Signs Of Virilization Research Articles

A CASE OF ADRENOCORTICAL HYPERFUNCTION NORMALIZED DURING THE SECOND AND THIRD TRIMESTERS OF THREE PREGNANCIES

ABSTRACT Detailed hormonal studies were performed before, during and after three pregnancies in an untreated patient with adrenocortical hyperfunction due to hyperplasia. The patient was clinically characterized by oligomenorrhoea and moderate hirsutism, but showed no signs of virilization or of Cushing's disease. In the non-pregnant state her 17-ketosteroid excretion was elevated to twice the normal value, the androsterone fraction being moderately and the aetiocholanolone fraction greatly elevated, whereas the excretion of dehydroepiandrosterone was essentially normal. In the non-pregnant state the excretion of 17-ketogenic steroids, tetrahydrocortisol, tetrahydrocortisone, cortisone and tetrahydrocorticosterone was also considerably elevated. On high doses of dexamethasone (8 mg daily) or cortisone (100 mg daily) all fractions of 17-ketosteroids as well as the cortisol metabolites were suppressed to about one-half. Without preceding or simultaneous steroid treatment the patient conceived three times. During all three pregnancies every sign of excessive hormone production ceased. The excretion of 17-ketosteroids in all fractions fell to 20–30%, that of 17-ketogenic steroids to between 30% and 35 %, and that of cortisol metabolites to between 5 % and 46 % of the levels found before and after the pregnancies. The considerable endocrine activity of the foeto-placental unit may have "normalized" the maternal hypothalamic-pituitary-adrenocortical feed-back mechanism, either by suppressing or by altering the sensitivity of the feed-back system. An alternative theory might be an accelerated rate of cortisol metabolism by the liver in the non-pregnant state which is normalized during the last two trimesters of the pregnancies. The findings are being published as a contribution to the elucidation of the endocrinology of pregnancy.

Virilizing luteoma of pregnancy: Report of a case with measurements of testosterone and testosterone binding in plasma

Virilizing luteoma of pregnancy with maternal and fetal virilization is reported in a 19 year old woman. Antepartum steroid determinations in the mother revealed an elevated urinary 17-ketosteroid excretion and markedly increased plasma testosterone levels. The percentage binding of testosterone in plasma was lower than expected for normal pregnancy. Surgical removal of the tumor resulted in complete regression of the signs of virilization in the mother and partial regression of the clitoral hypertrophy in the infant. These changes were associated with a return of the biochemical findings to normal.

Studies on the pathogenesis of the pseudohermaphroditism in the mouse with testicular feminization.

The pathogenesis of the male pseudohermaphroditism in the mouse with X-linked testicular feminization (Tfm) has been investigated by comparing testosterone formation, the effects of androgen administration, and the metabolism of testosterone-1,2-(3)H in normal mice and Tfm mice of varying ages. First, it was established that the adult Tfm animal, in contrast to the human with testicular feminization, has both a low serum testosterone and a low rate of testosterone formation as assessed in slices of testes utilizing a variety of precursors. However, the formation of testosterone from pregnenolone-7alpha-(3)H was shown to be normal in newborn Tfm testes, suggesting that a defect in testosterone synthesis may not be primary to this mutation. Second, to establish that the pseudohermaphroditic state is due to androgen resistance rather than to diminished androgen biosynthesis during fetal life, the effect of the administration of dihydrotestosterone to pregnant animals was studied in male, female, and Tfm offspring. Whereas normal and carrier female littermates demonstrated striking virilization of the internal genital tract after such treatment, there was no sign of virilization in the Tfm animals. This finding provides direct experimental evidence in support of the view that male pseudohermaphroditism in testicular feminization is the result of resistance to androgen action during androgen-mediated sexual differentiation in embryos. Third, the metabolism of testosterone-1,2-(3)H was investigated both in tissue slices and in functionally hepatectomized animals. Dihydrotestosterone formation in tissue slices of the fetal anlage of the male organs of accessory reproduction is normal in the Tfm animal, suggesting that the primary defect in this disorder involves an intracellular event subsequent to this step and that the deficient dihydrotestosterone formation observed in the adult genital tract of the Tfm mouse is secondary to the failure of differentiation in these tissues. Finally, deficient binding of testosterone in the nuclei of the submandibular gland of adult Tfm animals, a known testosterone target tissue, was demonstrated in functionally hepatectomized mice. This finding could either be a manifestation of the primary genetic defect in this disorder or might reflect another acquired abnormality due to incomplete differentiation of adrogen-sensitive cell lines.

