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Individuals with differences/disorders of sex development (DSD) have increased rates of infertility. For children and youth undergoing prophylactic gonadectomy for malignancy risk, our institution offers gonadal tissue cryopreservation, an experimental technique to preserve fertility cryopotential. An 11-year-old girl with partial androgen insensitivity syndrome presented for evaluation for fertility preservation in the setting of a planned bilateral gonadectomy at an outside institution. At presentation, the patient had begun puberty with an elevated serum androgen level and was experiencing undesired virilization. She expressed a strong female gender identity, an understanding of the various treatment options, and a preference for gonadectomy to prevent further virilization. After thorough counseling with the patient and family in our institution’s multidisciplinary DSD clinic, she underwent bilateral gonadectomy with gonadal tissue cryopreservation. Her gonadal pathologic examination demonstrated well-developed peripubertal testes, with present, albeit decreased, numbers of spermatogonial germ cells, decreased Leydig cells, and nonspecific degenerative changes. The patient and her family chose to maintain the cryopreserved tissue for the patient’s potential future use. To the best of our knowledge, the present case is the first reported case of gonadal tissue cryopreservation in a patient with partial androgen insensitivity syndrome. Storage of gonadal tissue is a feasible method of germ cell preservation in patients with DSD undergoing gonadectomy, although further research advances are required to facilitate development of this tissue into mature gametes capable of biological fertility.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a form of primary adrenal insufficiency characterized by impaired cortisol secretion and elevated androgen production, is the leading cause of atypical genitalia in the female newborn. Females with classic CAH, either salt-wasting or simple-virilizing form, usually present at birth with atypical genitalia ranging from clitoromegaly to male-appearing genitalia, due to in utero to elevated androgens (androstenedione and testosterone). Females with mild nonclassic CAH usually present with typical genitalia. Proving the importance of always keeping an open mind for exceptions to the rule, we report on 3 female newborns who presented with the nonvirilized genitalia, salt-wasting CAH phenotype and genotype most consistent with simple-virilizing CAH. It is only through a positive newborn screen identifying the females with CAH that they were diagnosed before developing adrenal and/or salt-wasting crisis.

Context 46,XX patients with classic congenital adrenal hyperplasia (CAH) are exposed to elevated androgens in utero causing varying levels of virilization. The majority undergo feminizing genitoplasty early in life, with potential impact on sexual function and health-related quality of life (HRQoL). Objective We aimed to determine how sexual and lower urinary tract function, body image, and global HRQoL differs between patients with classic CAH and controls and to characterize how gynecologic anatomy contributes to outcomes. Methods 36 patients with classic CAH and 27 control women who were matched for age, race, and marital status underwent standardized gynecological examination and validated questionnaires. The responses were analyzed in relation to gynecological measurements, genotype, and disease status. Results Compared with controls, patients with CAH were more likely to have sexual dysfunction (P = 0.009), dyspareunia (P = 0.007), and other pelvic pain (P = 0.007); were less likely to be heterosexual (P = 0.013) or ever have been sexually active (P = 0.003); had poorer body image independent of body mass index (P Conclusions 46,XX patients with CAH have increased rates of sexual dysfunction, poor body image, and poor HRQoL, which is mitigated by having a larger vaginal caliber. Management aimed at optimizing vaginal caliber might improve sexual function.

