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Purpose: To investigate predictors of testicular response and non-reproductive outcomes (height, body proportions) after gonadotropin-induced puberty in congenital hypogonadotropic hypogonadism (CHH)., Design: A retrospective analysis of the puberty induction in CHH male patients, undergoing an off-label administration of combined gonadotropin (FSH and hCG)., Methods: Clinical and hormonal evaluations before and during gonadotropin stimulation in 19 CHH patients genotyped by Targeted Next Generation Sequencing for CHH genes; 16 patients underwent also semen analysis after gonadotropins., Results: A lesser increase in testicular volume after 24 months of induction was significantly associated with: (I) cryptorchidism; (II) a positive genetic background; (III) a complete form of CHH. We found no significant correlation with the cumulative dose of hCG administered in 24 months. We found no association with the results of semen analyses, probably due to the low numerosity. Measures of body disproportion (eunuchoid habitus and difference between adult and target height: deltaSDSth), were significantly related to the: (I) age at the beginning of puberty induction; (II) duration of growth during the induction; (III) initial bone age. The duration of growth during induction was associated with previous testosterone priming and to partial forms of CHH., Conclusions: This study shows that a strong genetic background and cryptorchidism, as indicators of a complete GnRH deficiency since intrauterine life, are negative predictors of testicular response to gonadotropin stimulation in CHH. Body disproportion is associated with a delay in treatment and duration of growth during the induction, which is apparently inversely related to previous androgenization., (© 2021. The Author(s).) more...

Objective: To verify the antagonistic effect of Bushen Tianjing Recipe (BTR) on environmental endocrine disruptors (EEDs) induced gonadal dysgenesis (GD) Sprague-Dawley (SD) male rat model., Methods: Totally 70 3-week-old male SD rats were randomly divided into seven groups, i.e., the control group (fed with corn oil), the model A group [di-2-ethylhexyl-phthalate (DEHP) 500 mg/kg], the CM A group (fed with DEHP 500 mg/kg + BTR 40 mL/kg), the exposed group B (fed with CYP 80 mg/kg), the CM B group (fed with CYP 80 mg/kg + BTR 40 mL/kg), the model C group [fed with DEHP 500 mg/kg + CYP 80 mL/kg], the CM C group (DEHP 500 mg/kg + CYP 80 mg/kg + BTR 40 mL/kg), respectively, 10 in each group. All were administered with corresponding medication by gastrogavage, once daily, for total 30 days. Rats were killed 24 h after the last administration, and their body weight and wet testis weight were weighed. The coefficient of testis was calculated. The serum testosterone (T) level was measured by chemiluminescent immunoassay. The histopathologic tissue was prepared. The ultrastructural changes of genital cells were observed by electron microscope., Results: Compared with the control group, there was no statistical difference in the body weight increase among all groups (P > 0.05). The time of testicular descent and preputial separation were significantly delayed in each exposed group (P < 0.01). In the exposed group A and the exposed group C, the wet weight of the testes was reduced and serum T level decreased (P < 0.01). The coefficient of testis significantly decreased in the exposed group A (P < 0.01). Compared with corresponding model group, the time of testicular descent and preputial separation were significantly fore-laid in each corresponding CM group (P < 0.01). The weight of the testes, the coefficient of testis, and the serum T level increased in the CM A group (P < 0.01). The serum T level obviously increased in the CM B group (P < 0.05)., Conclusions: The GD rat model was successfully duplicated by using DEHP. EEDs were proved to have significant anti-androgen activities. BTR was verified to have significant antagonistic to its anti-androgen effect. more...

Systemic lupus erythromatosus (SLE) is an autoimmune disease, which affects mainly women in the reproductive age and is influenced by hormonal changes. Therefore, hormone supplementation for patients with SLE either as contraceptives or as postmenopausal supplementation remains a controversial issue. Herein, we report a case of a 22-year-old woman with a history of ovarian agenesis, treated for several years with hormone therapy in order to reduce the risk of osteoporosis and other estrogen-deficient disorders. At the current evaluation, she met 3 of 11 diagnostic criteria for SLE along with a strong familial autoimmune predisposition. Precipitation of SLE in patients treated with hormonal therapy has been previously described. This prompted us to seek alternative drug therapies that prevent both the onset of overt SLE as well as the progression of estrogen-deficient phenomena. This unique case illustrates the dilemma of using hormone therapy in patients at risk to develop SLE and the current therapeutic alternatives. more...

