Absence Of Virilization Research Articles

SAT-069 A Case of Congenital Hypoaldosteronism Due to Aldosterone Synthase Deficiency Misdiagnosed as Classic Congenital Adrenal Hyperplasia

Background: The clinical presentation of congenital hypoaldosteronism due to aldosterone synthase (aka corticosterone methyloxidase; CMO) deficiency varies with age and infants present with signs/symptoms of isolated mineralocorticoid deficiency. Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is characterized by combined glucocorticoid, mineralocorticoid deficiency and androgen excess. Clinical Case: A 6.8 y/o Female was referred for genetic testing for classic 21OHD CAH. Past History: Birth weight/length: 7.9 lbs/20 inches at term, uncomplicated pregnancy. Normal female genitalia. She presented within the 1st week of life with poor feeding and poor weight gain. Newborn screen - normal. Inpatient admission at 1 month for failure to thrive. Initial workup significant for Na 127 mg/dL (135 - 145), K 6.5 mg/dL (3.4 - 5.3), mildly elevated random 17hydroxyprogesterone (17OHP) 241 ng/dL (32 - 139) and cortisol 11.6 mcg/dL. She was diagnosed with CAH and initiated on hydrocortisone and fludrocortisone therapy. Medications: Hydrocortisone 2.5 mg twice daily (6.3 mg/m2/day), fludrocortisone 50 mcg daily. Family History: Non-contributory, mid-parental height 154.9 cm. Physical exam: Height 115.6 cm (20th %ile), weight 19.8 kg (18th %ile), BP 109/65 mmHg (95th/ 84th %ile). Well-appearing with no cushingoid features. Genital/pubertal exam: Prepubertal, normal female external genitalia. Laboratory tests: ACTH stimulation test was performed which showed - 0min: 17OHP 19 ng/dL, Cortisol 8 mcg/dL; 60min: 17OHP 155 ng/dL (<1000), Cortisol 23.4 mcg/dL (normal response >18), ruling out the diagnosis of classic 21OHD CAH. Hydrocortisone was discontinued. Further workup (holding fludrocortisone for 48hrs) showed mildly elevated plasma renin activity 3.5 ng/mL/hr (0.8 - 2), low aldosterone 1.8 ng/dL (3.5 - 124), normal 18-hydroxycorticosterone 11 ng/dL (6 - 85). 18-hydroxycorticosterone/aldosterone ratio 6.1 (ratio <10) - suggesting the diagnosis of CMO type I deficiency (1). Targeted genetic testing for CYP11B2 revealed a novel homozygous frameshift alteration in exon 3: p.Phe157Serfs*108 (c.451_469dup), a pathogenic variant predicted to lead to protein truncation and loss of function. Conclusions: This case demonstrates that the clinical presentation of isolated mineralocorticoid deficiency often overlaps features of combined glucocorticoid and mineralocorticoid deficiency. Normal newborn screen along with absence of virilization in a female infant should alert a clinician to consider isolated mineralocorticoid axis defects. The gold standard ACTH stimulation test should be performed to rule out classic CAH and avoid unnecessary glucocorticoid replacement and its long-term side effects. Reference: 1. Root AW, Disorders of aldosterone synthesis, secretion, and cellular function. Curr Opin Pediatr. 2014 Aug;26(4):480-6.

Clitoral Abnormalities in the Absence of Virilization: Etiology and Treatment Strategies

To report 3 cases of pseudoclitoromegaly and to describe the strategies used for differential diagnosis and treatment. Three cases and a literature review were described in this study. Three cases referred for treatment of clitoromegaly were in fact cases of pseudoclitoromegaly caused by a hamartoma, a neurofibroma, and a hemangioma of the clitoral prepuce. Abnormal virilization was excluded and the tumors were successfully treated by surgical resection and genital esthetic reconstruction. Clitoral abnormalities not associated with virilization syndromes are rare. Isolated abnormalities may affect the clitoris and the clitoral prepuce (pseudoclitoromegaly) and have multiple causes. The most frequent are inclusion cysts secondary to female circumcision, but a multiplicity of tumors, usually benign, may be found. Treatment is surgical, except for most infantile hemangiomas. Before deciding to offer surgical treatment, one should consider the degree of genital deformity and the risks of sensitivity loss and/or clitoral ischemia.