BACKGROUND: PCOS is the most common cause of hirsutism in women of reproductive age. The presence of virilization in addition to hirsutism should alert to the possibility of less common causes of hyper-androgenization (HA) in this population including otherwise uncommon functional ovarian neoplasms (FON). We present 3 cases of women initially thought to have PCOS in whom virilization was the prime clue to the correct diagnosis of FON. Clinical Case series: Case 1 is a 40yr old woman with obesity and dysmetabolic syndrome referred for hirsutism presumed due to PCOS. She had noted symptoms over 2–3 yrs with amenorrhea and associated infertility. Examination revealed marked hirsutism and virilization with Ferriman-Galleway score (FGS) of 20. Lab tests confirmed marked male range HA. Multiple imaging tests revealed no adrenal or ovarian mass lesions. FDG-PET scan finally revealed a left ovarian focus for which she has left oophorectomy that revealed a 1cm Leydig cell tumor, Her HA resolved post-op and spontaneous periods resumed. Case 2 is a 45yr old woman referred with possible PCOS who had 5 mth history of progressive hirsutism and generalized hypertrichosis, dull lower abdominal pain and amenorrhea. Examination revealed marked hirsutism with generalized hypertrichosis and virilization. FGS was 25 and clitoral index was 935mm2. Lab tests confirmed marked male range HA and abdominopelvic imaging show no adrenal lesions but a 5.2cm left ovarian mass. Left salpingo-oophorectomy revealed a steroid cell tumor and postoperatively her androgen levels normalized. Case 3 is 37 yr old woman with SLE and obesity with prior gastric bypass referred with presumed PCOS but presenting with 1 yr history of progressive hirsutism. She was initially thought to have non classical CAH and treated with oral glucocorticoids with no symptom improvement. Examination revealed marked hirsutism, virilization with elevated FGS and clitoromegaly. Lab tests showed marked male range HA but multiple imaging studies revealed no apparent adrenal or ovarian lesions. Patient had no fertility interests and so had elective total hysterectomy and bilateral salpingo-oophorectomy. Histopathology revealed a 2.5cm left ovarian Leydig cell tumor not apparent at surgery and post op her androgen levels normalized. Conclusion: The distinction between PCOS which is ubiquitous and FON which is rare hinges on careful history and examination. Rapid onset hirsutism with virilization should prompt suspicion of FON. Marked male range HA (total serum testosterone >250ng/dl) is another “red flag” finding. Persistent radiologic search for such lesions should continue as they may not be immediately apparent on routine abdominopelvic imaging.

Introduction: The conversion of testosterone into dyhidrotestosterone is catalyzed by the 5 α reductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants (AV) in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported at early 70’s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge about the molecular bases of androgen regulation. Methods: We searched for SRD5A2 AV in the literature (Pubmed, EMBASE, Medline) and websites (ensemble, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous (HM) or compound heterozygous state (CH) and 5ARD2 phenotype were included. The AV were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender change, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using CONSURF platform. For categorical variables we used X2 test and Cramer’s V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 40 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). 69% were assigned as female. There were 70% of AV in HM and 30% in CH state. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along all exons with exon 1 (33%) and exon 4 (25%) predominance. AV in the exon 4 (NADPH-binding domain) resulted in lower virilization (F=10.5; p

Introduction: Ovarian sex cord-stromal tumors are a rare type of ovarian tumor which can be benign or malignant. Steroid cell tumors are a subtype of these tumors, representing Case Report: A 58 year old post-menopausal white female presented with deepening of voice, male pattern hair loss, increased muscle mass, weight gain, clitoromegaly, acne, increased axillary & facial hair growth. This had occurred over a period of 1.5 years. Initial investigatory labs revealed markedly elevated testosterone level of 630 ng/dL (n 2-45ng/dL). Normal FSH/LH, morning ACTH and cortisol, DHEAS, 17 OHP, androstenedione, prolactin and IGF1. Exogenous intake of testosterone was excluded. A transvaginal ultrasound showed thickened and cystic endometrial lining but no cysts or masses in the ovaries. An endometrial biopsy was normal. In the absence of a definitive source of elevated androgens, CT abdomen pelvis was done & showed remarkable for bilateral adrenal adenomas. Serum metanephrines were normal. An overnight dexamethasone suppression test was abnormal; morning cortisol level 3.1 (n 4.0-22.0). With a normal DHEAS these adenomas were considered to be the less likely etiology of her virilization. Given concern for an ovarian malignancy, a hysterectomy was recommended. Her total testosterone level right before surgery was 954 ng/dL. Post-operatively, not only did the total testosterone levels drastically fall to 18 ng/dL merely on POD 4, but the patient reported new scalp hair growth, decreased abdominal girth & skin smoothing. Her surgical pathology was with that of a steroid tumor of the ovary. Conclusion Steroid cell tumors of the ovary can be benign or malignant. A prompt diagnosis is critical. In the presence of elevated testosterone levels or virilizing symptoms, an ovarian etiology must be suspected. Given the malignant potential of these tumors, if there is clinical suspicion, an expedited total hysterectomy and bilateral salpingo-oophorectomy is recommended. The objective of surgical treatment is to relieve symptoms and for staging in the case of malignancy. Timely management of the tumor can reduce metastasis and significantly improve quality of life, as seen in our case. References 1.Kurman, R. J., Ellenson, L. H., & Ronnett, B. M. (2011). Blaustein’s pathology of the female genital tract (6th ed.). New York; London: Springer.