In oocyte donation cycles where hormone replacement is given to recipients, progesterone administration is necessary to induce the luteal phase and synchronize the endometrium with the embryo stage. Most studies suggest that 5-7 days of progesterone are needed to prepare the endometrium for a day-5 embryo transfer and provide optimal implantation rate. This paper reports a case where an agonadal oocyte recipient received only 2 days of progesterone prior to the embryo transfer of a day-5 embryo. She subsequently had a clinical pregnancy and a live birth., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.) more...

Triple-X female characterized by primary amenorrhea and pure gonadal dysgenesis is extremely rare. We present a patient of triple-X syndrome who has not had menarche or the development of the secondary sexual characteristics. She had a hypoplastic uterus and streaked gonads on both sides with a twisted mucinous cystadenoma in the right adnexa. more...

This is a report of a 16 year-old 46,XY male who was reassigned female and had feminizing surgery during infancy because of what was judged to be inadequate genital masculinization. This patient had a dysgenetic testis that was shown to be producing testosterone during infancy. Although initially the reassignment appeared to be successful, psychological problems became progressively more severe during childhood to incapacitation by age 10 years. After it was verified that he had a male sexual identity, reassignment as male began, initially by living as a boy, then with testosterone therapy. Staged phalloplasty surgery was begun at age 16 years. Currently he has an adult-sized penis, although its function is not yet clear. Sadly, none of the steps to align his sex assignment to his perception as male has significantly alleviated his psychological issues and he continues to be severely impaired and socially compromised. Major issues include the crippling psychiatric disease that is resistant to psychotherapy and surgical problems with phalloplasty after surgery at infancy that involved reduction of the phallus with recession of the glans to the typical clitoral location. The glans was left intact at the anterior base of the phallus. Genital responsiveness during sexual activity and satisfaction are as yet unknown. more...

A prospective, multicenter study of patients with Ullrich-Turner syndrome (UTS) was conducted to estimate the prevalence of autoantibodies to tissue transglutaminase (tTg), thyroid stimulating hormone receptor (TSH-R), thyroglobulin (TG) and thyroid peroxidase (TPO) in relation to adult height after long-term growth hormone (GH) treatment. Out of 347 near-adult (> 16 years) patients with UTS from 96 German centers, whose longitudinal growth was documented within the Pharmacia International Growth Study (KIGS), 188 returned for a standardized follow-up visit at a median chronological age of 18.7 (16.0-23.6) years (bone age > 15 years). Serum samples of 120 patients were obtained for central measurements of TSH, thyroxine (T4) and free T4 and autoantibodies by standard immunoassays. Information regarding thyroid disease, karyotype and anthropometric data was extracted from the KIGS database. Thirty-six percent of the patients with UTS had positive TG and/or TPO autoantibodies and 4% had positive tTg autoantibodies, whereas 2% had positive TG and/or TPO autoantibodies as well as positive tTg autoantibodies. TSH-R autoantibodies were undetectable in all patients. The detection of autoantibodies was unrelated to a specific karyotype. Median height standard deviation scores (SDS, UTS) at start of GH treatment (0.43; -1.07, 1.85) and at follow-up (1.36; -0.11, 2.57) were comparable in all patients independent of their antibody status. The total deltaheight SDS, however, was higher in patients with negative autoantibody titers (1.08; -0.03, 2.25) compared to those with positive antibody titers (0.68; -0.44, 1.82; p < 0.01). Our study confirms the high prevalence of autoantibodies in patients with UTS predisposing them to autoimmune thyroid disease and celiac disease, and indicates for the first time that autoimmune pathologies may interfere with GH therapy and thus compromise final height. Therefore, medical care for patients with UTS should routinely include screening for these autoimmune disorders in order to assure early detection and appropriate treatment. more...

Gonadal dysgenesis with female phenotype is defined as the absence or insufficient development of the ovaries. Hypogonadism or impuberism are variable, depending on the degree of gonadal development. Mayer-Rokitansky-Küster-Hauser syndrome is a rare malformative anomaly (1/5000 women) associating uterine and vaginal aplasia with normal ovaries. We report the case of a 19-year-old woman who presented primary amenorrhea and impuberism. Hormone assay revealed hypergonadotrophic hypogonadism. The karyotype was normal, 46XX. Internal genitalia could not be identified on the pelvic ultrasound. Laparoscopy was undertaken and revealed concomitant ovarian dysgenesis and Mayer-Rokitansky-Küster-Hauser syndrome. There were no other morphological malformations. An association between these two conditions is very exceptional and appears to be coincidental, independent of chromosomal anomalies. Hormone substitution therapy remains the only therapeutic option. Hormone substitution is aimed at triggering the development of secondary sexual characters and prevent osteoporosis. There remains the unsolved problem of infertility. more...

