followed by IVF/ICSI. Microsurgical reanastomosis in cases with damage to vas is an alternative option; however one can postulate a low success rate or failure because the likelihood that sperm will return to the semen and pregnancy after microsurgical reanastmosis is inversely related to the duration of obstruction . Since PMDS has an autosomal recessive inheritance pattern, genetic counseling before pregnancy is strongly encouraged.
After puberty these individuals present with normal pubic hair and penile size, but small testes and azoospermia . Endocrine studies usually show hypergonadotropic hypogonadism secondary to testicular failure with elevated FSH, LH and decreased testosterone. Testicular biopsy typically reveals a decrease in the size and number of seminiferous tubules, peritubular fibrosis, absence of germ cells and hyperplasia of Leydig cells. Accordingly, these findings indicate permanent infertility in these individuals . Donor sperm is the sole option for pregnancy in 46,XX men with testicular DSD.
Congenital adrenal hyperplasia
While 11-OHD is often considered the second most common cause of CAH, the disease is rare, occurring in only <1 in 100,000 births . Like 21-OHD, women with 11-OHD experience irregular menses and hirsutism or male pattern baldness . Hypertension is common, with a prevalence of 60-70% ; in cases of severe hypertension, cardiomyopathy, blindness and death have been reported . Patients who desire pregnancy warrant management by a multidisciplinary team consisting of maternal fetal medicine and cardiology specialists. Women attempting pregnancy should stop Spironolactone and substitute intensified glucocorticoid therapy. A successful pregnancy has been reported in one woman with 11-OHD treated with Dexamethasone, Metformin and Clomid . 3β-HSD II is an enzyme defect that impairs steroidogenesis in the adrenals and gonads, leading to glucocorticoid and mineralocorticoid deficiency . Unlike 21-OHD, no data are available concerning pregnancy in women with 3β-HSD II . PGD has greatly improved genetic counseling of families with CAH. In couples that are at risk for conceiving an affected child, PGD is able to detect affected embryos resulting from In-Vitro Fertilization (IVF). However, the ability of PGD to select the unaffected embryo for transfer is based on prior identification of the disease causing mutations in the family due to broad range of mutations causing CAH .
Feto-Placenta enzyme deficiency
Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)
Fertility in women with MRKH has been achieved by IVF/surrogacy . A large retrospective study conducted in 1997, consisting of 162 IVF/surrogacy pregnancies, did not show any increased risk of congenital anomaly in offspring; however, due to the survey nature of the study, the associated congenital abnormality in MRKH patients is not clear . Risk of transmission to offspring is unknown due to limited data. Introducing a uterine transplant was a breakthrough in the field of reproductive medicine for treatment of uterine factor infertility (e.g., MRKH). As of today, a total of eleven cases of human uterus transplantations have been reported worldwide, conducted in three different countries [147-149]. The results of these initial experimental cases far exceed what might be expected. The first human live birth was reported in 2014 . The recipient, a 35-year-old woman with MRKH syndrome, was transplanted with a live donor uterus from a 62-year-old postmenopausal family friend. Menstruation occurred 43 days post surgery and continued with regular intervals (26-36 days). Twelve months after the transplantation, the organ recipient had a single embryo-transfer that was immediately successful and resulted in a live birth of healthy boy at 31.5 week via C-section . However, one should keep in mind that this procedure is still investigational and before introducing uterus transplantation in a wider general setting, several more carefully monitored pregnancies are required to evaluate major obstetrical risks, including miscarriage, preeclampsia, preterm birth, and fetal growth restriction.
In an observational study of fertility and obstetric outcomes involving the largest cohort of female patients with classical bladder extrophy , 68% of those attempting conception were successful; 21% with spontaneous pregnancy within 1 year and 26% after having received fertility treatments. Overall, this report suggests that women with bladder exstrophy may experience difficulty with fertility, most likely the result of tubal obstruction or some other genital complication following surgical reconstruction. Currently, more than 80 pregnancies in women with bladder exstrophy have been reported . Pregnancy is high risk for both mother and fetus with higher risk of urinary infection, pelvic prolapse, C-section, prematurity and stillbirth. A preconception renal evaluation for all women in this group should be offered in an effort to optimize renal function . Additionally due to higher risk of prenatal morbidity, single embryo transfer is strongly recommended in patients who undergo IVF treatment. Although vaginal delivery has been described, it should be avoided as it may jeopardize previous reconstruction and subsequently lead to urinary incontinence. Therefore, elective caesarian section by experienced staff is strongly recommended before the onset of labor.
The literature has shown a 400-fold increased risk of cloacal exstrophy in offspring of affected individuals , but not of any other congenital anomalies. Accordingly, these patients need an interdisciplinary approach that includes an urologist, reproductive endocrinologist and experienced obstetrician.
Disorder of Sex Development
Sex Chromosome DSD
Severe forms: Streak gonads with no oocyte
Severe forms: Motherhood possible with oocyte donation (high-risk pregnancies)
Severe decreased sperm production with small testes
Fatherhood is possible by TESE or MicroTESE with IVF/ICSI. Fertility preservation through sperm cryopreservation in early puberty (fertility preservation through testicular tissue cryopreservation and in vitromaturation of immature sperm is investigational)
47, XYY syndrome
Varying degree of infertility ranging from normal fertility to azoospermia. High prevalence of abnormal sperm chromosomal constitution
Severe forms: IVF with or without ICSI based on semen analysis
Variable phenotype from complete gonadal failure to oligozoospermia or oligoasthenoteratozoospermia
Fertility possible through TESE or Micro TESE with IVF/ICSI
Unknown nature or function of gonad with regards to fertility potential
46, XY DSD
Complete Gonadal Dysgenesis (Swyer syndrome)
Motherhood possible with oocyte donation (high-risk pregnancy)
Testicular Regression syndrome
Streak testes or no testes
Fatherhood is possible by donor sperm (a case report on successful testicular transplant in identical twin)
Disorders in Androgen Synthesis 17- hydroxysteroid dehydrogenase deficiency
Non functional testes and eventually gonadal failure and azoospermia Based on enzyme activity varies from normal spermatogenesis to azoospermia
No reports on fertility preservation or pregnancy 2 case reports of spontaneous pregnancy. In azoospermia: TESE or MicroTESE followed by IVF/ICSI and sperm cryopreservation for future fertility
Defects in Androgen Action
Azoospermia and gonadal failure
Mild forms: TESE or MicroTESE followed by
Luteinizing Hormone Receptor
Varies ranging from azoospermia
Human chorionic gonadotropin (HCG) injection
AMH/AMH Receptor Defects
MESA, PESA, TESE followed by IVF/ICSI
46, XX DSD
Varies from functional gonad to gonadal failure
Case reports of spontaneous pregnancy after removal of testicular tissue gonad. No reports on fertility in male
Hypergonadotropic hypogonadism with azoospermia
Fatherhood is possible by donor sperm
Hyperandrogenemia and ovulatory dysfunction
1. Intensify glucocorticoid therapy
Feto-Placenta Enzyme Deficiency
Male: Oligospermia with or without asthenospermia Female: hypergonadotropic hypogonadism
No data on fertility potential and options
Motherhood through gestational surrogacy
David Sandberg Contribution: 1) contributions to conception and design, literature search and acquisition of data 2) help in drafting the article for important intellectual content, and 3) final approval of the version to be published.
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Citation: Foyouzi N, Sandberg DE (2019) Fertility in Disorders of Sex Development: Evidence and Uncertainties. J Reprod Med Gynecol Obstet 4: 015.
Copyright: © 2019 Nastaran Foyouzi, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.