Context The steroidogenic enzyme aromatase (CYP19A1) is required for estrogen biosynthesis from androgen precursors in the ovary and extragonadal tissues. The role of aromatase, and thus estrogens, is best illustrated by genetic variations of the CYP19A1 gene leading to aromatase deficiency or excess. Objective The objective of this work is to characterize novel CYP19A1 variants. Design, setting, and patients Variants causing aromatase deficiency were suspected in four 46,XX children of African and Indian origin by careful clinical phenotyping. Sequencing of the CYP19A1 gene identified novel variants. Minigene experiments, aromatase activity assay, and computational, and histological analysis were used to characterize the variants. Main outcome measure and results CYP19A1 variants were found in all patients: a deletion in intron 9 leading to p.P423_H503del, a delins variant at p.P154, and point variants p.V161D, p.R264C, p.R375C. Except for R264C, all variants showed a loss of function. Protein structure and dynamics studies were in line with functional assays. The 2 female patients with delins variants manifested with ambiguous genitalia at birth. Histologic investigation revealed normal ovarian tissue on one side and a streak gonad on the other. Two female patients presented with abnormal pubertal development and polycystic ovaries. Conclusion In girls, aromatase deficiency usually manifests at birth, but diagnosis may also be made because of abnormal pubertal development or ovarian torsion due to (poly)cystic ovaries. The ovary harboring CYP19A1 variants may present as streak gonad or appears normal at birth, but is then at very high risk to produce cysts with aging and is therefore prone to ovarian torsion.

Patients with Turner syndrome (TS) are known to be at risk for excess androgen production and virilization associated with gonadoblastoma and Y chromosome mosaicism, and excess androgens are a risk factor for the development of hepatocellular carcinoma. However, virilization and hepatocellular carcinoma have not been described in a patient with TS. A 10-year-old with nonmosaic 45,X TS presented with clitoromegaly, accelerated linear growth velocity, advanced bone age, and elevated testosterone levels as well as a second occurrence of hepatocellular carcinoma. Gonadectomy was performed, and pathology revealed hilus cell hyperplasia. Immunohistochemical staining of both the original and recurrent hepatocellular carcinoma tissues was diffusely positive for androgen receptors. After gonadectomy, testosterone levels were measurable but normal, with no further virilization; however, the liver mass continued to grow. Ovarian hilus cell hyperplasia should be considered a potential etiology for virilization in the TS population. Excess endogenous testosterone exposure in girls and women with TS may be associated with hepatocellular carcinoma expressing the androgen receptor, though normalizing testosterone levels may not lead to tumor regression in these cases., We present the case of a preadolescent girl with TS who developed ovarian hilus cell hyperplasia, excess testosterone production, virilization, and androgen receptor‒positive hepatocellular carcinoma.

