Marvin A. Kirschner

Androgen production and metabolism in normal and virilized women

Abstract There is considerable biologic evidence indicating that testosterone is the most important androgen in women. Testosterone production rates have been elevated in almost every virilized patient studied to date. Clinical evaluation of the hirsute patient, however, is complicated by the observation that plasma testosterone alone may not adequately reflect testosterone production. This relates to the fact that plasma androgen levels in women may be independently influenced by the rate of steroid entry into blood (production rate) as well as removal from blood (clearance). The testosterone production rate must be measured in hirsute women if a complete assessment of androgen metabolism is to be made. The origin of testosterone in normal and virilized women can best be determined by a combination of steroid kinetic studies and direct sampling of adrenal and ovarian venous effluents. In normal women about 65% of plasma testosterone is derived from plasma prehormones (androstenedione and dehydro-epiandrosterone) and 35% is apparently secreted by adrenals and ovaries. In clear-cut cases of adrenal or ovarian disease, excessive androgen production can usually be traced to the abnormal organ. In most women with idiopathic hirsutism, the ovaries, rather than the adrenals, are the most common sites of androgen oversecretion.

Ectopic ACTH syndrome

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushings disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.

A comparison of androgen production and clearance in hirsute and obese women

Virilization in women is associated with increased production of testosterone as well as a variety of androgenic prehormones, including androstenedione, androstenediol, DHEA, DHEA-sulfate, dihydrotestosterone and androstanediol. Of these hormones, it is likely that testosterone is the androgen which initiates a series of androgen-receptor mediated events resulting in stimulation of 5 alpha reductase in the skin and hair follicles, producing dihydrotestosterone locally. The metabolism of testosterone to dihydrotestosterone within the hair follicle results in increased clearance of testosterone, however at the expense of hair follicle stimulation. Increased 5 alpha reductase of the skin and hair allows other prehormones to be metabolized to dihydrotestosterone and androstanediol, further stimulating the hair follicle (multiplier effect). In obese women, androgen production rates are elevated and SHBG levels are depressed, in many cases to the same magnitude as that observed in hirsute women. Increased androgen production rates in obesity, however, are associated with major increases in clearance rates of these androgens. Resultant androgen blood levels are even lower than observed in the non-obese population. It appears likely that adipose tissue is the site of the increased clearance rates and metabolism of prehormones to dihydrotestosterone and androstanediol. A delicate balance likely exists between production and clearance of these biologically active hormones. Minor aberrations in this balance may result in the increased incidence of hirsutism seen in the obese female population.

The role of hormones in the etiology of human breast cancer.

It has long been suspected that endocrine factors play a promoting or contributory role in the genesis of human breast cancer. Attempts to define and quantify such factors, however, have proven elusive. 1) Estrogens: Women at increased risk for breast cancer were shown to excrete less estriol (E3) vs estrone and estradiol. Conversely, women at low risk for breast cancer had higher urinary “estriol ratios.” These data led to the hypothesis that E3 is a “protective” estrogen. Recent studies of estriol production rates, its origin and circulating levels, however, have shown no differences in these crucial parameters in women with high E3 ratios vs low E3 ratios or in women with previous breast cancer. These data imply that high vs low urinary E3 ratios simply reflect different pathways of estrogen metabolism, and not differences in estrogen production. In women with established breast cancer, earlier studies of urinary estrogens as well as recent measurements of estrogen blood production rates have shown no significant abnormalities. Further, the contribution of androstenedione, estrones principle prehormone, is normal in women with breast cancer. 2) Androgens: Earlier studies by Bulbrook in women with breast cancer correlated decreased urinary 17‐KS with poor responses to endocrine ablative procedures. These workers also found low urinary etiocholanolane in women destined to develop breast cancer. Thus, decreased androgen excretion seems to be associated with poor response to endocrine therapy and increased risk for breast cancer. Similarly, dehydroepiandrosterone and its metabolites were found to be decreased in women with breast cancer. Androstenedione production, however, was found to be normal in women with post‐menopausal breast cancer. The significance of androgen alterations in women with breast cancer (or at high risk) is still unclear. 3) Progesterone: No abnormalities in progesterone production have been reported in women with breast cancer. The Sherman‐Korenman hypothesis that women with inadequate corpus luteum formation are at increased risk for breast cancer still requires confirmation. 4) Prolactin: Most reports to date indicate no abnormalities of prolactin in women with breast cancer. Hendersons data showing high plasma prolactin and estradiol in daughters of women with breast cancer (high risk) need confirmation. 5) Thyroid: In spite of several intriguing associations of thyroid function with steroid and peptide hormone metabolism, no consistent evidence has emerged implicating abnormal thyroid function in women with breast cancer. From the above, it is apparent that in spite of tantalizing bits of data linking breast cancer development with possible alteration of endocrine function, no clear‐cut or comprehensible patterns are yet evident.

