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Milestones only feel monumental when you get some perspective, and you look back and see some of the tremors that started to pave the way for a seismic shift. The [...]

Estradiol pellet implantation for contraception offers another alternative in conception control. The occurrence of only two pregnancies in 1,668 cycles (Pearl index: 1.42) reflects its efficacy. The advantages over oral contraceptives are: (1) absence of gastrointestional symptoms, (2) minimal untoward effects, (3) no patient failure, and (4) convenience. Progressive stepdown in dose reduces the total amount of steroid used in long-term contraception. Contraceptive effect may not occur during the first month of implantation; adequate precaution should be taken. Because of the efficacy, minimal untoward side effects, and excellent patient acceptability, this regimen may be considered for contraception in developing countries and when other modalities are contraindicated.

An antigonadotropic agent, Danazol, was used in the management of 48 patients with either primary or secondary sterility. All patients were infertile for 3 or more years before Danazol was employed. In Group 1, 11 of 21 had proved endometriosis histologically; the rest had suspected endometriosis by history and examination. In the second group of 27, no reason for infertility was found. A dose of 200 mg. was given orally for 100 days to all patients, but, in the group with endometriosis, the dosage was increased to 400 mg. in 3 and 800 mg. in 5 in order to induce abatement of severe pelvic discompfort. None conceived while on therapy while about 40 per cent did conceive within 4 months after discontinuation of the drug.

Danazol,**Danazol was supplied by Sterling-Winthrop Research Institute, Rensselaer, New York.an impeded androgen with moderate antigonadotropin properties, was administered to 58 patients with a variety of benign breast disorders. The disturbances were present from 3 months to 20 years; the ages ranged from 21 to 50 years. The dose varied from 100 to 400mg. per day for 74 to 310 days, depending upon the severity of the disorder. Most of the patients had favorable responses: 44 (75.8 per cent) experienced complete relief of subjective discomfort with disappearance of clinical signs: 17 ( 65.3 per cent) of the 26 patients followed from 11 to 32 months after discontinued therapy, remained symptom-free, while the others experienced moderate to complete recurrence. Fifty per cent of the women did not menstruate while on medication. Side effects were few and transient.

Benign breast disease, aside from fibroadenomas and intraductal papillomas, frequently responds favorably to hormonal therapy. Although the use of estrogen, androgens, and progestogens often proves useful, danazol, in our hands, was found more consistently effective. Danazol, an impeded androgen derived from a progestogen, 17α-ethinyltestosterone, was employed in doses of 100 to 400mg/day for 3 to 6months in the treatment of fibrocystic disease. This agent proved efficacious in eliminating nodularity in the majority of cases, with partial resolution in most of the others. Many women to whom surgery had been previously suggested were spared surgical interference because of a satisfactory response to danazol therapy.

The cytogenetic and phenotypic findings in 15 patients with 45,X/46,XY mosaicism are described. Six patients presented with delayed sexual development without masculinization. The remaining nine patients had varying degrees of masculinization, ranging from clitoromegaly to hypospadic male phenotypes. Cardiovascular/renal anomalies were detected in 2 of the 15 patients. Gonadoblastomas were present in two patients and did not appear to correlate with the degree of masculinization or percentage of 46,XY cells present. Structural Y chromosome abnormalities were seen in three of the 45,X/46,XY probands. MZ twinning occurred in one of the 45,X/46,XY sibships.

Serum FSH and LH levels were determined at different time intervals after the subcutaneous administration of 100 g LHRH to 24 females. Serum FSH levels were of the same order in the oligomenorrheaamenorrhea and the SteinLeventhal group of patients but elevated in gonadal failure. There was a great degree of overlap between serum LH values in the three groups. Gonadal failure patients, however, could be distinguished from the other two groups because these patients had an elevation of both serum FSH and LH, and the response to LHRH was considerably exaggerated in comparison to the other two groups.

Two cases of Swyer's syndrome, characterized by rudimentary streaks in association with a 46, XY chromosome karyotype are reported. Both individuals were tall, with sparse axillary and pubic hair, and breasts were undeveloped in one and well developed in the other (she had some estrogen therapy). One had infantile but otherwise normal external genitals, while the other had poor development of labia majora and no clitoris. The vagina in each was normal, with a small cervix and uterus, and vaginal smears of the preadolescent type. Urinary 17-ketosteroids were normal, while gonadotropin levels were elevated. The gonadal streaks were extirpated, and histologic examination revealed the presence of fibrous stroma but no ova or follicles. Scattered clumps of Leydig cells and mesonephric remnants were found in one patient. Both patients reponded well to cyclic hormonal therapy, i.e., menstrual withdrawal bleeding and breast development.