A 60-year-old female presented with a three-year history of virilizing symptoms including facial hirsutism and deepening of voice. Her medical history was significant for renal transplantation with immunosuppressive therapy consisting of mycophenolate, cyclosporine, and low-dose prednisone. She was noted to have temporal balding and darkly pigmented terminal hair on the upper lip, cheeks, chin, shoulders, and sternum. Pelvic examination revealed clitoromegaly. Menarche occurred at age 12 with regular menstrual cycles until menopause which occurred at age 50. She had two pregnancies: a miscarriage followed by a successful pregnancy. Labs revealed an elevated total testosterone of 530 ng/dL (< 60 ng/dL), free testosterone 14.8 ng/dL ( A thorough history and physical exam is vital in determining the cause of hirsutism. Medications, including over-the-counter and herbal formulations should be carefully reviewed. Although cyclosporine has been associated with hirsutism, patients typically present with vellus hair formation in the affected areas rather than darkly pigmented terminal hair. In this case, hirsutism progressively worsened following menopause and physical examination was significant for virilization. Hirsutism in a combination with virilization is typically neoplastic in nature. Endogenous androgen production can originate from either the adrenal glands or ovaries. In our patient, with workup showing both ovarian and adrenal as potential sources of endogenous androgen production, an adrenal cause was excluded due to a normal DHEA-S level at baseline and a lack of suppression of testosterone after dexamethasone suppression testing. As a result, the source was localized to the ovary. While excessive androgen production resulting in virilization is seen with ovarian tumors, Leydig stromal cell tumors are extremely rare and account for less than 0.1% of all ovarian tumors.

Introduction: Primary aldosteronism (PA) accounts for ∼10% of cases of hypertension in adults, however it’s a rare disease in children. We present a rare pediatric case with PA as the initial presentation of adrenocortical multiple hormone producing tumor. Case: A 7-year-old Japanese girl, who had right-sided hypoplastic leg and foot syndactyly, presented to our hospital due to abnormal ECG of ST depression at V6 on school health check-up. She showed normal growth, no signs of virilization nor Cushingoid appearance. She had elevated blood pressure (164/98 mmHg), low potassium (2.6–3.0 mEq/L) and low cardiac ejection fraction (30–40%). Her plasma aldosterone concentration (PAC) was 441 pg/mL and aldosterone/renin ratio (ARR) was 1470. Contrast-enhanced CT and MRI showed a right adrenal mass (34×22×30 mm) with high lipid content, which led to the diagnosis of primary aldosteronism by the right adrenal adenoma. Adrenal venous sampling failed to identify localization of aldosterone production. Since the possibility of bilateral production of aldosterone remained, the girl was treated with multiple anti-hypertensive medicine including spironolactone and potassium supplementation. Although the serum potassium levels were maintained within normal range, exercise-induced PVCs occurred 6 months after first visit. Abdominal US showed no changes in size of the tumor. Ten months later, she showed gradual weight gain without growth deceleration. Twelve months later, abdominal US revealed apparent enlargement of the right adrenal mass, and MRI scan showed a 156% increase in size of the right adrenal mass (32×50×53 mm). She showed further weight gain with moon face, hirsutism and acne. Hormonal analysis revealed elevated serum and urine cortisol levels (30–40μg/dL and 269–337 μg/m2/day, respectively), and suppressed ACTH levels with no diurnal variation. Serum testosterone levels elevated to 1.00 ng/mL and serum DHEA-S to 273 μg/dL. Retrospective analysis of serum testosterone at the first visit was already mildly elevated to 0.47 ng/mL. Although no distant metastases were detected before surgery, direct liver invasion was found at right adrenal tumor rejection. Clinical Lessons: Primary aldosterone producing adenoma is extremely rare in childhood. In our case, initially the adrenal tumor produced aldosterone predominantly, and it revealed to produce glucocorticoid and androgen later on. Androgen producing adrenal tumor in children tends to have malignant nature. Although initial presentation was compatible with the primary aldosteronism, intense follow-up with detailed monitoring of various hormone levels and images, and early surgical intervention should be considered.