PRECOCIOUS PUBERTY WITH MASCULINIZATION DUE TO TERATO-CHORIO-GONADOBLASTOMA

Summary Precocious puberty with signs of masculinization and elevation of choriogonadotrophic activity in a girl 7½ years old was found to be due to a hormonally active ovarian tumour. The tumour was composed of germ cells, Leydig cells, Sertoli granulosa-like cells, trophoblastic and teratoid portions, and was therefore, termed a terato-chorio-gonadoblastoma. Hormonal data were correlated with the histological and ultrastructural findings. This unusual tumour caused precocious puberty coupled with virilization and high choriogonadotrophic activity in a girl 7½ years old.

Attitudes of Lower Class Males toward Taking a Male Birth Control Pill

This study is based on interviews regarding attitudes toward birth control pills for men vasectomy and birth control pills for women. Responses are from 93 lower-class males (9 1/2 years education $4500 per year income average age 39 married 15 years 41% while and 59% Black mostly Protestant). 47% objected to use of a male pill 51% objected to a female pill 59% objected to vasectomy. Younger men objected less to pills but more to vasectomy. Education regarding the subject is positively related to favorable attitudes toward all 3 types of birth control especially toward a male pill. Whites objected less to male contraception while Blacks objected less to female use of the pill. The fathering of children if often thought to be a sign of masculinity among lower-class males. Reeducation to the idea that voluntary temporary sterilization with a pill or permanent sterilization through vasectomy should not be thought of as emasculation will be necessary.

Further in vivo studies in male pseudohermaphroditism with gynecomastia due to a testicular 17-ketosteroid reductase defect (compared to a case of testicular feminization).

A patient with masculine pseudohermaphroditism was considered as a normal female until puberty. At puberty she had normal breast development, primary amenorrhea and marked signs of virilism. The peripheral and spermatic venous plasma concentration of dehydroepiandrosterone (DHA) and its sulfate, androstenedione (Δ), testosterone (T), estrone (E1) and 17β-estradiol (E2) were measured in this patient and in a case of testicular feminization syndrome. In the latter patient T was the principal androgen secreted by the testicle and E2 the principal estrogen. In the first patient, the secretion of T was small, and that of Δ greatly increased; the secretion of E1 was increased more than that of E2. Following orchidectomy, in both patients, the concentration of plasma androgens was quivalent to that in a normal female, and the estrogens similar to a post-menopausal woman.

Precocious puberty with masculinization due to terato-chorio-gonadoblastoma.

SummaryPrecocious puberty with signs of masculinization and elevation of choriogonadotrophic activity in a girl 7½ years old was found to be due to a hormonally active ovarian tumour. The tumour was composed of germ cells, Leydig cells, Sertoli granulosa‐like cells, trophoblastic and teratoid portions, and was therefore, termed a terato‐chorio‐gonadoblastoma. Hormonal data were correlated with the histological and ultrastructural findings. This unusual tumour caused precocious puberty coupled with virilization and high choriogonadotrophic activity in a girl 7½ years old.

Effect of aminoglutethimide on extraglandular metabolism of exogenous testosterone

Aminoglutethimide (AG), an inhibitor of steroid biosynthesis, seems to have an extraglandular site of action on steroid catabolism. To study this effect, five males with peripheral hypogonadism were first given testosterone propionate and then the same dose was repeated combined with AG and urinary testosterone, and its metabolites were measured. AG was shown to have a very evident effect on the peripheral degradation of exogenous testosterone. This may be responsible for a few signs of virilization and fetal masculinization in women taking AG.