The Role of Hormones in the Development of Human Breast Cancer

It has been long suspected that endocrine factors play a promoting or contributory role in the genesis of human breast cancer. Since growth of normal breast tissue is influenced by the hormonal environment, it seemed reasonable to suspect that growth of neoplastic breast tissue could be similarly influenced by the hormonal milieu. Carcinoma of the breast thus represents one of an intriguing class of cancers arising in target tissues which normally respond to hormonal influences. In humans, such hormone-dependent cancers include also those of the prostate, thyroid, endometrium, and possibly kidney.

Free testosterone levels during the menstrual cycle in obese versus normal women

In a group of seven normally ovulating moderately obese women, testosterone parameters were studied throughout the menstrual cycle and compared with values obtained in normal-weight control women. Plasma T, percent free T (unbound), and free T concentrations were higher and exhibited little variation during the phases of the cycle compared with the normal-weight controls. Testosterone production and its parameters thus are higher in even moderately obese women.

Serum testosterone fractions in women : normal and abnormal clinical states

The potential usefulness of determining serum testosterone (T) fractions in women, ie, sex hormone-binding globulin (SHBG)-bound T, albumin-bound T (Alb-T), and free T (FT) fractions, was explored in a variety of clinical situations. Serum T, SHBG, and albumin concentrations were measured by standardized methods and using binding constants of T to SHBG and albumin, we calculated serum T fractions, which agreed remarkably with measured values of SHBG-T and nonbound T. Serum T levels did not change in normal women examined during the follicular and luteal phases of the menstrual cycle, but SHBG levels were elevated in the luteal phase, changing the distribution of T, with increased SHBG-T and less T distributed to other fractions. Women taking oral contraceptives had decreased serum T levels, but use of androgen-like oral contraceptives decreased SHBG levels and T distribution to this binding protein, whereas use of non-androgen-like oral contraceptives increased SHBG levels, resulting in the expected shift of T fractions. Women receiving phenytoin for seizure disorders and women with Graves disease exhibited increased SHBG levels with concomitant increased SHBG-T and decreased distribution of T to nonbound fractions. Women with hirsutism exhibited decreased SHBG levels irrespective of total serum T levels, and the T/SHBG ratio was elevated in this population. However, of interest were women with morbid obesity (nonhirsute) who had similar low levels of SHBG and T/SHBG ratios that were indistinguishable from those of hirsute women.(ABSTRACT TRUNCATED AT 250 WORDS)

Monthly cyproterone acetate in the treatment of hirsute women: clinical and laboratory effects *

Cyproterone acetate given as a single intramuscular dose of 300 mg monthly for 6 months resulted in significant reduction of hirsutism without appreciable side effects. This regimen resulted in decreased levels of luteinizing hormone (LH) and estradiol in the eight women studied. No significant changes were observed in total serum testosterone (T) levels, however, there was a reduction in sex hormone binding globulin (SHBG), resulting in lowered SHBG-bound T, and an increase in non-SHBG-T over this time. Serum androstanediol glucuronide levels decreased in three of four women, although not to normal levels.

The effects of spironolactone on testosterone fractions and sex-hormone binding globulin binding capacity in hirsute women

This study explored the effect of the anti-androgen spironolactone on sex-hormone binding globulin (SHBG) and the distribution of circulating testosterone (T) into various free and bound fractions in seven women with hirsutism assessed before and then monthly for three months on a regimen of spironolactone, 100 mg bid as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgen parameters and serum T fractions studies. None of the women were judged obese based upon body mass index values. After three months of spironolactone therapy, there was little change in the hirsutism index, and measurement of serum T, androstenedione, DHEA-S and 17ß-estradiol showed no significant changes, the same occurring with SHBG-binding capacity. However, there was a shift in the distribution of circulating T, with a decrease in SHBG-bound T and an increase in albumin-bound and free T (non-SHBG-bound fractions). As previous reports suggest that non-SHBG-bound fractions represent bioavailable fractions, the current data suggests that T fraction studies may not be clinically useful parameters of hyperandrogenism in women receiving antiandrogen therapy.