Disorders of sex development and female reproductive capacity: A literature review

ABSTRACT

Disorders of sex development (DSD) are a wide-ranging group of complex conditions that influence chromosomal, gonadal, and phenotypic sex. The prevalence of DSD is very low, but affected patients deserve individualized management to improve psychological, sexual, and reproductive outcomes. This review aims to clarify the fertility potential of DSD patients who can be reared as females and their chance of becoming pregnant, especially using assisted reproductive techniques (ART). Due to the effects of DSD on internal and external genital organs, these conditions result in varying degrees of fertility potential. Fertility rate depends on the phenotype and is inversely related to the severity of the disorder. Reproductive endocrinologists and infertility specialists must be considered active partners of the interdisciplinary treatment team. With current advances in ART, pregnancy is more achievable in patients who were considered infertile at first glance. Due to the complexity of the medical management in DSD patients, more studies should be conducted to conclusively suggest the best choice for improving their fertility potential.

Abbreviations: AIS: Androgen Insensitivity Syndrome; AMH: Anti-Müllerian Hormone; ART: Assisted Reproductive Technology; ASRM: American Society for Reproductive Medicine; CAH: Congenital Adrenal Hyperplasia; CAIS: Complete Androgen Insensitivity Syndrome; DHT: Dihydrotestosterone; DSD: Disorders of Sexual Development; FSH: Follicle Stimulating Hormone; GD: Gonadal Dysgenesis; ICSI: Intracytoplasmic Sperm Injection; IUGR: Intrauterine Growth Restriction; IVF: In Vitro Fertilization; IVF-ET: IVF and Embryo Transfer; LH: Luteinizing Hormone; MGD: Mixed Gonadal Dysgenesis; MRI: Magnetic Resonance Imaging; MRKH: Mayer-Rokitansky-Kuster-Hauser; US: Ultrasonography; HSG: Hysterosalpingography; PAIS: Partial Androgen Insensitivity Syndrome; PGD: Preimplantation Genetic Diagnosis; POR: P450 Oxidoreductase; PROM: Premature Rupture of Membranes; TS: Turner Syndrome; 17β-HSD III: 17β-Hydroxysteroid Dehydrogenase III; 21-OHD: 21-hydroxylase deficiency; 5α-RD-2: 5α-reductase-2

KEYWORDS:

• Disorders of sex development
• female fertility
• reproductive techniques

Introduction

Disorders of sex development (DSD) refer to a broad spectrum of phenotypic variations, including congenital discordance between external and internal genitalia, gonadal mal-differentiation, and sex chromosome abnormalities (El-Sherbiny 2013). Previously, terms such as intersex hermaphroditism or pseudohermaphroditism were commonly used for DSD disorders based on phenotypic characteristics. However, the current nomenclature relies on the molecular genetic information of the affected individuals. (El-Sherbiny 2013). The Chicago consensus statement of 2006 recognizes three broad categories of DSD-based karyotypes, i.e., 46, XX DSD, 46XYDSD, and sex chromosome DSD (Table 1) (Lee et al. 2006).

Table 1. Disorders of sex development (DSDs) classification based on the Chicago consensus

Sex chromosome DSD	46,XY DSD	46,XX DSD
1. Androgen excess Fetal (21- or 11β-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase type II deficiency) Fetoplacental (aromatase deficiency, P450 oxidoreductase (POR) deficiency) Maternal (maternal virilizing tumors, exogenous) 2. Disorders of ovarian development Gonadal dysgenesis Ovotesticular DSD Testicular DSD 3. Other Syndromic associations (e.g., cloacal anomalies) Mullerian agenesis (e.g., MRKH) Vaginal atresia Uterine abnormalities Labial adhesions	1. Disorders of testicular development A. Complete or partial gonadal dysgenesis B. Ovotesticular DSD C. Gonadal regression 2. Disorders of androgen synthesis or action A. Disorders of the androgen-dependent target tissues Androgen insensitivity syndrome Drugs and environmental modulators B. Disorders of androgen synthesis LH receptor mutations Smith-Lemi-Opitz syndrome Steroidogenic acute regulatory protein mutations Cholesterol side chain cleavage (CYP11A1) 3 β-hydroxysteroid dehydrogenase 2 (HSD3B2) 17 α-hydroxylase/17,20-lyase (CYP17) P450 oxidoreductase 17 β-hydroxysteroid Dehydrogenase III 5α-reductase-2 deficiency 3. Other A. Syndromic associations of male genital development B. Persistent Mullerian duct syndrome C. Vanishing testis syndrome D. Isolated hypospadias E. Congenital hypogonadotropic hypogonadism F. Cryptorchidism G. Environmental influences	1. 47,XXY (Klinefelter syndrome and variants) 2. 45,X (Turner syndrome and variants) 3. 45,X/46,XY (Mixed gonadal dysgenesis)

Individuals with DSD face many challenges throughout their lives because of their atypical genitalia as children and fertility problems as adults. Patients may encounter intense social stigmatization due to local mores and lack of medical sophistication. (Dessens et al. 2017). Cross-gender preferences can arouse criticism and victimization in restricted communities. In some communities, cultural and religious beliefs value reproductive success, and infertility issues lead to social isolation with attendant stress. (Ediati et al. 2015). Because of these challenges, the affected individuals and their close relatives need extensive consultation (Wisniewski 2017; Wolfe-Christensen et al. 2017). Psychosocial and medical care professionals should consider that these patients will have the chance for self-actualization and social participation during childhood and adulthood (Sandberg et al. 2012; Dessens et al. 2017).