The Mixed Gonadal Dysgenesis represents the 7.6% of all our patients with intersexual states. We report 14 patients who present Mixed Gonadal Dysgenesis. We have studied: diagnosis age; external genitalia description; sex assigned in birth and if has changed; the karyotype; sex chromatine; hormonal study; genitography; internal genitalia and internal Mullerians ducts structures; gonadal histologycal study; surgical treatment and hormonal treatment. The results show that 50% of the cases presents a 46XY karyotype and the other 50% mosaicisme 45XO/46XY. The histological study is very distinctive. A vulvovagynoplasty and clitoroplasty was made in all the cases. Four patients must follow an hormonal treatment after reaching puberal age. Summing up, with patients having ambiguous genitalia we can suspect it consists of a Mixed Gonadal Dysgenesis. The diagnosis must be precocious. And this diagnosis will be based in an ambiguous genitalia, with a karyotype 46XY or 45XO/46XY, the persistence of the internal Müllerian duct structures, and the histological study with a dysgenetic testis. These patients should be raised as females because they can obtain a good morphological and functional development like a normal female. more...

The aim of this analysis is to evaluate the gonadal function in children with true undescended testes and in those with retractile testes, in order to verify a possible impairment of the testicular steroidogenesis due to the permanent or transitory anomalous position of the gonad outside the scrotum. The authors carried out a prospective study on 29 prepubertal children affected by true undescended testes (monolateral in 20 cases and bilateral in 9), as well as on 25 prepubertal children with retractile testes (monolateral in 10 cases and bilateral in 15), assaying the testosterone (T) levels, basal and 72 hours after stimulus with human chorionic gonadotrophin (HCG) administered in a single dose of 100 U/kg i.m. Further-more, to verify the hypothesis of a possible progressive reduction of the Leydig cells function, particularly in the gonads bilaterally affected, the authors also evaluated the testosterone response to gonadotrophic stimulus compared to age (> 0 < 4 years). This study in agreement with data already published, confirms the normality of gonadal function both in children with mono or bilateral true undescended testes and in those with retractile testes. The lower the age of the subject the higher is the peak of testosterone after stimulus, confirming the active steroidogenesis of the gonads in infants and small children and sustaining the "non quiescence" of this organ during infancy, even in cases of true undescended testes. more...

Seventy-nine patients with sexual development retardation were examined, 24 of these suffered from ovarian genesis condition and 55 from central genesis condition. The findings evidence that detection of the uterus and gonads presenting as cords is one of the diagnostic criteria indicating gonadal dysgenesis. Echographic examinations carried out over the course of therapy yield a more accurate picture of ovarian function. No increase in uterine size on the echogram after discontinuation of hormonal therapy and the appearance of follicles in the ovaries after treatment point to normally functioning ovaries and helps specify the origin of sexual development retardation. In sexual development retardation of a central origin ultrasonic scanning helps assess the therapy efficacy and predict its outcome. more...

Eleven teenage boys with bilateral anorchia and 12 with gonadotrophin deficiency were treated by injections of testosterone ester (enanthate) at an initial dose of 100 mg every six to eight weeks, rising to 250 mg every four weeks after three to four years. In the anorchic boys average adult height was 177.1 cm, compared with a mean mid-parental height of 174.4 cm, and mean predicted adult heights of 177.0 cm (Tanner-Whitehouse method) and 178.0 cm (Bayley-Pinneau method). In the patients with gonadotrophin deficiency, mean adult height was 176.9 cm, compared with a mean mid-parental height of 176.1 cm, and mean predicted adults heights of 174.0 cm (Tanner-Whitehouse method) and 177.3 cm (Bayley-Pinneau method). We conclude that this testosterone regimen allows achievement of full growth potential in such patients. more...

A successful triplet gestation in a 45,X/46,XY woman is presented. A previously hypoplastic uterus was prepared for implantation by exogenous hormone replacement. Conception was achieved through in vitro fertilization of donor oocytes and transfer of four embryos into a hormonally primed endometrium. This case illustrates that some women with 45,X/46,XY karyotype can have a successful triplet pregnancy. Therefore, a conservative approach during gonadectomy in patients with a Y chromosome may be warranted. more...