Background: Patients with NNT (Nicotinamide Nucleotide Transhydrogenase) gene mutations, a rare cause of glucocorticoid and mineralocorticoid deficiency require hormone replacement therapy. Adrenal Rest Tumor (ART) in females is very rare ( Clinical presentation and Method: A 15-year-old girl, with homozygous G200S NNT-mutation that caused adrenal insufficiency reappeared to follow-up after several years with severe virilization and elevated serum testosterone (28.3 nmol/l) and ACTH (> 1500 pmol/l) levels. Pelvic MRI and Ultrasound demonstrated one sided para-ovarian round tumor with pathological vascularization. Laparoscopic exploration revealed bilateral para-ovarian mesosalpinx masses involving the serosa of the Fallopian tube (3 and 1 cm in diameter); the testosterone level normalized within one day after removal of those masses (0.2 nmol/l). Results: Histopathology demonstrated a pattern of adrenal rest tissue with strong intracellular positive staining for adrenal markers such as SF-1, calretinin, MART1, inhibin and the pituitary corticotroph marker-ACTH. The staining for ovarian characteristic markers such as PAX 8 was negative. Studying mRNA extracted from the tissue by RT-PCR revealed the presence of CYP17A1, CYP21A2 and MC2R (ACTH receptor) cDNA confirming typical adrenocortical transcriptional pattern in the tissue. cDNA of POMC was not detected suggesting that in spite of dense ACTH staining the tissue is not classically originated from pituitary corticotrophs. Methylome studies to further characterise the tissue are underway. Conclusion: This study exemplifies severe virilization that resulted from a unique and rare type of ART in ovarian related tissue that was caused by incompliance to treatment in a patient with NNT gene mutation. Given the ubiquitous expression of NNT and its reported pathophysiology as free radicals scavenger in all adrenocortical layers, it is surprising to have high ACTH induced severe virilization in spite of severe NNT dysfunction and adrenal insufficiency. This study may indicate timely testosterone screening in females with NNT mutation and when increased they should probably be laparoscopically surveyed for ART even when not detected by imaging. How NNT mutation damages mineralo and glucocorticoid secreting cells while androgen secreting cells are rescued is a theme for further studies.

The main complain of patients with partial androgen insensitivity patients (PAIS) is undervirilization signs and the small penile length. Supplemental androgen therapy has enhanced virilization in only a few patients with PAIS. Aromatase inhibitors as anastrozole and letrozole are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450 reducing estrogen and estrone levels and increasing LH and FSH levels and consequently testosterone levels. We hypothesized that the combination of high-dose testosterone with anastrozole can maintain a sustained elevated testosterone levels and also deviated testosterone metabolization from estrogen to DHT, therefore increasing penile length. Case Report This experimental treatment was proposed and both patient and parents willing to participate. Patient was firstly evaluated at 7 yrs of age. The hemizygous c.2599G>C; p.V867L AR in the ligand-binding domain (LBD) was found in both affected siblings. He was previously submitted to three unsuccessful genital masculinizing surgeries and bilateral orchidopexia. The external genitalia presented a microphalus (penile length of 2 cm, -4.5 SDS), perineal hypospadias and bilateral topic testis. He received testosterone cypionate (50 mg IM injections monthly, for 3 times at age of 7 and 200 mg IM injections monthly, for 4 times at age of 8); topic DHT gel (5-10 g/daily for three months at age of 7 yrs). At age of 12.3 yrs, the genital masculinization surgeries were completed, penile length was 3.5 cm (-2.6 SDS), testicular size of 2.6x1.5 cm and pubic hair Tanner II stage. LH and FSH levels were (9.4 and 3.2 IU/L respectively), testosterone (304 ng/dL), DHT (26 ng/dL) and estradiol (