In patients with DSD, fertility problems result from the endocrine, gonadal or anatomical abnormalities inherent to the condition. (Guercio et al. 2015). Additionally, medical and surgical management can affect the fertility potential of these patients. Age at the time of DSD diagnosis is another factor connected to the fertility potential (Slowikowska-Hilczer et al. 2017). As fertility problems largely affect the quality of life, consideration of the fertility potential of a DSD patient while performing other medical management is of critical importance (Van Batavia and Kolon 2016).

In a study conducted by Slowikowska-Hilczer et al. (Słowikowska-Hilczer et al. 2017), fertility outcomes were investigated in patients with different forms of DSD. Their results demonstrated that 33% of the studied population lived with a partner, and only 14% had a child. Among the group who had a child, 3.5% had been pregnant without receiving assistance for reproduction, 7% underwent assisted reproduction, and 4% adopted a child. A total of 72% of the participants declared that information regarding their fertility potential was given to them; however, 17% were not satisfied with the information received. These data highlight the need for individualized medical care for DSD patients emphasizing their fertility potential.

In this review, we have discussed the fertility potential and chance of pregnancy in DSD patients who can be reared as females based on the Chicago Classification of Causes of DSD (Table 1). In addition, the potential choices that assisted reproductive technology (ART) can provide for the treatment of infertility in these patients have been discussed in the possible cases. In general, ART practices such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) cycles, along with preimplantation genetic diagnosis (PGD), fertility preservation, donation programs, and pregnancy surrogacy have been reasonably successful in managing fertility problems in the affected women. The present study is a comprehensive review of the current published literature regarding the chance of pregnancy in the DSD patients who can be reared as female, especially using ART practices. We considered 125 papers published from 1990 to 2020 discussing DSD retrieved from the PubMed and Google Scholar databases, using the following keywords: ‘Disorders of Sex Development,’ ‘Fertility,’ and ‘Reproductive Techniques’ to highlight the underlying biology.

1) DSD patients with 46, XX karyotype

A) Androgen excess

High embryonic levels of androgen generally occur if there is an error in steroid synthesis, most commonly seen in congenital adrenal hyperplasia (CAH). In other cases, androgen excess can be responsible for a virilized 46, XX DSD phenotype (Reisch 2019). Although 46, XX DSD may be a result of other conditions like aromatase and P450 oxidoreductase (POR) deficiencies (Table 1), CAH due to 21-hydroxylase deficiency (21-OHD) has been recognized as the most frequent etiology for 46, XX DSD with a masculinized female phenotype at birth (Erdoğan et al. 2011; Öcal et al. 2015). CAH results in an increased level of adrenal androgens or progesterone that can disturb gonadotropin secretion, generating a spectrum of pathophysiological consequences with various levels of chronic anovulation (Hagenfeldt et al. 2008). Gender role reversal is relatively common in affected adult women. In addition, prepubertal girls with CAH may present masculine and slight feminine interests and preferences (Sandberg et al. 2012; Kim 2019).

A broad spectrum of pathophysiological symptoms and different fertility rates are reported in 46XX DSD patients. The most severe form of classical CAH, i.e., 21-OHD, has the lowest pregnancy rate and success (Hagenfeldt et al. 2008; Meyer-Bahlburg et al. 2008). In comparison, the pregnancy rate in women with milder forms of CAH is closer to normal (Bidet et al. 2010; New et al. 2019). Once pregnancy is achieved, individuals with classic CAH can expect a successful pregnancy outcome except for an increased occurrence of gestational diabetes and cesarean section due to the stenosis or scarring of the vaginal canal caused by previous vaginoplasty (Witchel 2012; Badeghiesh et al. 2020).

Like the women with 21-OHD, individuals with 11-beta-hydroxylase deficiency (11β-OHD) experience irregular menses and hirsutism (White et al. 1994; Elfekih et al. 2020). Hypertension is common in these women (Valadares et al. 2018). In severe cases, blindness, cardiomyopathy, and death have been reported (Auchus and Chang 2010), mandating multidisciplinary management with cardiology specialists throughout pregnancy to control hypertension. A successful pregnancy has been reported, with strengthened glucocorticoid therapy (Simm and Zacharin 2007).