The maturation of the potential for ovulation in man is reviewed in the light of recent data quantitating gonadotropins and gonadal steroids in the prepubertal child. The primary limitations of the hypothalamic-pituitary-gonadal axis are seen as related to feedback control mechanisms. Based on preliminary data obtained in patients with gonadal dysgenesis, a hypothesis which links positive and negative feedback maturation is proposed. The development of full reproductive potential in man is clearly a process which extends over a decade or more. more...

We have reported observations of growth and development made over a 16-year period on a subject who suffered bilateral congenital anorchia and his uniovular twin brother. The anorchic individual was treated with oxandrolone for a period of 3.6 years prior to the testosterone replacement therapy. The oxandrolone therapy produced a significant increment in the height age without excessive gain in bone age. At the age of 20.9 years the anorchic twin is 5.4 cm taller than his normal twin. Other differences observed between the twins reported here include the following: the anorchic subject had longer extremities, greater biacromial and biiliac distances and a smaller penis than his normal sibling. Oxandrolone therapy does appear to modify the ultimate height in children. more...

A 16-year-old woman who presented with amenorrhea had absence of the uterus, a normal vagina and gonadal dysgenesis.

Behavioral studies of an XY gonadal dysgenetic chacma baboon prior to and during testosterone propionate treatment were carried out. The orchidectomized dysgenetic individual, two intact males, a castrate male, and two ovariectomized females were pair-tested with a group of eight ovariectomized stimulus females prior to and during their treatment with estradiol benzoate. Three test series were carried out. One series occurred prior to any treatment of the agonadal focal subject animals. During this series it was only the intact males who showed behavior change during their testing with the estrogen treated females. A second test series occurred after a month of daily testosterone propionate injections (1 mg/kg/day) had been given to the four agonadal subjects. During this test series the castrate male ejaculated once with one of the estrogen-treated females. All of the treated subjects showed increases in their frequency of yawning. Upon completion of this test series the androgen dosage was increased (2 mg/kg/day) and 2 weeks later a third test series was carried out. During this series the castrate male ejaculated with five of his eight estrogen-treated partners. The yawning of all the treated subjects continued. As had been the case in the second series the XY gonadal dysgenetic individual continued to behave as did the ovariectomized females. None of these animals showed any increase in any measure of male sexual behavior. This study establishes the fact that a genetic male primate deprived of in utero exposure to testicular hormones will go on to develop as a normal genetic female and will fail to exhibit increased levels of male sexual behavior during androgen treatment. more...

During treatment of girls with oestrogen deficiency we observed different patterns of breast development in response to therapy. The forty-five girls studied fell into four groups: Group A, gonadal dysgenesis; Group B, isolated gonadotrophin deficiency; Group C, multiple pituitary hormone deficiencies; Group D, congenital adrenal hyperplasia (17-alpha-hydroxylase deficiency). Treatment with oestrogen was given in an identical manner to all. In the patients with gonadal dysgenesis, in whom the hypothalamic-pituitary function was normal, treatment led to full breast development. In isolated gonadotrophin deficiency and multiple pituitary hormone deficiency breast development was incomplete even after 3 years or more of oestrogen treatment. The conspicuous difference in the hormonal status is that the latter two groups lack gonadotrophins, while in gonadal dysgenesis these hormones are grossly elevated. Our conclusion is that gonadotrophins play an important role in mammary gland development, a finding not previously described. In the girl with 17-alpha-hydroxylase deficiency we observed that cortisol was necessary, in addition to sex hormones, for normal breast development. more...

During puberty growth velocity increases within 3 years from a prepubertal nadir to a maximum, in male to 9-10 cm/year, in female to 7-9 cm/year. This spurt is triggered by the androgenic steroids, in male mainly by testicular testosterone. In patients with anorchia the pubertal growth spurt is missing. The androgens have a dual effect. 1. As comes forth from observations in hypopituitary dwarfs being treated with constant replacement doses of hGH, these steroids potentiate the growth-stimulatory effect of hGH. In order to continue growing at all, these dwarfs need the additional medication of androgenic or anabolic steroids if they are hypogonadotrophic. 2. As demonstrated by our measurements of the nocturnal hGH secretion, androgenic steroids enhance the spontaneous production of hGH by a factor of 2-3. Biologically active androgens appear to be a conditio sine qua non for longitudinal growth after age 11-12. This is in concordance with the statement that adult male castrates are no giants as has often been claimed. The rather tall eunuchs in Istanbul were no Turks but as a rule Sudanese negroes who are racially much taller than Turks. more...