Our present knowledge of the role of sex steroids in the development as well as the prevention of endometrial cancer is reviewed. Factors which increase the exposure of the uterus to unopposed estrogens, either exogenous or endogenous, are associated with increased risk of endometrial adenocarcinoma. However, there is increasing evidence that progestogens can reverse endometrial hyperplasia and protect against the development of endometrial cancer. The mechanisms to explain the antiestrogenic effects of progestogens include changes in enzyme activity and steroid receptors in endometrial tissue. Postmenopausal women treated with combined estrogen and progestogen have the lowest incidence of endometrial carcinoma. Oral contraceptives containing both estrogen and progestogen in each tablet are protective against adenocarcinoma of the endometrium, while the sequential oral contraceptive pills afforded less protection. The risks and benefits of these hormone therapies are discussed in relation to the etiology and prevention of endometrial cancer.

Menopausal symptoms are a consequence of the decline in sex hormone production, and hormone replacement therapy aims not only to relieve these symptoms but also to prevent the development of diseases of old age such as osteoporosis.

Relative contribution of the ovaries and adrenals to the pool of steroids in postmenopausal women is still the subject of much controversy. Estradiol, >4-androstenedione, and testosterone were assayed in peripheral blood, adrenal, and ovarian vein blood of II postmenopausal patients. Intravenous administration of hCG resulted in increased androgen production by the ovaries but not estrogens while intravenous administration of adrenocorticotrophic hormone did not result in the enhancement of ovaria and adrenal estrogens.

Oral contraceptives are associated with serious untoward effects and have been proscribed for women over 35years of age. It was thought that the use of a natural estrogen (pellets of 25mg of 17,β-estradiol) implanted in descending doses (four, three, two, one) at 6-month intervals might cause less disturbance in metabolic parameters and side effects. Our experience with this regimen encompasses 18,480cycles or 1,540 woman years. The corrected Pearl index was 0.273, which compares favorably with other modes of conception control. Pellet implants proved to be quite acceptable to those who could not tolerate oral contraceptives

Three groups of women with benign breast disease were treated with danazol for 3 to 6 months. Doses of 100 mg per day were given to 40 patients, 200 mg to 55, and 400 mg to 35. The age range of the patients was 20 to 48 years. The patients were rechecked at 6-month intervals over a period of 48 months. Most of them were seen four or more times after completion of therapy. Elimination of nodularity occurred in about two thirds; three experienced no improvement, and partial resolution was obtained in the remainder. untoward effects were minimal or trivial. Danazol proved to be an excellent hormonal agent in the management of fibrocystic disease of the breast.

The polycystic ovary has the capacity to produce excessive androgens (Δ4-androstenedione, dehydroepiandrosterone, and testosterone). Whether this disorder is caused by constant pituitary priming of the ovaries due to hypothalamic-pituitary derangement or an ovarian enzyme defect, the end result is the same, i.e., abnormal androgen production. In an effort to explain the syndrome, we offer the hypothesis of an inherently sensitized adrenal secreting excessive androgen which leads to an imbalance in the hypothalamic-pituitary axis. The result is a tonic stimulation of the ovaries eventuating in “the androgenic polycystic ovary.”

Fibrocystic disease of the breast (FCD) is an exaggeration of the normal physiologic response to cyclic estrogen and progesterone stimulation. The disorder can persist, with much less severity, in the menopausal woman. Whether FCD predisposes to mammary cancer remains moot. A new steroidal agent, danazol, can eliminate nodosities in the majority of women with FCD. Thermography may identify women who are at greater risk because of increased heat production. Mammography should be employed in women with persistently abnormal thermograms, even though no suggestive breast masses are palpable. Needle biopsy or surgical biopsy should be undertaken whenever a firm indurated mass is palpated, regardless of negative findings with a thermogram or mammogram. In a series of 1548 women treated for 10,715 women‐years, the incidence of breast cancer after prolonged estrogen therapy was not increased. Although estrogens and prolactin have been incriminated in the etiology of mammary cancer, no hard facts exist to confirm such allegations.