Comparing Women and Men’s Experiences with Kallmann Syndrome

Topic: Kallmann syndrome (KS) is a congenital olfacto-genital disease. Affected persons show an absence of physical pubertal development, and their sense of smell is reduced or absent (anosmia). The prevalence is 1:40,000 in women and 1:8000 to 1:10,000 in men. Development of gender identity corresponds to the assigned gender at birth. The cause of KS is a genetic defect. To date, only a few systematic investigations have delved into the psychological disstress and consequences of the somatic characteristics of KS. In order for affected persons to be appropriately informed, well-founded research results are necessary. The focus of the present study aims at examining the similarities and differences between the psychological disstress and consequences women and men experience through the development, on the one hand, and through its medical treatment on the other. The present text complements current findings on the psychological consequences of KS in men [1] and women, respectively [2]. Two questions lie at the center of the comparison: 1) Which similarities and which gender-specific differences are there concerning the perceived burdens? 2) Which coping strategies have been developed in dealing with the burdens and consequences caused by KS in the affected women and men? Which similarities and which gender-specific differences are there with respect to these coping strategies? Methodology: The survey has been carried out by means of topically focused narrative interviews of 16 men and 5 women. Based on the qualitative content analysis according to Mayring [3], categories have been generated and evaluated on the basis of the interview material. The results of the male and female samples have been contrasted and analyzed in gender-specific relevant key subjects [1,2]. Results: The comparison shows that the burdens women and men experience through KS go beyond the somato-medical problems, and that the psychosocial consequences are a heavy burden for the members of both groups. Men bear a heavier burden through insecurities and shame about the absence of virilization and subsequently suffer more from bullying and marginalization experiences. They also perceive mood changes more frequently and as more burdensome through the course of hormone treatment. Women also develop shame due to the absence of female body development; they do, however, perceive this as less burdensome than do men. They suffer particularly from a loss of libido before and also during hormone treatment. Differences occur concerning the gender-specific hormone treatment and its effects on mood and libido. Wellfounded statements relating to this do, however, require further-reaching studies. In women, KS is frequently misdiagnosed as simply estrogen deficiency, which could be an explanation for the differing degree of prevalence. The preferred coping strategies for both sexes include confidential talks with suitable people, such as parents, the partner, friends, or a psychotherapist. Using support from psychotherapists, sex education, and/or sexual therapists is recommended when necessary. Conclusion: Psychotherapeutic/psychological support is recommended for both women and men diagnosed with KS, taking into account the gender-specific differences in dealing with the burdens KS imposes. The focus for both sexes should be on developing and strengthening body image and self-esteem. In medical treatment for both women and men, normal or inconspicuous body development should be emphasized. Particularly in the case of women, sex therapy should be available for support due to loss of libido. For men, therapy should be recommended, so as to strengthen their social capabilities and self-confidence. Additional studies are necessary for examining the effects of hormonal treatment on mood and libido and phenotyp.

English

Sertoli-Leydig cell tumor (SLCT) is a rare (less than 0.5%), primary malignant sex cord stromal tumor of ovary, which may present with or without hormonal manifestations. Literature regarding biological behavior during pregnancy and/or puerperium is sparse. We aim to report an androgen producing SLCT, in a 22 year old post partum (8 months) female, who presented with torsion and no clinical features of virilization. The detailed clinicopathological characteristics are presented with a review of relevant literature. SertoliLeydig cell tumor, though rare, should be kept as a differential diagnosis in the evaluation of unilateral adnexal mass with features of hyperandrogenemia. To the best of our knowledge, this is possibly the first case of SLCT presenting with torsion in the absence of virilization; inspite of biochemical evidence of androgen excess.

Normal Spermatogenesis in a Man with Mutant Luteinizing Hormone

Men with mutations in LHB, the gene encoding the beta subunit of luteinizing hormone (LHB), have azoospermia with absent or few fetal Leydig cells. We report a mutation in LHB in a man and his sister. The man presented with absence of virilization, undetectable luteinizing hormone, and a low serum testosterone level. He had complete spermatogenesis with a normal sperm count. The mutant luteinizing hormone had a low level of partial activity in vitro. We concluded that the residual luteinizing hormone activity, resulting in the expression of steroidogenic enzymes in few mature Leydig cells producing small amounts of intratesticular testosterone (20.2 ng per gram), was sufficient for complete and quantitatively normal spermatogenesis.

Bilateral asynchronous adrenocortical adenoma in a girl with beckwith-wiedemann syndrome.

