Danazol in the treatment of infertility.

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 roughtly 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.

The estrogen--cancer controversy.

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 as monthly intevals. The benefits of hormone replacement therapy for the postmenopausal woman far outweigh the putative risk of endometrial cancer.

Estrogen-androgen levels in aging men and women: therapeutic considerations.

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.

Role of the hypothalamus in the aging woman.

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.

The role of estrogens in mastopathy and mammary cancer in perimenopausal women.

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.

Update on the male and female climateric.

The gonadal steroids--estrogens and androgens--appear to have a mood-elevating, psychotonic effect. The improved sense of well-being and increased vigor probably is engendered by restoration of somatic efficiency and psychic equilibrium. 1. The male climacteric, as observed in a limited number of men, is associated with a low level of serum testosterone. The levels of follicle-stimulating hormone and luteinizing hormone are not elevated because estrogen concentration continues unaltered well into old age. Androgen replacement therapy often lessens fatigue, depression and headaches, and headaches, and improves libidinous drives. 2. In the aging female, many climatric symptoms other than those due to vasomotor instability were heretofore considered merely coincidental. Recent studies suggest that the metabolism of cerebral hormones is markedly influenced by endogenous and exogenous gonadal steroids. Thus, postmenopausal depression, headaches, and nervousness may be hormone-dependent symptoms. 3. The incidence of endometrial cancer is no greater and is probably less in estrogen-treated women than in women not treated with estrogen, if regular cyclic courses of an oral progestogen are added to the regimen.

Primary empty sella syndrome with elevated serum prolactin.

A young, adult, white female with long-standing amenorrhea-galactorrhea syndrome and known pituitary enlargement since 1969 is presented. Further evaluation revealed PRL levels elevated in the microadenoma range and an empty sella. The presence of a pituitary adenoma, however, could not be confirmed by our studies. The question now arises--in a young woman desirous of pregnancy, should an induction of ovulation be attempted in view of the elevated serum PRL and an empty sella?

FSH and LH response to LHRF in Kallman's syndrome.

The olfacto-genital syndrome (Kallman's syndrome) is believed to be primarily an hypothalamic disorder resulting in hypogonadotropic hypogonadism or hypo-ovarianism and anosmia. The pituitary response in 2 patients was measured on dialy subcutaneous injections of 100 mug of LHRF. One of the patients was also studied in a similar fashion by administration of LHRF intravenously for 4 consecutive days. A greater response occurred with the subcutaneous route.

A case of bilateral gonadoblastoma in streak gonads.

A report of a patient with bilateral gonadoblastomas who sought consultation for primary amenorrhea and infertility is presented. Thelarche and adrenarche occurred spontaneously at age 13. Clitoromegaly and a hypoplastic uterus were noted on physical examination. Flat plate X-ray of the abdomen demonstrated radiopaque material in both adnexa. Urinary 17-ketosteroid levels were normal, but the serum testosterone concentration was elevated. Serum gonadotropin values were markedly elevated, and total serum estrogens levels were very low. The karyotype was XY. The gonads were extirpated, and typical histology is demonstrated. A postulate was made to explain the clinical findings.

Effect of LHRH stimulation in anovulatory women.

Serum FSH and LH and levels were determined at different time intervals after the subcutaneous administration of 100 mug LHRH to 24 females. Serum FSH levels were of the same order in the oligomenorrhea-amenorrhea and the Stein-Leventhal group of patients but elevated in gonadal failure. There was a great degree of overlap between serum LH values in the three groups. Gondal 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 considereably exaggerated in comparison to the other two groups.

Ovarian and adrenal steroid production in the postmenopausal woman.

Relative contribution of the ovaries and adrenals to the pool of steroids in postmenopausal women is still the subject of much controversy. Estradiol, delta4-androstenedione, and testosterone were assayed in peripheral blood, adrenal, and ovarian vein blood of 11 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 ovarian and adrenal estrogens.