A less common cause of CAH is 17-hydroxylase deficiency (17-OHD), in which successful pregnancy has been reported with the aid of an IVF cycle and cryopreserved embryo transfer (PHdM et al. 2016). However, there is no information about pregnancy in women with 3-beta-hydroxysteroid dehydrogenase type II deficiency (3β-HSD II).

Aromatase and POR deficiencies are two uncommon enzyme deficiencies related to androgen excess. These conditions are different from classical CAH since they affect both the fetal adrenal gland and placenta. Aromatase deficiency originates from the autosomal recessive inheritance of mutations in which fetal androgens are not converted to estrogens (Meinhardt and Mullis 2002). This leads to virilization of the female fetus so that at puberty, affected females experience acne, hirsutism, primary amenorrhea, and enlarged ovarian cysts (Meinhardt and Mullis 2002). POR enzyme deficiency is possibly the most complex form of CAH as it influences the activity of all P450 enzymes associated with steroidogenesis (Meinhardt and Mullis 2002; Fukami et al. 2006). To the best of our knowledge, no pregnancies have been reported in POR deficient patients.

Pregnancy may be associated with some complications in CAH patients based on the severity of their condition. This necessitates precise monitoring by an experienced obstetrician (Foyouzi 2019). It is critical to keep the patient’s serum testosterone concentration no higher than the normal upper range throughout the pregnancy (Group 2002). The main goal is to minimize the genital masculinization of the female offspring and avoid the reconstructive surgeries and distresses related to the delivery of a child with atypical genitalia (Sandberg et al. 2012; Xu et al. 2020). Another technique that can help females with CAH is preimplantation genetic diagnosis (PGD) which detects affected embryos prior to transfer in an ART cycle. However, application of PGD needs prior identification of the associated CAH mutation (PCotSfAR and Medicine 2008; Foyouzi 2019) to detect this autosomal recessive disease (Sandberg et al. 2012).

There are very few studies reporting fertility preservation in CAH patients (Kalra et al. 2019). Similar to others, women with CAH are susceptible to the age-related decline in oocyte quality and fertility.

B) Disorders of ovarian development

I. Ovotesticular DSD

Ovotesticular DSD, also known as a true hermaphrodite, is associated with different karyotypes, including 46, XX (60% of the cases), mosaic 46, XX/XY (30% of the cases), and 46, XY (10% of the cases). This DSD is manifested by bilateral ovotestes or a healthy ovary/testis with a contralateral ovotestis. The ovotestis may contain numerous primordial follicles (El-Sherbiny 2013; Diamond and Yu 2016). The development of the internal ducts depends on the associated gonads (El-Sherbiny 2013). In other words, normally developed ovarian tissues determine the final phenotype of external and internal genitalia (Diamond and Yu 2016).

To maximize the fertility potential of patients with ovotesticular DSD raised as females with intact Mullerian structures, all discordant male testicular and Wolffian tissue are excised (Diamond and Yu 2016). This prophylactic gonadectomy and excision of testicular tissue help to lower the androgen level and increasing the chance of ovulation (Williamson et al. 1981). With pregnancy, close monitoring is recommended (Diamond and Yu 2016) because of the high reported rates of preterm labor, neonatal death, or problems in parturition (Williamson et al. 1981; Schultz et al. 2009). Cases of spontaneous pregnancies have been reported in ovotesticular DSD, mainly after surgical testicular resection (Table 2) (Williamson et al. 1981; Schultz et al. 2009).

Table 2. Summary of fertility potential and suggested interventions for patients with disorder of sex development who can be reared as female

Disorder of Sex Development (DSD)			Fertility Potential	Potential Intervention	Reported Pregnancy
46, XX DSD	Androgen Excess		Hyperandrogenemia, Ovulatory Dysfunction	Glucocorticoid Therapy, if glucocorticoid therapy fails; Oocyte Donation and IVF	(Claahsen-van der Grinten et al. 2006; Simm and Zacharin 2007; PHdM et al. 2016)
	Disorders of Ovarian Development	Ovotesticular DSD	Different from functional gonad to gonadal failure, Uncommon Fertility, Subfertile if internal genitalia are intact	Testicular tissue removal at puberty	(Williamson et al. 1981; Schultz et al. 2009; James et al. 2011)
		Gonadal Dysgenesis	Streak Gonads	Surgical removal of gonadal streaks, Oocyte Donation, IVF, Hormonal Replacement	(Kokcu et al. 2010; Creatsas et al. 2011; Aziken et al. 2015; Taneja et al. 2016)
	Mullerian Agenesis		Normal Ovaries	Gestational Surrogacy, Uterine Transplantation	(Brännström et al. 2015)
46, XY DSD	Disorders of the Androgen-Dependent Target Tissues	Complete AIS	Absence of Müllerian Structures, Gonadal Failure	Gonadectomy, Vginal Dilatation, Hormonal Replacement	No data on pregnancy
		Partial AIS
	Disorders of Androgen Synthesis or Action	5α-reductase-2 deficiency	Absence of Müllerian Structures, Gonadal Failure	Gonadectomy, Vginal Dilatation, Hormonal Replacement	No data on pregnancy
		17β-hydroxysteroid dehydrogenase-3 deficiency
	Disorders of Testicular Development	46,XY Gonadal Dysgenesis (Swyer Syndrome)	Streak Gonads	Surgical removal of gonadal streaks, Oocyte Donation, IVF, Cesarean Section	(Creatsas et al. 2011; De Santis et al. 2013; Taneja et al. 2016; Kalra et al. 2017)
Sex Chromosome DSD	Turner Syndrome		Mosaic Forms: Primary Ovarian Insufficiency (Spontaneous Pregnancy) Severe Forms: Streak gonads with no oocyte	Oocyte Donation, IVF, Pregnancy Counseling (high risk of morbidity and mortality)	(Hovatta 1999; Bryman et al. 2011; Hadnott et al. 2011; Folsom and Fuqua 2015; Shankar and Backeljauw 2018)
	Mixed Gonadal Dysgenesis		Complete Gonadal Failure	Gonadectomy, Hormonal Replacement, Oocyte Donation (if the uterus is fully developed), IVF	No data on pregnancy