We report a case of asynchronous occurrence of bilateral adrenocortical adenoma in a 13-yr-old girl with Beckwith-Wiedemann syndrome. A right virilizing adrenal adenoma was surgically removed at age 6, following clinical manifestation of virilization such as acne, voice change, clitoris hypertrophy and overgrowth. Histopathological examination of the resected specimen revealed an adrenocortical adenoma predominantly composed of eosinophilic tumor cells expressing all the steroidogenic enzymes. High serum levels of DHEA-S (6,380 ng/ml) and testosterone (547 ng/dl) were noted prior to the operation. Postoperative course was unremarkable. Menstruation started at age 11, with a regular interval. At the age of 13 yr old, a high serum level of DHEA-S (8,250 ng/ml) was detected. In contrast to the episode of virilization at age 6, however, the serum testosterone level was not so high (122 ng/dl), and no clinical symptoms of virilization were apparent. Abdominal ultrasonography demonstrated the presence of a left adrenocortical adenoma. Pathological examination of the resected specimen revealed a circumscribed and well encapsulated tumor with essentially the same histological features as the tumor previously removed, except that the tumor cells showed a more prominent morphological similarity to the fetal adrenal cortex and did not express 3β HSD. The absence of virilization at the second episode was due to the relatively low serum level of testosterone compared with that of DHEA-S.

Male pseudohermaphroditism due to nonsalt-losing 3β-hydroxysteroid dehydrogenase deficiency: Gender role change and absence of gynecomastia at puberty

Adrenal and gonadal functions were evaluated on two adult cousins with male pseudo-hermaphroditism due to congenital 3β-hydroxysteroid dehydrogenase deficiency (3β-HSD) without clinical salt-losing. Both patients had been reared as females since birth. Case 1 presented at age 17 with perineal hypospadias virilization without gynecomastia and a female to male gender role change at puberty. Case 2 had previously undergone bilateral orchidectomy in childhood and presented “primary amenorrhea”, absence of virilization and a female gender role at the age of 24. In the basal state, as well as after ACTH and hCG stimulation, 3β-hydroxy-5-ene-steroid levels were disproportionately elevated, resulting in abnormal 3β-hydroxy-5-ene: 3-oxi-4-ene steroids ratios. Normal basal serum cortisol with inadequate cortisol response to ACTH was observed in both patients. Elevated basal plasma renin activity (PRA) and normal basal serum aldosterone (ALDO) were present in both subjects. After ACTH stimulation serum ALDO rose adequately in Case 1 but subnormally in Case 2. Salt restriction resulted in an increase in serum ALDO and no salt loss in Case 1 whereas in Case 2 the substantial rise in PRA and serum ALDO were unable to prevent slight urinary sodium loss. Case 1 had normal basal serum testosterone with subnormal response to hCG stimulation. Incubation of testicular tissue in vitro with [ 3H]HEA resulted in large Androstenediol production but diminished testosterone conversion confirming the 3β-HSD deficiency in the testes. We conclude that (1) absence of gynecomastia and a female to male gender role change may be observed in the male pubertal presentation of nonsalt-losing 3β-HSD deficiency and (2) the different functional behavior of zona glomerulosa in our patients suggests the presence of variable degrees of 3β-HSD deficiency in the zona glomerulosa of the nonsalt-losing form.

ANDROGEN SECRETION BY A FEMINIZING GRANULOSA CELL TUMOR

The majority of granulosa cell tumors cause feminization, although in a few women virillzation has occurred. MacDonald et al (Obstet. Gynecol. 47:649, 1976) have recently documented that a post-menopausal woman with an androstenedione (A) producing ovarian adenocarcinoma became estrogenized as a result of extraglandular conversion of A to estrogens. A 4 year old girl with a small right sided granulosa cell tumor presented with rapidly progressing breast enlargement, vaginal bleeding, but without androgen dependent signs of precocity. Pre-operative plasma steroid determinations revealed: estradiol (E2) 62 pg/ml, estrone (E1) 12 pg/ml, A 0.1 ng/ml, testosterone (T) 0.02 ng/ml. Serum LH was 0.1 and rose to 1.2 MIU/ml (LER 907) after LHRH, while FSH remained suppressed. ACTH stimulation caused no effect, but a single injection of human chorionic gonadotropin resulted in a 20-fold rise in T and A while E1 and E2 increments were only 2 to 4-fold. Very high androgen concentrations were also found in right ovarian venous samples (A 94, T 11, E2 2.55 and E1 0.55 ng/ml). After tumor removal, plasma steroid levels returned to prepubertal values, breast size declined and LHRH caused an exaggerated FSH but normal prepubertal LH response. It is concluded that the absence of virilization in this girl with an androgen secreting granulosa cell tumor resulted from extraglandular conversion of androgens to estrogens.