The administration of estrogens for gonadal dysgenesis is sometimes associated with the development of endometrial neoplasms. An approach which minimizes the inadvertent side effects while still providing the desired therapeutic effects may be to imitate the hormonal milieu of the normal menstruating woman. Oral administration of estradiol will not necessarily accomplish this, because of the intestinal conversion of estradiol to estrone. That problem can be overcome by the vaginal administration of estrogens. more...

The factors responsible for the elevation of circulating somatomedin-C/insulin-like growth factor I (Sm-C) during normal pubertal development are uncertain. To assess the role of ovarian estrogen secretion during puberty, we examined the effect of estrogen deficiency due to primary hypogonadism on Sm-C levels in late childhood and early adolescence. The concentration of immunoreactive Sm-C was measured in 36 untreated patients with gonadal dysgenesis (age, 4-16 yr); results were compared with the pattern of change in Sm-C in 153 age-matched normal girls. Between ages 4-9 yr, patients with gonadal dysgenesis had Sm-C levels similar to those in the age-matched normal subjects. In contrast to the normal girls, Sm-C levels in patients with gonadal dysgenesis did not rise after 10 yr of age and were significantly lower than those in normal girls at 11-16 yr of age. The effect of low dose estrogen therapy was assessed in eight patients with Turner's syndrome. Their Sm-C levels were measured before and during 2-12 months of treatment with ethinyl estradiol (90-220 ng/kg X day). The mean Sm-C concentration rose from 0.72 +/- 0.06 U/ml (+/- SEM) before treatment to 1.17 +/- 0.17 U/ml during estrogen treatment (P less than 0.04). In three patients who had a similar increase in Sm-C during estrogen treatment, interruption of therapy was associated with a fall in Sm-C concentrations; when estrogen therapy was reinstituted in two of these patients, Sm-C levels rose again. These results suggest that increasing endogenous estrogen production is a major determinant of the rise of circulating Sm-C that occurs during pubertal development in normal girls. Chronic estrogen deficiency, as in untreated patients with gonadal dysgenesis, is associated with failure to manifest the elevation of Sm-C that occurs during normal puberty. more...

Among 42 patients with GD, one had clinical diabetes and 10 had chemical diabetes (26%) when tested by OGTT. The insulinogenic index was lower in patients with chemical diabetes than in patients with normal OGTT. Among 19 patients with isolated hypogonadotropic hypogonadism, similarly tested, three had chemical diabetes (15%). In a prospective study of 29 patients with GD tested repeatedly, the incidence of diabetic OGTT increased significantly with age. As glucose tolerance deteriorated, the plasma insulin response was delayed and the insulinogenic index decreased. The carbohydrate tolerance was unrelated to weight, estrogen replacement therapy, chromosomal pattern, and GH response. In six GD cases studied at a 6 year interval, the tolerance to oral glucose decreased with time whereas glucose utilization following its intravenous injection or tolbutamide administration was only slightly diminished; the plasma insulin was reduced by approximately 50% in response to each of these stimulations. These studies suggest that carbohydrate intolerance is frequently associated with GD and is due to a diminished beta-cell function. more...

Two sisters, ages 18 and 25, presented with primary amenorrhea and underwent clinical, hormonal, cytogenetic, and pathologic evaluation. Both were of normal stature and lacking of somatic stigmata. Both patients had normal 46,XX karyotype on peripheral blood. Streak gonads were seen in both patients and a rather scanty number of primordial follicles was found in one patient. FSH, LH, and urinary estrogens were consistent with streak gonad syndrome. Autosomal recessive inheritance has been suggested in familial aggregates with XX gonadal dysgenesis. more...

Fifteen years' experience in a Menstrual Disorder Clinic revealed that gonadal dysgenesis was the commonest cause of primary amenorrhoea. Investigations using Barr Body study and laparoscopic examination were unsatisfactory and inaccurate. The invasive nature of laparoscopy was the likely principal cause for the high default rate in the early years of the Clinic. The availability of hormone radioimmunoassay and cytogenetic study has improved the diagnostic acuity. Gonadal malignancy associated with the "Y" chromosome could also be identified at its early stage. Oestrogen replacement therapy has been found to be beneficial and is associated with little side effects and no endometrial pathology has been identified. more...