In 46, XY/46, XX mosaicism, also known as chimerism, some cells carry the XY karyotype while others carry the XX karyotype (Aruna et al. 2006). The patients with sex chromosome mosaicism always have clinical abnormalities, generally with an ovotestis and uncertain genitalia to various extents (Williamson et al. 1981; James et al. 2011). In 2011, a completely healthy woman in her fourth pregnancy was highly mosaic in sex chromosomes (James et al. 2011). Due to unpredictable characteristics of sex chromosome chimeric cases, no precise information on actual prevalence, clinical sequelae, and patients’ fertility potential are available yet (Sugawara et al. 2012). Hence the fertility potential of women with ovotesticular DSD should be considered uncertain, and specialized counseling and interventions should be considered. (Schoenhaus et al. 2008).

Ii. XX gonadal dysgenesis

In patients with an XX hypogonadic genotype and gonadal dysgenesis (GD), both ovaries are formed in a streak shape due to an unknown cause. A point mutation in the follicle-stimulating hormone (FSH) receptor gene has been mentioned as a possible etiology (Huang et al. 2016; Manne et al. 2016). The uterus and fallopian tubes have a normal structure in these patients, but the streak of the gonads produce insufficient amounts of estrogen and testosterone. At the same time, the levels of FSH and luteinizing hormone (LH) are high (Pertusa and Palacios 2009; Manne et al. 2016). In these cases, the female phenotype is manifested by hypoestrogenism with primary amenorrhea and also lacking sufficient secondary female sex characteristics such as breast growth and pelvis anatomy (Massin et al. 2006; Master-Hunter and Heiman 2006; Kariminejad and Kariminejad 2015). The lack of secondary sexual characteristics after puberty is the most common path to diagnosis (Kariminejad and Kariminejad 2015). It has been mentioned that the patients with XX GD are at risk of abnormal growth of gonadal tissue, so the surgical removal of the tissue is necessary to avoid the possibility of neoplasia (Kohmanaee et al. 2015).

Most successful pregnancies in 46, XX GD cases have been reported using ART such as IVF (Creatsas et al. 2011; Aziken et al. 2015; Taneja et al. 2016). However, these pregnancies were accompanied by notable complications, including oligohydramnios, gestational hypertension, preeclampsia, preterm labor, premature rupture of membranes, and spontaneous abortion (Kariminejad and Kariminejad 2015). It was primarily believed that the pregnancy could only be achieved through IVF/ICSI cycles using oocyte donation and hormone replacement therapy during the first trimester (De Santis et al. 2013; Aziken et al. 2015). However, a case report in 2010 presented a pure 46, XX GD patient who got pregnant without medical interventions, 10 years after the diagnosis, and had a successful delivery via cesarean section (Kokcu et al. 2010).

C) Mullerian agenesis

Mullerian agenesis, also known as Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, is characterized by the failure in the development of the Mullerian duct, resulting in the absence or shortening of the vagina, or the absence or hypoplasia of the uterus; however, the ovaries are normal in most cases (Folch et al. 2000; Stanhiser and Attaran 2016). MRKH is commonly associated with vertebral, renal, and, to a slighter degree, cardiac and auditory defects (Strübbe et al. 1994). Secondary sexual characteristics seem normal, but the absence of a vagina and uterus precludes pregnancy (Stanhiser and Attaran 2016). Mullerian agenesis is the second most common cause of primary amenorrhea (Londra et al. 2015).