Correlation between follicle-stimulating hormone, luteinizing hormone, prolactin, and testosterone with sperm cell concentration and motility.

Follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and testosterone were measured by radioimmunoassay in blood and seminal plasma of normo-spermic and oligospermic men. These parameters were correlated with sperm cell concentration as well as sperm motility. Average motility in the oligospermic group was significantly decreased as compared with the normospermic group (P less than .001). A significant reciprocal correlation was demonstrated between blood LH concentrations and sperm cell concentrations (P less than .05) as well as sperm motility (P less than .02). In contrast, a significant positive correlation was demonstrated between seminal LH concentrations and sperm cell count and motility (P less than .001). Seminal FSH and testosterone concentrations were positively correlated with sperm output but not sperm motility (P less than .05). The increased concentrations of LH in circulation accompanying idiopathic oligospermia suggests that LH secretion may be linked to the factors regulating spermatogenesis. The significant correlation between seminal testosterone and sperm concentration demonstrated in this study offers further support to this hypothesis. The significance of the correlation between the levels of LH and FSH in seminal plasma and sperm cell concentration and sperm motility is unknown.

Intrasellar subarachnoid herniation or empty sella associated with galactorrhea.

Eight of 115 patients with empty sella had concurrent galactorrhea. All 8 patients had abnormal sellae, and the diagnosis of empty sella was made by polytome pneumoencephalography. There were no obvious endocrine dysfunctions, but 2 patients had elevated prolactin levels. One mechanism for production of galactorrhea may involve compression of the hypothalamus and/or pituitary stalk; this was suggested by most of our observations. There may be a coincidental association of empty sella with galactorrhea, and this association is probably more common than previously noted. Evaluation of patients with galactorrhea and abnormal sellae by polytome pneumoencephalography is emphasized.

Oral contraceptives: the state of the art.

PIP: This paper presents a state-of-the-art review of oral contraceptives (OCs), termed one of the epochal developments of modern times. OCs have had both direct and indirect influences on moral, social, and cultural values and on the interaction of population resources and the environment. In recent years there has been a trend away from OC use because of increased mortality rates, especially in women over 35 years of age and smokers. However, epidemiologic studies have indicated that the incidence of death from cardiovascular disease, thromboembolic disease, and stroke was greatly reduced when newer preparations with lower steroidal doses became available. The reduction of the estrogen content from 150 mcg of ethinyl estradiol-3-methylether to 30-35 mcg of ethinyl estradiol and of the progestin component from 10 mg of norethindrone to 1 mg or less has not interefered with effective conception control. The progestin component of the pill was linked to high blood pressure, lipid changes, and cardiovascular changes with an unfavorable impact on arterial disease. Although many insist that the question of whether OCs cause or predispose to cardiovascular problems cannot be answered at this time, the potential risks involved in OC use are generally regarded to be outweighed by the benefits. Reductions in OC dosages have also reduced the incidence of galactorrhea, amenorrhea, and on-pill amenorrhea. New triphasic formulations that more closely imitate the hormonal fluctuations of the menstrual cycle are considered to hold much promise in terms of safety and effectiveness.^ieng

Danazol treatment of endometriosis: long-term follow-up.

Forty-nine women diagnosed as having pelvic endometriosis were treated with 800 mg of danazol/day for a mean duration of 6 months. The average length of the follow-up period was 78 months. Side effects were minimal, and regular ovulatory menses returned within 25 to 90 days (average 42 days). Forty-two (85.7% of these women had associated infertility. Recurrence of symptoms was reported in 33% but in no patient were the symptoms worse than before entering the study. Of 30 patients desirous of pregnancy, 20 were potentially fertile; of these, 10 conceived within 6 months of discontinuing therapy, for a conception rate of 50%. Nine of the remaining ten patients required additional therapeutic procedures (surgery and/or danazol), and four of these conceived within 12 months. These results compare favorably with those of other investigations, since most of our patients were referred to us after being subjected to a variety of regimens, both hormonal and surgical.