Background: Adrenocortical carcinoma is a rare, often aggressive tumor that is more common in women than men. The tumors are more often than not biochemically active in adults, and the majority secrete glucocorticoids alone (1,2).Clinical case: A 57yo woman w/ longstanding hypertension and history of total abdominal hysterectomy presented with shortness of breath. She reported worsening of her hypertension over the past six months associated with male pattern balding, body hair growth, anxiety, facial and abdominal swelling for the past four months. Computed tomography PE protocol showed bilateral pulmonary emboli and multiple pulmonary nodules. Subsequent computed tomography chest/abdomen/pelvis revealed pulmonary nodules in both lungs, the largest being 3.7cm x 2.5cm in the right upper lobe, and a large right retroperitoneal mass centered at the expected position of the right adrenal gland measures 12.4cm x 10.5cm causing mass effect on the inferior surface of the liver along with bulky mediastinal, hilar, paratracheal, gastrohepatic, portocaval, and retroperitoneal lymphadenopathy. Exam was significant for cushingoid habitus with central obesity, rounded facies, supraclavicular and dorsocervical fat pads, proximal muscle weakness, frontotemporal balding, severe hirsutism consistent with modified ferriman-gallwey score of 13, and an annular, scaly rash along gluteal cleft. 8am serum cortisol was 65mcg/dL. 24 hour urinary cortisol was 450mcg/24 hour. ACTH was undetectable

Introduction: Bioidentical hormones (BH) are compounds that have the exact chemical and molecular composition as hormones produced in our bodies. The term typically refers to testosterone, progesterone, and androgens. Compounding pharmacies market these products as being individually tailored, safer, and more effective than modified hormones synthesized under FDA supervision. These compounded products are not subject to FDA approval for dose, purity, safety, or efficacy, which poses a risk to patients. Our case highlights the dangers of unmonitored BH replacement therapy (BHRT) use and the importance of patient education regarding these products. Clinical Case: A 48 year-old woman presented to our clinic for evaluation of elevated testosterone levels. She underwent a total hysterectomy and bilateral oophorectomies 8 years prior for heavy menses. She was briefly placed on estradiol replacement which was discontinued due to tobacco abuse. She presented to a “hormone clinic” where she was told that her testosterone levels were low and was started on BHRT pellets. The composition of these pellets were not disclosed on the manufacturer’s website. They were to be inserted every 3 months. The patient had received two pellet insertions prior to her initial visit. The patient reported feeling miserable with nausea, headaches, hot flashes, severe hirsutism, hair loss, severe aggression, increased libido, and clitoromegaly (the size of a ping-pong ball). Physical exam was notable for hirsutism of the upper lip, cheeks, and chin. No obvious foreign objects were identified in the buttocks. Genital exam was declined. Lab results prior to pellet insertion showed: total testosterone 6 ng/dL (N: 8-60 ng/dL), FSH 96.4 mU/ml (post-menopausal: 20-100 mU/ml) and estradiol < 5 pg/mL (post-menopausal < 41 pg/mL). After the initial pellet insertion: total testosterone 320 ng/dL, FSH 85.3 mU/mL, and estradiol 36.2 pg/mL. Five months after the second pellet insertion, total testosterone was 112 ng/dL, DHEAS 15.2 ug/dL (N: 35.4-256.0 ug/dL), FSH 74.9 mU/mL, and estradiol 46 pg/mL. Ultrasound of the buttocks revealed 1 ovoid hypoechoic structure in each buttock. The patient underwent surgical removal of the pellets. Post-procedural total testosterone was < 12 ng/dL (N < 40 ng/dL). Her aggression and hirsutism improved, but libido became low and clitoromegaly remained unchanged. Conclusion: The misunderstanding that BHRT is safer and more effective than synthesized, FDA-regulated hormones can lead to harmful adverse effects as seen in our patient with significant signs and symptoms of virilization. Patient education regarding the safety and efficacy of unregulated use of these compounds is crucial along with heightened physician awareness for appropriate patient guidance.