Pregnancy complications in women with MRKH syndrome are generally managed with the help of gestational surrogacy (Raziel et al. 2011; Anchan et al. 2013). As ovarian development is separate from that of the fallopian tubes and uterus, the production of normal oocytes is independent from menstruation timing and is hyperresponsive to stimuli (Ben-Rafael et al. 1998; Raziel et al. 2011; Cakmak and Rosen 2015). The success rates of oocyte retrieval, fertilization, high-quality embryo production, and pregnancy are marginally under the normal values for MRKH patients; nevertheless, IVF is still attractive for these patients (Folch et al. 2000; Pabuccu et al. 2011; Raziel et al. 2011). Due to the unique pelvic structure of MRKH patients, vaginal oocyte retrieval is not possible, and the transabdominal route is required (Londra et al. 2015). Uterine transplantation is an innovative method in reproductive medicine and is used to manage infertility caused by a uterine anomaly; however, few cases of human uterine transplantations have been reported worldwide (Ozkan et al. 2013; Brännström et al. 2014; Johannesson and Järvholm 2016). Brännström et al. reported the first live birth after the uterine transplantation followed by IVF (Brännström et al. 2015). Nevertheless, uterine transplantation is still under investigation. Numerous pregnancies should be achieved to carefully assess the possible obstetric risks before universally recommending any technique.

Overall, a correct and comprehensive diagnosis and psychosocial consultation are necessary for determining the best treatment protocol for patients with Müllerian agenesis (Weijenborg et al. 2019).

2) DSD patients with 46 XY karyotypes

A) Disorders of the androgen-dependent target tissues

Androgen insensitivity syndrome (AIS) is referred to a condition in which the androgen-dependent target tissues are insensitive to the androgens. This condition leads to a dysmorphic appearance and developmental disorders in the target organs (Singh and Ilyayeva 2020). It has been demonstrated that AIS is caused by an X-linked mutation in the androgen receptor (AR). The result is a wide range of phenotypes categorized into complete AIS (CAIS) or partial AIS (PAIS). AIS phenotype ranges from an infertile male appearance to a female with typical external genitalia (Verim 2014). The undervirilization degree of external genitalia at the time of birth and the under-masculinization degree at the time of puberty depends on the level of androgen insensitivity in the target tissues (Wisniewski and Mazur 2009). Gonadectomy is suggested after puberty due to the risk of malignancy before sexual maturity (Cools et al. 2006; Diamond and Yu 2016).

Individuals with CAIS are generally raised as girls and retain their female gender identity throughout their lives despite the 46, XY genotype (Wisniewski and Mazur 2009; T’Sjoen et al. 2011; Batista et al. 2018). A typical CAIS patient is a tall female with a feminine distribution of adipose tissue, breast growth, and external genitalia, usually with sparse or no sexual hair (Wisniewski and Mazur 2009). Most often, inguinal testes are present that can descend a bit with time to become more palpable. Affected individuals can present as adults with amenorrhea but sexual hair and normal breasts (Batista et al. 2018). Currently, CAIS cases are considered sterile because they have no ovaries or uterus (Melo et al. 2003). However, some studies have detected germ cells in the abdominal gonads (Hannema et al. 2006; Finlayson et al. 2017). The presence of germ cells raises the possibility of future fertility by preservation, but this option is merely experimental at this stage.

PAIS cases are typically born with varying degrees of under-masculinization and genital ambiguity, leading them to be reared as either male or female. Gender identity demonstrations have greater variability among individuals born with PAIS (Richter-Appelt et al. 2005; Finney et al. 2019). If the individual is reared as a female, she might undergo surgery to remove the male sex organs and be given estrogen therapy after puberty (Hughes et al., 2012). Also, the vagina may be formed in partial or full length (Melo et al. 2003; Purves et al. 2008). At present, fertility is nearly impossible for individuals with PAIS raised as females (Van Batavia and Kolon 2016). Generally, AIS patients require a variety of individualized management plans. The team of medical professionals assigned to manage these patients should consider the psychosocial aspects including gender choice, psychosexual outcomes, gender reconciliation counseling, and the clinical aspects, including external genitalia concordance, hormonal needs, and hormonal needs, gonadectomy indications, and infertility possibilities.

B) Disorders of androgen synthesis or action

I. 5α-reductase-2 deficiency

Patients with 5 alpha-reductase-2 (5α-RD-2) deficiency demonstrate normal female external genitalia with male internal sex ducts (Katz et al. 1997; Costa et al. 2001). 5α-RD-2 metabolizes testosterone to dihydrotestosterone (DHT) required for virilization of the genitalia (Mendonca et al. 2016). Like testosterone, DHT is a ligand for androgen receptor with higher affinity critical during the fetal stages. After birth, somatic masculinization progresses under the influence of testosterone (Katz et al. 1997; Wisniewski and Mazur 2009). During sexual maturity, testosterone also induces muscularity, penile growth, and testicular descent (Van Batavia and Kolon 2016). Undiagnosed cases are frequently reared as female in childhood; however, they present male phenotype after puberty (Van Batavia and Kolon 2016). Infertility is definite in those who have been raised as female. In these cases, vaginal dilatation and orchiectomy are considered for satisfactory sexual activity and inhibition of virilization (Katz et al. 1997; Wisniewski and Mazur 2009).