APPARENT LACK OF OVARIAN OESTROGEN SYNTHESIS ASSOCIATED WITH OVULATION AND CORPUS LUTEUM FORMATION

A patient is described with primary amenorrhoea, elevated urinary pregnanediol and pregnanetriol and diminished aldosterone excretion and with clinical signs of hypooestrogenism, but without signs of virilization. Sequential stimulation by large doses of human menopausal and chorionic gonadotrophins resulted in the formation of several Graafian follicles and fresh corpora lutea. These morphological changes were not accompanied by any clinical signs of an increased oestrogen secretion or by an increased urinary oestrogen excretion. Tracer studies revealed that the patient was capable of carrying out a 17α-hydroxylation, but not the removal of the steroid side-chain. It is concluded that ovulation and corpus luteum formation in women are not dependent on a concomitant oestrogen synthesis by the maturing follicle.

Luteomas of pregnancy: A cause for maternal virilization

A case of marked maternal virilization, developed in the last trimester of pregnancy, is reported. During cesarean section, large luteinized cystic ovaries were found, and one ovary was removed. Histology revealed thecomatosis with extensive luteinization and multiple cystic follicles. Markedly increased levels of testosterone and Δ4-androstenedione were found in plasma and follicular fluid, while dehydroepiandrosterone was normal. Urinary 17-ketosteroids, 17-ketogenic steroids, androsterone, and etiocholanolone were elevated as well. In spite of the high levels of androgens which caused maternal virilization, the female neonate was not virilized. A second pregnancy was uneventful without any signs of virilization. Since this lesion is benign and regresses after pregnancy, treatment should be conservative.

Male external genitalia of a girl caused by a virilizing adrenal tumour in the mother. Case report and steroid studies.

ABSTRACT A 7-year-old normal looking »boy« presented bilateral cyptorchidism. At surgery female internal genitalia (uterus, Fallopian tubes, ovaries) were found. The caryotype was 46 XX. Congenital adrenal hyperplasia could be excluded and no androgens or gestagens were given to the mother during pregnancy. The mother in spite of regular menstrual cycles showed some signs of virilization. Further examination revealed the presence of an adrenal cortical adenoma in the mother. To our knowledge, this is the first case of complete masculinization of a girl caused by an adrenal tumour in the mother.

ACTION D'UNE SUBSTANCE PROGESTATIVE SYNTHETIQUE 17α-ALLYL-4-OESTRENE-17β-OL SUR LA DIFFERENCIATION SEXUELLE DES FOETUS DE RAT

ABSTRACT Allylestrenol was given to pregnant rats from day 13 to day 20 or 21 of pregnancy. Four different treatments were used: 1) drug given subcutaneously to castrated mother animals 2) drug given subcutaneously to non castrated mothers; 3) drug given by mouth to castrated mothers; and 4) drug given by mouth to non castrated mothers. At term anomalies of the genital tract of the female foetuses were observed in groups 2, 3 and 4; the highest frequency and severity was observed in group 4, and the lowest in group 2. The trans-intestinal route and the presence of the maternal ovaries favour the occurrence of anomalies (by metabolic conversion of the drug?). The males were normal. In the female foetuses the main anomalies were: complete or partial persistence of the Wolffian ducts in many foetuses; inhibition of the separation of the posterior vaginal cord from the urethra; slight anterior flexure of the uro-genital sinus and some increase in the length of the ano-genital distance; slight anomalies of the genital tubercle. In females from group 4, reared postnatally until adult, the Wolffian ducts retrogress and there is late development of the vaginal cord (and duct); but the posterior vagina and the clitoris remain abnormal. The anomalies produced by allylestrenol in females are more similar to those produced by oestrogens than to those produced by androgens (the latter are permanent and include masculinization of the uro-genital sinus). But in pregnant rats given oestrogens the male foetuses are abnormal. It is not justifiable to interpret the persistence of Wolffian ducts or vaginal inhibition at birth as signs of masculinization when they are not permanent, since similar transient anomalies can be produced by oestrogens. For these reasons, and also for testing the reproductive capacities of animals treated pre-natally with steroids, the evaluation of the effect of a new compound on the young should include postnatal rearing and study.