The treatment of benign breast disease with danazol.

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, 17 alpha-ethinyltestosterone, was employed in doses of 100 to 400 mg/day for 3 to 6 months 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.

Fibrocystic breast disease: the significance of beta-human chorionic gonadotropin and other polypeptides in breast cyst fluid.

Breast cyst fluids from 118 women, aged 29 to 69 years, were analyzed by radioimmunoassays for beta-human chorionic gonadotropin (beta-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 beta-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 beta-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 muIU/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 less than 0.05) enhanced, even in the presence of the antiserum. These data suggest that BCF contains biologically active hCG.

Peripheral, ovarian, and adrenal vein steroids in hirsute women: acute effects of human chorionic gonadotropin and adrenocorticotrophic hormone.

In an attempt to localize the source of excessive andogens in hirsute women, various steroids were determined in peripheral blood, left ovarian venous blood, and left adrenal venous blood, using radioimmunoassay techniques developed in our laboratory. Peripheral serum levels of dehydroepiandrosterone, androstenedione, 5alpha-dihydrotestosterone, testosterone, progesterone, and 17 alpha-hydroxyprogesterone were elevated in several hirsute patients, compared with those of a group of normal, cycling women of the same age. There was direct evidence to show that the ovaries and/or adrenals were secreting androgens in these hirsute patients. Saline infusion brought about minor changes in peripheral and left ovarian vein steroid levels; however, episodic fluctuations occurred in the adrenal vein samples. Adrenocorticotrophic hormone infusion brought about dramatic increases in adrenal vein steroid concentrations, while ovarian vein concentrations were unaffected, compared with peripheral steroid levels. Human chorionic gonadotropin (HCG) infusion brought about increases in left ovarian vein steroids in some patients; however, those patients with corpus luteum on the right ovary or under chronic ovarian suppression did not respond to HCG. HCG was ineffective in altering adrenal steroid secretion. It was concluded that selective venous cannulation may be of some use when the ovary is the site of excessive androgen secretion. However, care must be taken in interpreting results when a corpus luteum is present in the contralateral ovary. Interpretation is difficult when the adrenal is suspect, because of the pulsatile nature of adrenal secretion or the possibility of stress-induced secretion.

A clinical and cytogenetic study of fifteen patients with 45,X/46XY gonadal dysgenesis.

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.

Gross cystic disease of the breast.

The aetiology of fibrocystic disease of the human breast remains problematical. While oestrogens may cause cystic lesions and epithelial proliferation in the mammary glands of experimental animals and certain progestogens (chlormadinone acetate and medroxyprogesterone acetate) may induce severe myoepithelial hyperplasia in beagles, the classical oral contraceptives (oestrogens and progestogens) reduce the incidence of fibrocystic breast disease in women. The role of prolactin in human breast disease is far from clear despite the fact that in rodents mammary tumors fail to develop following oestrogen administration in the absence of prolactin. Because women with gross cystic disease of the breast are at four times greater risk of developing malignant breast disease, it is felt that the administration of courses of danazol, an impeded androgen derived from the progestin, 17 alpha-ethinyl testosterone, has proved effective in lessening fibrocystic disease of the breast, frequently obviating the need for breast biopsy. The study of the hormonal content of fluid aspirated from gross breast cysts should help elucidate the pathophysiology of breast disease. Breast cyst fluid is rich in androgens, particularly dehydroepiandrosterone sulfate; concentrations of polypeptide hormones like FSH, LH, TSH, PRL, and calcitonin are invariably present sometimes in less and at other times in greater amounts than that found in plasma. Of particular interest is the finding of measurable levels of beta-hCG in cyst fluid but not in the serum. The question arises whether the beta-hCG is biologically active or are the assay values merely the expression of radioimmunoassayable components? Preliminary (as yet unpublished) studies reveal excellent bioactivity as measured by testosterone production in Leydig cell cultures. Time will tell whether elevated levels of bioactive beta-hCG portend neoplastic potential.