Ii. 17β-Hydroxysteroid dehydrogenase III deficiency

17β-Hydroxysteroid dehydrogenase-3 (17β-HSD III) converts androstenedione to testosterone (Akesode et al. 1977). The majority of patients born with a 17β-HSD III deficiency have an apparent female external phenotype. In contrast, they have internal testes located in the abdomen or inguinal canal and lack Mullerian ducts (Wisniewski and Mazur 2009). Similar to CAIS cases, impaired function of 17β-HSD III can result in a clinical presentation of female external genitalia before puberty (Imperato-McGinley et al. 1979). In cases where testes remained in situ, masculinization occurs at puberty, similar to a 5α-RD-2 deficient case (Cohen-Kettenis 2005).

In the majority of 17β-HSD III deficient patients, penile growth and virilization occur at puberty resulting in gender reassignment (Wisniewski and Mazur 2009). Orchiectomy and estrogen replacement have been employed for the patient who identifies herself as female, (Chuang et al. 2013; Van Batavia and Kolon 2016). Even if 5α-RD-2 and 17β-HSD III deficient cases are reared as females, they are considered infertile due to the lack of oocytes.

C) Disorders of testicular development

I. 46, XY gonadal dysgenesis

46, XY gonadal dysgenesis (GD) results from mutations in any gene involved in gonadal formation. NR5A1, MAP3K1, and SRY are the genes that have been most reported to be involved in 46 XY GD (Bastian et al. 2015). In these cases, abnormal development of the gonads is complete or partial (Bastian et al. 2015). Complete 46, XY GD, also known as Swyer syndrome, is characterized by bilateral GD and a physiologically efficient uterus and normal endometrial response (Kariminejad and Kariminejad 2015). These individuals have streak gonads, fallopian tubes, a small uterus, and female external genitalia (Chen et al. 2005; Jorgensen et al. 2010). Full features of the secondary sexual traits do not develop due to the incapability of the streak gonads in the production of the sex hormones at normal amounts (Jorgensen et al. 2010). Despite the XY dysgenesis, successful pregnancy is possible using oocyte donation (Kariminejad and Kariminejad 2015; Taneja et al. 2016). However, the number of reported live births is rare for such patients (Creatsas et al. 2011; Kalra et al. 2017). Taneja et al. reported a successful normal pregnancy and delivery with donor oocyte in a patient with Swyer syndrome (Taneja et al. 2016). Santis et al. also reported a successful twin pregnancy in a patient with Swyer syndrome following oocyte donation and IVF cycle (Paternoster et al.). Recently, Kalra et al. reported a successful pregnancy and live birth after ART in a case of Swyer Syndrom (Kalra et al. 2017). If a patient with Swyer syndrome becomes pregnant, they will possibly require delivery by cesarean section due to their android shape of the pelvis or a hypoplastic uterus (Taneja et al. 2016). Gonadoblastoma and germ cell malignancies are prevalent in these patients and are currently managed by gonadectomy (Azidah et al. 2013). In addition, multi-disciplinary care is needed for managing patients with Swyer syndrome in order to properly control malignancy and osteoporosis, induce pubescence, optimize fertility, and support psychological circumstances. The primary care physician has a critical role in the timely referral of the patient to the tertiary centers.

Partial 46, XY GD is an uncommon disorder characterized by uncertain genitalia and a variable degree of testicular dysgenesis with or without Müllerian structures (Crone et al. 2002). The degree of genital ambiguity differs along a spectrum, ranging from an overt male phenotype with isolated hypospadias at one extreme to an overt female phenotype with clitoromegaly (or macroclitoris) at the other (Ap et al. 2013; Gabriel Ribeiro de Andrade et al. 2014). Similar phenotypes can also occur from a mixed GD (Gabriel Ribeiro de Andrade et al. 2014). Mixed GD involves XY females and involves various karyotypes, including 45, X/46, XY mosaicism (Jorgensen et al. 2010). For individuals who are reared as female, hormone therapy consists of the administration of estrogen and progesterone for those with a uterus to induce menstruation and the administration of estrogen in those without a uterus at 10 years of age to avoid extreme bone maturation (Mendonca Berenice Bilharinho et al. 2009). Surgery before age 2 is essential for enabling the development of suitable external genitalia and removing unsuitable internal structures to determine social sex (Mendonca Berenice Bilharinho et al. 2009). Bilateral gonadectomy must be performed before puberty in the individuals who are raised as females because of the relatively high risk of gonadal malignancies (Costa et al. 1997; Berberoğlu and Şıklar 2018). To the best of our knowledge, no pregnancies have been reported in these patients.

