The combination of a rising incidence of early-onset cancer and the trend towards delayed parenthood has made the impact of treatments on fertility highly significant. While there is abundant evidence on oncofertility outcomes of anti-cancer treatment protocols used in people with breast cancer and haematological malignancies, data regarding gonadal toxicity and fertility preservation in young people with other cancers are lacking. We aimed to systematically review gonadal toxicity, fertility outcomes, and preservation strategies in people with gastrointestinal, sarcoma, lung, and melanoma cancers.

MCM8/MCM9-related syndromes are characterized by primary gonadal insufficiency (hypergonadotropic hypogonadism) and increased risk of early-onset germ cell tumors in females. Hypergonadotropic hypogonadism can present in females as primary amenorrhea, secondary amenorrhea/oligomenorrhea, underdeveloped uterus, or small/streak ovaries, and in males as impaired spermatogenesis (nonobstructive azoospermia, oligospermia, or Sertoli cell-only syndrome); incomplete or delayed pubertal development is more often seen in females. MCM9-related syndrome is also associated with increased susceptibility to colorectal polyposis (adenomas, hyperplastic or sessile serrated polyps), early-onset colorectal cancer (CRC), and early-onset gastric cancer.

Dysgerminoma, the most common malignant ovarian germ cell tumor, has a significantly increased incidence in individuals with 46,XY complete gonadal dysgenesis (Swyer syndrome). However, primary amenorrhea is the hallmark presentation of Swyer syndrome in adolescence. This case highlights the critical intersection of these conditions and the oncologic risks of diagnostic delay. A 16-year-old phenotypic female presented with primary amenorrhea. Physical examination revealed normal secondary sexual characteristics and unremarkable pelvic findings. Laboratory evaluation revealed hypergonadotropic hypogonadism with markedly elevated FSH and LH levels. Karyotype analysis revealed a 46,XY chromosomal complement, diagnosing Swyer syndrome. Imaging identified multiple pelvic masses, including a 10.4 cm anterior uterine mass and a para-aortic mass, highly suspicious for malignancy. Exploratory laparotomy with tumor resection and staging confirmed bilateral ovarian dysgerminoma with para-aortic and pelvic lymph node metastasis, classified as FIGO Stage IIIC (pT1bN1Mx). The patient was referred for adjuvant chemotherapy. This case underscores that primary amenorrhea with hypergonadotropic hypogonadism mandates karyotype analysis to exclude 46,XY DSD and its associated high risk of gonadal malignancy. Symptomatic treatment without definitive etiological investigation can lead to dangerous delays, allowing for progression to advanced cancer. A prompt, systematic diagnostic approach is essential to prevent serious oncologic sequelae in these patients.

The luteinizing hormone/choriogonadotropin receptor (LHCGR) is essential for Leydig cell function, gonadal steroidogenesis, and male sexual differentiation. Loss-of-function variants in LHCGR are a rare cause of 46,XY differences of sex development (DSD). We report 2 46,XY adult sisters born to consanguineous parents, who presented with primary amenorrhea and absent secondary sexual characteristics. Both exhibited tall stature, female external genitalia, hypergonadotropic hypogonadism with very low testosterone levels. Imaging revealed bilateral cryptorchid testes and absence of Müllerian structures. Both sisters underwent bilateral gonadectomy, and histopathological findings provide strong morphological support for Leydig cell hypoplasia. Genetic testing identified a novel homozygous splice-site variant (c.384-2A>G) in LHCGR, predicted to cause aberrant splicing and a loss of receptor function. These findings expand the mutational spectrum of LHCGR-related DSD, a rare cause of 46,XY DSD.