CUSHING'S SYNDROME IN INFANCY

Cushing's syndrome in infancy is usually due to adrenal tumor which is often malignant. Three cases are described in which the disorder was due to adenoma and surgical cure was achieved. The clinical picture is strongly suggestive if not diagnostic. Its hallmark is generalized obesity with typical facies; also present are hypertension and signs of virilization. Striae were not found in our patients. Increased excretion of both 17-hydroxysteroids and 17-ketosteroids is characteristic; this excretion was not suppressed by dexamethasone in two of these patients in whom it was tested. Intravenous pyelogram was distinctly abnormal in all cases and indicated the presence and location of the tumor. The diagnosis can be made efficiently and surgical treatment can be promptly instituted with reasonable expectation of cure. Careful attention must be paid to preoperative and postoperative administration of adrenal steroids.

Apparent lack of ovarian oestrogen synthesis associated with ovulation and corpus luteum formation.

Abstract. A patient is described with primary amenorrhoea, elevated urinary pregnanediol and pregnanetriol and diminished aldosterone excretion and with clinical signs of hypooestrogenism, but without signs of virilization. Sequential stimulation by large doses of human menopausal and chorionic gonadotrophins resulted in the formation of several Graafian follicles and fresh corpora lutea. These morphological changes were not accompanied by any clinical signs of an increased oestrogen secretion or by an increased urinary oestrogen excretion. Tracer studies revealed that the patient was capable of carrying out a 17α‐hydroxylation, but not the removal of the steroid side‐chain. It is concluded that ovulation and corpus luteum formation in women are not dependent on a concomitant oestrogen synthesis by the maturing follicle.

Familial syndrome of primary testicular insufficiency with normal virilization, blindness, deafness and metabolic abnormalities.

In spite of the presence of small testes and elevated urinary gonadotropin levels, two brothers with a new syndrome of familial hypogonadism had normal secondary sex characteristics. Associated findings were blindness, deafness and several metabolic abnormalities, including hyperuricemia and elevated serum triglyceride and pre-beta-lipoprotein values. Testicular-biopsy specimens showed small hyalinized tubules and abundant Leydig cells. The plasma testosterone levels of both siblings were below the adult male range, but similar to those of adolescent males with established signs of masculinization. Chorionic gonadotropin in large doses did not raise the plasma testosterone level, suggesting decreased Leydig-cell reserve. This syndrome resembles that described by Alstrom and his co-workers, but is clearly distinguishable from other known types of familial hypogonadism.

Medroxyprogesterone acetate in the treatment of renal cell carcinoma (hypernephroma).

Medroxyprogesterone acetate, a potent synthetic progestational steroid, was administered to 23 patients with metastatic renal cell carcinoma. Seven patients received 300 mg/d orally. Six patients received 100 mg/d intramuscularly of the commercial preparation Provera. Ten patients were given 400 mg/w intramuscularly of an investigational preparation. Twenty-one patients completed a minimum treatment period of 6 weeks and were considered evaluable. There were one complete and two partial objective remissions to the parenteral preparations. No responses were observed with the oral preparation. The dose to response varied from 5.2 to 9.0 Gm and the duration of response from 4 to 30+ months. There did not appear to be a correlation of response with age, duration of disease, or histologic grade or cell type. A “symptom status” indicating severe disability from disease did adversely affect response. Minimal side effects were weakness in two patients, loss of libido in one male patient and minimal signs of virilism in one female patient. Eleven patients who showed progressive disease after an adequate trial of medroxyprogesterone acetate received further treatment with testosterone. There was one partial objective response of 5 months' duration. These results are superior to those obtained with chemotherapy.