In patients with GD, gender identity in childhood may differ from the gender adopted as an adult (Hamin et al. 2012). This possibility must be considered when counseling parents of affected children. Avoiding genital surgery in infants and children is now a preferred practice at some pediatric hospitals. In addition, the possibility of gonadal tumorigenicity must be considered (Crone et al. 2002; Kim et al. 2020). Parents must be involved in the final decision based on a comprehensive investigation of the individual case.

3) Sex chromosome DSD

A) Turner syndrome

The partial or complete absence of an X chromosome or structural alterations in the sex chromosome results in a feminine phenotype called Turner Syndrome (TS) (Gravholt et al. 2019). The complete absence of a sex chromosome can be defined as 45, X/46, XX mosaicism or 45, X monosomy (Shankar and Backeljauw 2018). TS females show a broad spectrum of clinical presentations such as short stature, delayed puberty, ovarian insufficiency, cardiac and renal abnormalities, sensorineural hearing loss, ophthalmologic problems, thyroid abnormalities, metabolic syndrome, inflammatory bowel disease, and neurocognitive issues (Shankar and Backeljauw 2018). TS females are infertile mainly due to premature ovarian failure (POF) with few or no oocytes (Saenger et al. 2001; Shankar and Backeljauw 2018). However, there are case reports of individuals with either 45, X monosomy or 45, X/46, XX mosaicism who had normal puberty and regular menses with the occurrence of a spontaneous pregnancy delivering healthy infants (Bryman et al. 2011; Folsom and Fuqua 2015). The TS cases who experience spontaneous pregnancies typically have a mosaic genotype (Bryman et al. 2011; Hadnott et al. 2011; Folsom and Fuqua 2015; Shankar and Backeljauw 2018).

It has been shown that serum anti-Müllerian hormone (AMH) is a sensitive and specific marker of ovarian function in TS patients (Kalra et al. 2019). In both prepubertal girls and adult women, AMH is produced by small antral follicles. In healthy adult women, circulating AMH levels reflect the number of primordial follicles and, therefore, predictive of the reproductive lifespan (Kalra et al. 2019). Although AMH levels are independent of the hypothalamic–pituitary–gonadal axis, it has been demonstrated that AMH is associated with LH and FSH levels in TS girls (Gravholt et al. 2019). The same study revealed that AMH level is linked with the karyotype and the spontaneous pubertal development in these patients (Gravholt et al. 2019). It has been suggested that the level of serum AMH should be evaluated twice in the prepubertal girls with TS. If a consecutive fall in AMH is observed, ovarian tissue cryopreservation should be considred. This option is also considered if the AMH level is low at the first analysis (Kalra et al. 2019). Ovarian tissue cryopreservation involves the complete removal of ovarian tissues in many of these cases. It has to be mentioned that hormone replacement therapy (HRT) should be considered following the removal of ovarian tissue in TS patients to avoid the symptoms of early menopause (Oktay et al. 2016).

During the post-pubertal life, the rate of follicle depletion and decline in fertility is notably high in TS patients, necessitating a need for fertility preservation regardless of the initial level of AMH (Ye et al. 2020). Controlled ovarian hyperstimulation (COH) and ovum pick-up through the transvaginal route is an option. However, there isn’t any report of a successful pregnancy using autologous frozen oocytes or ovarian tissue from TS patients. In some cases, a sparse ovarian reserve may preclude fertility preservation. In these patients, oocyte or embryo donation may offer hope for creating a family.

Today, ART practices have increased the chance of a successful pregnancy in TS women up to 40% utilizing their own fresh or donor oocytes (Folsom and Fuqua 2015; Foyouzi 2019). However, there is an increased risk of various complications in these cases, including pregnancy-induced hypertensive disorders, preeclampsia, gestational diabetes, preterm labor, multiple gestations, low birth weight, spontaneous abortion, as well as inherent sex chromosome or endometrial abnormalities, and even death due to the complications of aortic dissection or rupture (Practice Committee of ASRM PCotASfRM 2012; Oktay et al. 2016). Since the uterine size is smaller than normal in TS women, single embryo transfer has been used (Folsom and Fuqua 2015).

The majority of authors declare that the mosaic karyotype is associated with gonadal tumors. Therefore a routine gonadectomy for these patients has been used (Mandelberger et al. 2016; Tam et al. 2016). Although there are reports of fertility in mosaic TS patients, data show that pregnancy is unlikely and fraught with complications if it does occur. Hence, gonads have been surgically before the age of fertility. Accordingly, pregnancy must be considered as a relative contraindication in TS patients. Individuals who seriously intend to receive oocyte donation must undergo thorough assessment and counseling. Spontaneous pregnancy should be avoided in patients with any significant cardiac irregularity. In these cases, surrogacy or gestational carrier cycles must be suggested (Medicine 2012). If spontaneous pregnancy occurs in a mosaic TS patient, the patient must be followed throughout the pregnancy by an interdisciplinary team of professionals, including obstetricians, endocrinologists, and cardiologists. Altogether quality of life is at risk in patients with TS as affected individuals often experience depression and low self-confidence. The medical team must be mindful of these psychosocial issues and empower self-esteem and avoid depression to improve overall well-being (Liedmeier et al. 2020).