Behavioral studies of an XY gonadal dysgenetic chacma baboon under estradiol benzoate treatment were carried out. The dysgenetic individual and two ovariectomized conspecific control females were given a total of three testing series. The dysgenetic individual showed progressive success in her sexual interactions with her male partners and during her third testing series she was copulated with to ejaculation by five of the eight male partners. This study provides the first supportive evidence from a nonhuman primate for the predicted development of female sexual behavior in a genetic male deprived of testes prior to the sensitive period for sexual differentiation. more...

The histologic pattern of the endometrium was studied in 38 patients, 19 to 44 years old, with primary hypoestrogenic amenorrhea treated by estrogen replacement therapy. At the time of endometrial biopsy 3 patients were receiving estrogens only and 35 patients were taking 1 of the following cyclic estrogen-progestogen combinations: 1) conjugated estrogens, 1.25 or 2.5 mg per day, combined with medroxyprogesterone, 5 or 10 mg for the last 5 to 10 days; 2) ethinyl estradiol, 50 microgram per day, combined with medroxyprogesterone, 5 mg per day for the last 5 days; or 3) mestranol, 40 microgram per day, in combination with norethindrone, 0.5 mg for the last 7 days. Evidence of endometrial hyperplasia was found in 3 patients. Two of them were taking unopposed estrogens and developed cystic hyperplasia; the other patient, treated with norethindrone in addition to mestranol, disclosed focal cystic glandular hyperplasia. This study and the review of the available data reported in the literature on the endometrial response to estrogen therapy in patients with gonadal dysgenesis stress the importance of appropriate estrogen and progestogen dosage to avoid the hazards of abnormal endometrial pattern in young patients receiving estrogen replacement therapy. more...

Cyclic replacement therapy using estrogen and progesterone was instituted in 28 patients with gonadal dysgenesis and 13 patients with hypopituitarism. When estriol was given at a dose of 2 mg per day, 10 patients (9 gonadal dysgenesis and 1 hypopituitarism) developed hyperreninemia and 3 of the 10 patients (all gonadal dysgenesis) were associated with hypertension. These side effects subsided within 6 months when the therapy was discontinued or the dose of estriol was decreased to 1 mg per day in addition to beta-blocker. Hypercholesterolemia was observed in 8 patients, but not related to high blood pressure. Attention should be paid to plasma renin activity and blood pressure when estrogen and progesterone are given for the development of genitalia in patients with gonadal dysgenesis. more...

Two cases of 17 alpha-hydroxylase deficiency are described. Both patients had primary amenorrhoea, total lack of female secondary sexual characteristics, slight hypertension and hypokalaemia. One patient was of male genotype (male pseudohermaphrodite), and in addition this patient had complete gonadal agenesis. The other patient was of female genotype. In both patients the level of plasma corticosterone was markedly increased, whereas the concentration of plasma cortisol was very low and plasma aldosterone low within the normal range. Furthermore, the plasma ACTH level was significantly increased and the plasma renin activity around the lower normal limit. The urinary excretion of corticosterone metabolites was markedly increased, whereas the excretion of both cortisol metabolites and tetrahydroaldosterone was decreased. The patients had no symptoms of glucocorticoid deficiency. Treatment with dexamethasone 0.5 mg daily completely suppressed the abnormal corticosterone production and normalized both blood pressure and serum potassium. In addition, the patient of male genotype has received sequential therapy with oestrogen and gestagen for 3 years, but so far no development of the secondary sexual characteristics has occurred. more...

Data reported since 1975 indicate that the natural hormone estrogen may act as a carcinogen when unopposed by an adequate amount of progesterone. Carcinogenesis may proceed when it is present at a high level for a short time. It is generally accepted that 3 groups of women have been at risk of developing cancer from exogenous estrogen exposure: 1) women who took sequential oral contraceptives; 2) post-menopausal women who received estrogen replacement therapy; 3) girls with ovarian dysgenesis who received unopposed estrogen therapy at puberty. Similarly, 4 groups of women appear to be at risk of developing cancer form endogenous estrogen sources: 1) women with granulosa-cell or theca-cell ovarian tumors; 2) anovulatory women; 3) obese postmenopausal women; 4) women with liver disease. The falling incidence of endometrial cancer associated with diminished estrogen sales is the final proof of an association of estrogen exposure with development of disease. more...