OCCURRENCE OF TUMORS IN DYSGENETIC GONADS

The occurrence of gonadal tumors was studied in 51 patients with gonadal dysgenesis. The patients have female legal sex and complained of primary amenorrhea. They were classified into two main groups: Turner's syndrome—25 cases; and gonadal dysgenesis (without somatic malformations)—26 cases. Of 25 cases of Turner's syndrome two cases of gonadal tumors were found—one gonadoblastoma and one interstitioma. Of 26 cases of gonadal dysgenesis without somatic malformations eight tumors were found—dysgerminoma (seminoma) in four cases, gonadoblastoma in three cases and a Brenner tumor in one. In all ten cases with gonadal tumors a negative sex chromatin pattern was found. Cytogenetic analysis revealed a normal male 46/XY karyotype in seven cases and in one case a 45/XO//46/XY mosaic was present. In all ten cases high secretion of gonadotrophins was encountered. The authors conclude that persistent germ cells from the embryonic stage, within malformed testicular elements or within so-called bisexual formations play an important role in pathogenesis. The authors point to the danger of gonadal neoplasm in patient with female phenotype, primary amenorrhea, signs of masculinization and presence of a negative sex chromatin pattern and a Y chromosome.

Occurrence of tumors in dysgenetic gonads.

The occurrence of gonadal tumors was studied in 51 patients with gonadal dysgenesis. The patients have female legal sex and complained of primary amenorrhea. They were classified into two main groups: Turner's syndrome—25 cases; and gonadal dysgenesis (without somatic malformations)—26 cases. Of 25 cases of Turner's syndrome two cases of gonadal tumors were found—one gonadoblastoma and one interstitioma. Of 26 cases of gonadal dysgenesis without somatic malformations eight tumors were found—dysgerminoma (seminoma) in four cases, gonadoblastoma in three cases and a Brenner tumor in one. In all ten cases with gonadal tumors a negative sex chromatin pattern was found. Cytogenetic analysis revealed a normal male 46/XY karyotype in seven cases and in one case a 45/XO//46/XY mosaic was present. In all ten cases high secretion of gonadotrophins was encountered. The authors conclude that persistent germ cells from the embryonic stage, within malformed testicular elements or within so-called bisexual formations play an important role in pathogenesis. The authors point to the danger of gonadal neoplasm in patient with female phenotype, primary amenorrhea, signs of masculinization and presence of a negative sex chromatin pattern and a Y chromosome.

STEROID SYNTHESIS IN CYSTADENOCARCINOMA OF THE OVARIES

Abstract Studies were done of in vitro transformation of C 14 and H 3 -labeled steroids by a primary papillary serous cystadenocarcinoma of the ovaries associated with a virilizing syndrome in a postmenopausal woman. A microsomal preparation from the tumor tissue converted progesterone to testosterone and androstenedione. Pregnenolone and 17-hydroxypregnenolone were converted to dehydroepiandrosterone. Aromatization of the substrate steroids apparently did not occur, since no steroid radioactivity was found in the phenolic fraction. Symptoms and signs of virilization gradually disappeared following surgical removal of the tumor and post-operative radiation therapy.

Steroid synthesis in cystadenocarcinoma of the ovaries

Studies were done of in vitro transformation of C14 and H3-labeled steroids by a primary papillary serous cystadenocarcinoma of the ovaries associated with a virilizing syndrome in a postmenopausal woman. A microsomal preparation from the tumor tissue converted progesterone to testosterone and androstenedione. Pregnenolone and 17-hydroxypregnenolone were converted to dehydroepiandrosterone. Aromatization of the substrate steroids apparently did not occur, since no steroid radioactivity was found in the phenolic fraction. Symptoms and signs of virilization gradually disappeared following surgical removal of the tumor and post-operative radiation therapy.