B) Mixed gonadal dysgenesis

Mixed gonadal dysgenesis (MGD) is characterized mainly by a 45, X/46, XY karyotype. The affected individuals have a streak ovary and ipsilateral dysgenetic testis (Flannigan et al. 2014; Kariminejad and Kariminejad 2015). This disorder results from Y chromosome mosaicism, hypothetically originating from a chromosomal missegregation after anaphase lag or chromosomal rearrangement during the first mitotic divisions of the early embryo (Layman et al. 2009). This chromosomal abnormality results in structural anomalies such as rudimentary Mullerian structures, incomplete Wolffian duct development, and undervirilization of external genitalia (Flannigan et al. 2014). In these cases, secondary female sexual characteristics may develop, such as breast growth and female-type pubic hair (Kariminejad and Kariminejad 2015). However, the internal genital organs are imperfect in the majority of these patients, e.g., they have a defective uterus and upper part of the vagina and/or two streaks of gonads with an ipsilateral fallopian tube (Robboy et al. 1982; Flannigan et al. 2014). Clinical manifestation is highly variable in MGD cases ranging from partial virilization to a complete male or female gender phenotype. A significant number of these patients exhibit abnormal genitalia or secondary sexual characteristics, with the majority having clitoromegaly (El Moussaif et al. 2011; Kariminejad and Kariminejad 2015).

Y-containing karyotype mixed internal genitalia MGD patients who prefer to be reared as females have been treated by bilateral gonadectomy and periodic treatment with estrogen and progesterone (Cools et al. 2006). If the uterus is fully developed, embryo or oocyte donation may facilitate a successful pregnancy. The literature regarding MGD patients reared as female is limited, with no pregnancies reported.

Conclusion

The management of DSD patients should not merely focus on medical-surgical treatments; social and emotional impacts should be considered. Due to the difficulties in managing these patients, the multidisciplinary team needs to consider various issues when counseling families about gender identity, the need for timing medicinal or surgical interventions, and the possible long-term consequences. Consideration of fertility potential is a critical point in the management program and is generally a fundamental concern for the parents of patients with DSD. The clear thing is that DSD individuals who are reared as female should be treated differently.

With current advances in ART, the opportunity for pregnancy and having offspring is becoming more achievable in patients who have been previously considered infertile. In addition to conventional IVF, other routes may bring the chance of fertility to DSD patients. For instance, uterine growth can be induced in hypoplastic uterine tissues by hormonal therapies to facilitate the pregnancy. Currently, uterine transplantation has shown promising results, and some live births have been reported using this method (Brännström et al. 2015; Carbonnel et al. 2020).

Due to the multifactorial causes of infertility in DSD patients, fertility preservation has limited choices for these cases. In addition, the risk of the development of germ cell cancers or undesirable hormone production should be carefully inspected while considering the transplantation of the cryopreserved tissues. Therefore, considering alternative options such as oocyte donation, pregnancy surrogacy and child adoption will help the affected individuals choose the safest route for having a child.

Traditionally, total removal of the gonads is routinely performed in DSD patients during childhood to avoid tumorigenicity, especially in Y chromosome cases that at significant risk of germ cell tumors after puberty. This prophylactic gonadectomy deprives the patient of fertility potential. Today, the approach to this issue is changing as individualized treatments become popular. Gonadectomy should be individually assessed based on the risk of tumorigenicity in the DSD patient.

Reconstructive surgery has been a critical step in DSD management for a long time without any debate. However, disquieting reports of undesirable consequences, including a high rate of complications and patient dissatisfaction, have seen its decline (Cools et al. 2018). Recently, modern reconstructive surgery methods offer the possibility of creating functional genitalia with cosmetically normal appearance; however, there is no consensus on the suitable indications, timing, and appropriate procedures.

Numerous questions remain unanswered regarding the genetic causes, clinical complications, and treatment options for the DSD patients who can be reared as female. Future studies are required to bring more information and consider treatment options enabling optimum management.

Disclosure of potential conflicts of interest

The authors declare no competing interests related to the subject matter or materials discussed in this article.

Authors’ contributions

Concept, format, revision, and editing: HH, YS; Literature search, extraction, and analysis: PY, FM, SN, SP, NA; Tables: PY, FM; Drafting of the manuscript: HH, SN, SP. All authors read and approved the final manuscript.

Acknowledgments

The authors gratefully acknowledge professor Norman Eizenberg from the University of Notre Dame, Melbourne VIC, Australia, for comprehensive edit of the manuscript.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work received no grant from any funding agency in the public, commercial, governmental, or academic sectors.