ABSTRACT: The influence of aging on serum levels of gonadotropins (FSH and LH), testosterone and estradiol was studied in the following groups: 4 normal men (ages 30 to 50), 38 men with symptoms of the male climacteric (ages 51 to 84), 25 men with relative impotence (ages 31 to 50), 10 normal women (ages 24 to 31), and 6 menopausal women (ages 58 to 76). FSH and LH levels began to rise in men in their 40's, and the increase became more conspicuous in the later age decades. The degree of elevation was nowhere comparable to that observed in the aging women. In the male, the serum testosterone levels showed a progressive decrease from the fifth age decade onward, whereas in the female there was an increase after the menopause. Estradiol levels showed no significant change in the aged male, but they were somewhat higher than in the aged female. Exceptions to the low‐testosterone and low‐gonadotropin relationship were observed in individual cases and might be explained by relatively high estradiol values. Proper replacement therapy by means of estrogens for the postmenopausal female and androgens for the aging male is often of great benefit, physically and emotionally.

ABSTRACT: Defective sexual adjustment can be managed more easily when there is some understanding of the respective roles of psychogenic and endocrine factors in sexual behavior. Millions of men and women are in need of help. The problems are discussed under the headings of maleness and femaleness, sex interest in the female, sexual inadequacy, and sexual gluttony. Only after differentiation of the psychogenic and endocrine factors can proper therapy be started.

Constant, adequate dosages of estrogen, androgen or estrogen‐androgen combinations provide relief from the migraine and migrainoid headaches often experienced by menopausal women. This form of therapy employs natural physiologic hormones in preference to synthetic nonphysiologic agents such as ergotamines, barbiturates or addictive drugs. In the author's studies of hundreds of women with menopausal headaches, such hormones administered by pellet implantation gave beneficial results superior to those obtained by oral or parenteral administration.

Danazol, an interesting pharmacologic steroid ‘in search of a disease’, was first used by my group in the management of endometriosis because of the marked anti-endometrial effects found during clinical trials. The results in alleviating dysmenorrhoea, dyspareunia, and pelvic discomfort were surprisingly good, but more important was the 40 to 50 % pregnancy rate that occurred following discontinuation of its use. In addition, because we suspected that women with unexplained infertility might be harbouring an occult or microendometriosis, a 3 month course of 200mg of danazol was tried in such patients, and proved effective in overcoming infertility in roughly 40% of patients within 6 months after discontinuation of medication. We serendipitously found that some habitual aborters carried to term after a course of danazol. Accordingly, a trial of 100mg daily for 3 months was undertaken with a satisfactory outcome in more instances than could be attributed to chance alone. To readily appreciate the effectiveness of this agent, one must be aware that conceptions may follow the use of placebos or whatever regimen is employed in about 15 to 20 % of infertile women. The unusually good results that we and other investigators in the field obtained with danazol rules out a placebo effect.

Breast cyst fluids from 118 women, aged 29 to 69years, were analyzed by radioimmunoassays for β-human chorionic gonadotropin (β-hCG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and thyroid-stimulating hormone (TSH). Blood was drawn at the same time in many cases to compare hormonal levels in serum with those in the breast cyst fluids (BCF). The levels of β-hCG in BCF were relatively high, with a mean (± standard error of the mean [SEM]) of 58.9±16.8 mIU/ml; serum levels of β-hCG were negligible. LH and TSH also were elevated in BCF compared with serum levels, exhibiting mean values (±SEM) of 26.7±4.3 mIU/ml and 6.4±0.44 μIU/ml, respectively. The levels of FSH and PRL in BCF were equivalent to the levels in the serum. The presence of biologically active hCG was suggested in several BCF samples using the rat ovarian hyperemia test. Samples of BCF were assessed for the capacity to stimulate Leydig cell testosterone production in vitro in the presence or absence of an anti-hLH antiserum. Testosterone production was significantly (P<0.05) enhanced, even in the presence of the antiserum. These data suggest that BCF contains biologically active hCG.

ABSTRACT: Relationships between the hypothalamus and the pituitary in the aging woman are discussed under the following subheadings: synthesis and release of follicle‐stimulating and luteinizing hormones, estrogen receptors, other releasing factors, neurotransmitters, and the mechanisms of hot flushes and migrainoid headaches. The hypothalamus is the main regulator of pituitary function. In the female, the hypothalamic‐pituitary axis appears to remain functionally intact well into old age.