Adult medulloblastoma is a rare cerebellar tumour with an incidence of 0.6-1 per million per year in post-pubertal patients. Craniospinal radiotherapy is a key component of treatment. Endocrine organs commonly involved in the radiation field - such as the hypothalamus, pituitary and thyroid gland - are particularly sensitive to radiation-induced damage, often resulting in hormonal deficiencies in a dose-dependent manner. We report the case of a 43-year-old woman who developed both hypopituitarism and primary hypothyroidism following craniospinal radiotherapy for medulloblastoma at the age of 34. She was diagnosed with primary hypothyroidism two years later. Seven years later, hormonal substitution therapy was started for menopausal symptoms, and nine years later, she presented with persisting long-standing fatigue, amenorrhoea, nausea upon waking, vomiting and anorexia. Laboratory testing was suggestive of hypopituitarism. Dynamic testing confirmed severe growth hormone deficiency but a normal cortisol response. Thyroid-releasing hormone stimulation test revealed a blunted and delayed response. Magnetic resonance imaging revealed significantly reduced pituitary height over time. Although radiation-induced endocrine dysfunction is well documented in children, its prevalence in adult populations also reaches 50%, and its clinical significance is increasingly recognised. Despite the common occurrence of hypothalamic-pituitary axis dysfunction and primary hypothyroidism following craniospinal irradiation, their simultaneous presentation provides an important educational example of the complex and multifaceted endocrine effects of radiation exposure. This paper highlights the importance of minimising radiation dose on these endocrine glands, as well as long-term multidisciplinary follow-up and screening after craniospinal radiotherapy. It also raises the question whether pituitary evaluation on surveillance imaging could help predict pituitary dysfunction, a possibility that warrants further exploration.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare congenital malformation characterised by uterine agenesis and absence of the upper two-thirds of the vagina in phenotypically normal females with a 46,XX karyotype. We report the case of a 22-year-old woman presenting with primary infertility. Clinical examination revealed normal external genitalia with a shallow vaginal dimple. Pelvic ultrasound and MRI showed complete agenesis of the uterus and upper vagina, with normal ovaries. Hormonal evaluation confirmed preserved ovarian function, and karyotyping revealed a normal 46,XX profile. Diagnostic laparoscopy confirmed the diagnosis of type I MRKH syndrome. This case highlights the importance of considering this diagnosis in any woman with primary amenorrhea, even when revealed late in the context of infertility.

Congenital anomalies of the genitourinary system are uncommon but clinically significant due to their impact on urinary and reproductive function. Zinner syndrome and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome are rare developmental disorders involving the mesonephric and Müllerian ducts, respectively, and often present with nonspecific clinical features, making imaging essential for accurate diagnosis. We present a series of three cases evaluated using magnetic resonance imaging (MRI). One case involved a young male presenting with dysuria and testicular discomfort, demonstrating unilateral renal agenesis, an ipsilateral seminal vesicle cyst, and an associated atretic ureter, consistent with Zinner syndrome. The other two cases involved young females presenting with primary amenorrhea. MRI revealed the absence of the uterus and upper vagina with normal ovaries in both cases, consistent with MRKH syndrome, with one case showing associated bilateral ectopic kidneys. MRI provided a comprehensive evaluation of pelvic anatomy, clearly delineating the congenital anomalies and associated findings. Recognition of characteristic imaging features is essential for accurate diagnosis and appropriate clinical management.

Primary amenorrhea (PA) in a young girl can result from structural, functional, or hormonal disorders. Accurate diagnosis is essential for counseling on hormone replacement and fertility. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by an absent or hypoplastic uterus and presents with PA. Congenital adrenal hyperplasia (CAH) is a steroidogenic defect that may present at any age but rarely as PA. We report a 33-year-old woman who initially presented at age 17 with PA and was labeled as having MRKH syndrome due to a hypoplastic uterus. She was treated by multiple dermatologists for resistant acne between ages 20 and 32. During evaluation of hyperandrogenism, her computed tomography scan of the abdomen revealed a right adrenal mass, prompting an endocrine referral. Our evaluation showed virilization, clitoromegaly, and a hormonal profile suggestive of simple virilizing CAH. Gene sequencing showed a homozygous missense variation in exon 4 of the CYP21A2 gene (chr6:g.32007203T>A) (c.518T>A) (p.Ile173Asn), confirming CAH. She was managed with glucocorticoids, antiandrogens, and estrogen supplements. She had menarche 6 months after therapy at age 33. We report this case to highlight the importance of detailed endocrine evaluation in patients with PA.