Ten women with estrogen deficiency symptoms because of premature menopause [3], gonadal dysgenesis [3], or surgical menopause [4] received subcutaneous implants consisting of 25--75 mg estradiol (E2) with or without 75 mg testosterone (T). All had elevated plasma FSH, and LH, and low E2 prior to treatment. Plasma levels of FSH, LH, E2, T and estrone (E1) were measured by specific radioimmunoassay techniques prior to treatment, three times a week for the first week and once a week for up to 76 weeks after implantation. Mean plasma E2 levels rose abruptly and reached a maximum of 190 +/- 35 pg/ml within 2 weeks. They fluctuated around 150 pg/ml for 46 weeks, then gradually declined, but remained above pretreatment values for more than 68 weeks. Plasma E1 increased to a lesser extent resulting in E2:E1 ratio between 1 and 5. Elevated FSH and LH titers became suppressed within 4--6 weeks. The lowest average E2 increased occurred after 25 mg implant and was associated with incomplete FSH and LH suppression. There were no differences in maximal E2 levels reached after 50 mg or 75 mg implant, however, after 75 mg implant, E2 levels appeared less variable and were sustained for a longer period of time, averaging 125 pg/ml for 70 weeks. Plasma FSH and LH concentrations were suppressed below pretreatment levels in all patients. The degree of suppression was related to the dose of E2 implanted and, therefore, to plasma E2 levels. The FSH and LH suppression appeared more complete in women with gonadal dysgenesis than in those with premature or natural menopause. Plasma T rose abruptly to a peak mean level of 2.5 +/- 1.6 ng/ml within 2 weeks of implantation. A precipitous and steady decline with return to preimplantation titers between 17th and 18th week were then observed. The E2:E1 ratio during the first 18 weeks after implantation was significantly higher in women who received E2 implant alone than in those who received E2 + T implant. Clinically, all patients had symptomatic improvement within 24--48 hours. Regular withdrawal bleeding followed administration of oral progestogen for up to 76 weeks after implantation in six patients with intact uterus. more...

The syndromes described are often related to primary endocrine or development defects, but may also result from purely educational or psychological problems. Adolescents may find it difficult to seek help, particularly in the younger age range where early medical intervention is important. While psychotherapy alone is often advisable, the use of anxiolytic agents may be an effective adjunctive treatment. Benzodiazepines are particularly useful because they do not stimulate enzyme activity as do some sedative agents. Teenagers are dependent on the expectations of their parents, and as ANTHONY and RIZZO [1971] have emphasized, the administration of drugs to a member of a family demands an understanding of such expectations, as well as a subtle awareness of the dynamic homeostasis and interactional patterns prevalent in the family at the time. The expectations of parents and the physician concerning the changes due to the drugs prescribed should be synchronized by mutual discussions and questioning. The adolescent has less anxiety tolerance, fewer brakes, less facilities for elaborating his symptoms on symbolic levels, and diminished capacities for postponement of impulsive gratifications; all these factors are important in achieving results by psychological methods alone. The time factor urges us to combine psychotherapy and pharmacotherapy; a well-selected drug in moderate dosage will not necessarily impair the transference. We may take the advise of Plato, who said that the drug effect should be supplemented with parleys ("epodai") which will guieten down or cheer up the soul. The modern sex therapist dealing with adolescents might follow this direction. more...

We describe the plasma levels of FSH and LH in ten patients with gonadal dysgenesis during treatment with a low dosage sequential estrogen-progestogen preparation. The daily dose of mestranol ranged from 12.5--50 microgram. Norethisterone was administered from day 16 onwards, the dose ranging between 0.75 and 1.5 mg. It was shown that 25 microgram mestranol was effective in lowering the elevated FSH levels significantly (alpha < 0.001). LH levels remained unaffected. The combination of 25 microgram mestranol and 1 mg norethisterone produced an increase of FSH and LH within 12 h, maximum levels being reached within 36 h after which there was a progressive decline. Low doses of estrogen and progestogen appeared capable of evoking physiological hypothalamic and pituitary responses in patients with gonadal dysgenesis. The doses employed were sufficient to induce breast development, growth of sexual hair, and withdrawal bleeding and were probably not high enough to induce rapid bone maturation and consequent stunting of growth. more...