Postmenopausal women should not be denied estrogen therapy because of the controversy about the alleged causal relationship of estrogens to endometrial cancer. A prestigious team of biostatisticians reviewed three publications that claimed this relationship and concluded that no such association could be confirmed. Although the incidence of endometrial cancer has doubled in the past 25 years, there is no valid basis for the assumption that the widespread use of estrogens is the cause. The incidence also has increased in Norway and Czechoslovakia where estrogens are rarely used. Moreover, the histologic pattern of endometrial dysplasias is such that many pathologists will make a diagnosis of endometrial cancer as a safeguard for the patient. Thus the statistics for the incidence of endometrial cancer may be inflated. As a test, the administration of 200 mg of an oral progestogen over 5–10 days will convert a histologic pattern of pseudomalignancy, but not of adenocarcinoma, into one of secretory endometrium. Unopposed endogenous or exogenous estrogens may induce hyperplasia, atypical adenomatous hyperplasia or adenocarcinoma in women who are genetically predisposed. To minimize such a possibility, it is advisable to give a 5–7 day course of an oral progestogen so that the endometrium will be shed at monthly intervals. The benefits of hormone replacement therapy for the postmenopausal woman far outweigh the putative risk of endometrial cancer

Adrenal tumors in children under 10 years of age are relatively rare. In 1951 one of us (R. B. G.) placed on record a case of a virilizing adrenal tumor in a 3-year-old girl1 and in reviewing the literature found 76 previously reported cases. From the time of that report until 1957, there have been approximately 30 additional cases.2-26 In the interim, primarily as a result of an increased understanding of adrenal physiology, there has been considerable improvement in the techniques for the diagnosis of adrenocortical tumors.As early as 1950, Wilkins27,28 reported that the administration of cortisone suppressed the excretion of androgens in congenital adrenal hyperplasia, and he suggested the use of cortisone in the treatment of this condition.29 The suppression of 17-ketosteroid excretion by cortisone was proposed as a test to aid in differentiating between adrenocortical tumor and hyperplasia.30The findings of Wilkins

Cushing's syndrome in infancy is very rare. Recently, Guin and Gilbert reviewed 28 cases of adrenal cortical carcinoma associated with this syndrome in persons less than 14 years old.1 They added one case, with onset at 6 weeks. In only 2 of the 29 cases did the symptoms appear before the age of 6 months. In reviewing the literature the impression is gained that Cushing's syndrome in the pediatric age group is usually caused by an adrenal tumor. Albright and Forbes were of the opinion that all such cases in infancy are caused by malignant tumors.2 Forsham and Thorn also believed that the adrenal lesion was oftenest a malignant one when the disease appeared before puberty.3 However, Powell cites two instances due to adrenal cortical adenoma within the first year of life.4,5 Furthermore, Talbot et al. claim that bilateral adrenal hyperplasia is more commonly the cause

A review of the literature, with notes on the etiology and treatment of dysmenorrhea, is offered.

An ovarian neoplasm is reported composed of broad sheafs of xanthofibromatous tissue interlobulating masses of granulosa cells of the diffuse trabecular type. The transition between the two types of tissue frequently was not sharply defined. Sudan III stains revealed that the granulosa cells exhibited meager to moderate pseudoluteinization. The fibromatoid tissue for the greater part showed intensive cytoplasmic accumulation of fine lipoid droplets. Where the fibromatoid tissue surrounded focal masses of granulosa cells, the peri-epithelial sudanophilic reaction was greatest. This process is strikingly analogous to the maturing normal follicle prior to rupture, when only feeble luteinization of the granulosa cells is present in contrast to the abundant lipoid deposition of the theca interna.

Three patients with arrhenoblastoma are presented. Symptoms and physical findings were similar in all, with amenorrhea, hirsutism, voice changes, masculine body habitus and clitoromegaly the prominent features. Each had different gross and microscopic pathology, though the presence of Leydig-like cells was constant in all. Testosterone in both peripheral and ovarian vein blood was elevated in the patients so studied. Virilization was incompletely reversed in all 3 women after the arrhenoblastoma was removed.

The literature related to the entity of uterine synechiae, which results in amenorrhea and infertility, has been correlated and the significant observations compared to the authors' experiences with six examples of the condition. It is emphasized that later pregnancy, a constant objective in most of such patients, may be complicated by abnormal placenta! implantations.

Oral mucosal and blood smears were studied in 90 sexually normal patients of both sexes, and in 12 patients with sexual abnormalities. In the normal cases the diagnosis was correct in 100 per cent of the oral mucosal smears and 97.14 per cent of the blood smears. In the abnormal group, there were 3 cases of gonadal dysgenesis in which the diagnosis was different in the blood and mucosal smears. Thirty patients with known endocrinopathies and other medical disorders were tested and the diagnosis was correct in 100 per cent of the cases. In our over-all studies to date 5 cases have been encountered in which there was a discrepancy between mucosal and blood smears.