Robert L. Rosenfield

Hirsutism: Implications, etiology, and management

Hirsutism usually results from a subtle excess of androgens. As such, it is a clue to possible endocrine disturbance in addition to presenting cosmetic problems. We use the term hirsutism to mean male-pattern hirsutism--excessive growth of hair in areas where female subjects normally have considerably less than male subjects. An elevation of the plasma free (unbound) testosterone level is the single most consistent endocrinologic finding in hirsutism. The plasma free testosterone level is sometimes elevated when the total level of plasma testosterone is normal because testosterone-estradiol--binding globulin (TEBG) levels are often depressed in hirsute women. Frequent blood sampling is sometimes necessary to demonstrate subtle hyperandrogenic states since androgen levels in the blood are pulsatile and seemingly reflect episodic ovarian and adrenal secretion. The source of hyperandrogenemia can usually be determined from dexamethasone suppression testing. Those patients whose plasma free androgen levels do not suppress normally usually have functional ovarian hyperandrogenism (polycystic ovary syndrome variants). Very high plasma androgen levels or evidence of hypercortisolism, which is not normally suppressible by dexamethasone, should lead to the search for a tumor or Cushings syndrome. Those patients in whom hyperandrogenemia is suppressed normally by dexamethasone have a form of the adrenogenital syndrome, a prolactinoma, obesity, or idiopathic hyperandrogenemia. In such patients, glucocorticoid therapy may reduce hirsutism and acne and normalize menses. The treatment of hirsutism resulting from functional ovarian hyperandrogenism is not as satisfactory; estrogen-progestin treatment is the most useful adjunct to cosmetic approaches to hirsutism in this country. However, other manifestations of polycystic ovary syndrome, such as infertility, may take precedence over hirsutism when an optimal therapeutic program is designed for many patients.

Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index.

BACKGROUND. The early onset of puberty may be related to obesity, so there is a need to know the prevalence of early pubertal milestones in nonoverweight children. OBJECTIVE. We compared attainment of stage 2 breasts, stage 3 (sexual) pubic hair, and menarche in the Third National Health and Nutrition Examination Survey sample of children with normal BMI with those with excessive BMI (≥85th percentile). DESIGN/METHODS. The ages at which 5%, 50%, and 95% of youth had attained key pubertal stages were estimated by probit models. Logit models were then fit to compare attainment of these milestones in children of excessive and normal BMI. RESULTS. Pubertal signs occurred before 8.0 years of age in <5% of the normal-BMI general and non-Hispanic white female population. However, pubertal milestones generally appeared earlier in normal-BMI non-Hispanic black and Mexican American girls; thelarche occurred before age 8.0 in 12% to 19% of these groups, and the 5th percentile for menarche was 0.8 years earlier for non-Hispanic black than non-Hispanic white subjects. Pubarche was found in ≤3% of 8.0-year-old girls with normal BMI of all of these ethnic groups but was significantly earlier in minority groups. Pubarche appeared before 10.0 years in <2% of normal-BMI boys. Girls with excessive BMI had a significantly higher prevalence of breast appearance from ages 8.0 through 9.6 years and pubarche from ages 8.0 through 10.2 years than those with normal BMI. Menarche was also significantly more likely to occur in preteen girls with an elevated BMI. CONCLUSIONS. Prevalence estimates are given for the key pubertal milestones in children with normal BMI. Breast and sexual pubic hair development are premature before 8 years of age in girls with normal BMI in the general population. Adiposity and non-Hispanic black and Mexican American ethnicity are independently associated with earlier pubertal development in girls.

Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.

The increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among women with polycystic ovary syndrome (PCOS) has been ascribed to the insulin resistance characteristic of PCOS. This study was undertaken to determine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. We studied three groups of women: PCOS with a family history of NIDDM (PCOS FHx POS; n = 11), PCOS without a family history of NIDDM (PCOS FHx NEG; n = 13), and women without PCOS who have a family history of NIDDM (NON-PCOS FHx POS; n = 8). Beta cell function was evaluated during a frequently sampled intravenous glucose tolerance test, by a low dose graded glucose infusion, and by the ability of the beta cell to be entrained by an oscillatory glucose infusion. PCOS FHx POS women were significantly less likely to demonstrate appropriate beta cell compensation for the degree of insulin resistance. The ability of the beta cell to entrain, as judged by the spectral power for insulin secretion rate, was significantly reduced in PCOS FHx POS subjects. In conclusion, a history of NIDDM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. The risk of developing NIDDM imparted by insulin resistance in PCOS may be enhanced by these defects in insulin secretion.

Detection of Functional Ovarian Hyperandrogenism in Women with Androgen Excess

BACKGROUND Distinguishing between ovarian and adrenal causes of androgen excess may be difficult. We have found that women with the polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to the gonadotropin-releasing hormone agonist nafarelin. We determined the usefulness of testing with nafarelin to distinguish ovarian causes of hyperandrogenism in women. METHODS We studied 40 consecutive women with hyperandrogenism who had oligomenorrhea, hirsutism, or acne. All 40 underwent testing with nafarelin, dexamethasone, and corticotropin with measurement of circulating concentrations of gonadotropins and steroid hormones, and 19 underwent ovarian ultrasonography. RESULTS The plasma 17-hydroxyprogesterone response to nafarelin was supranormal in 23 of the 40 women (58 percent), and the plasma androgen response to corticotropin was elevated in 23; 13 women had both abnormalities. Only one woman had conclusive evidence of a steroidogenic block; she had nonclassic adrenal 21-hydroxylase deficiency. Of the 23 women with abnormal responses to nafarelin, only 11 (48 percent) had elevated base-line serum luteinizing hormone concentrations. Of the 13 women with abnormal responses to nafarelin who underwent ultrasonography, 7 (54 percent) had polycystic ovaries. Peak plasma 17-hydroxyprogesterone concentrations after nafarelin administration correlated closely with plasma free testosterone concentrations after dexamethasone administration (r = 0.75, P less than 0.001). CONCLUSIONS Approximately half of women with oligomenorrhea, hirsutism, or acne have an abnormal response to the gonadotropin-releasing hormone agonist nafarelin, suggesting an ovarian cause of their androgen excess.

Pituitary-Ovarian Responses to Nafarelin Testing in the Polycystic Ovary Syndrome

To investigate the basis of polycystic ovary syndrome, we examined the responses of patients to nafarelin, a specific gonadotropin-releasing-hormone agonist, given to stimulate pituitary and gonadal secretion. We compared 16 normal women in the follicular phase, 5 normal men, 8 women with polycystic ovary syndrome, and 1 woman with polycystic ovary syndrome caused by a 3 beta-hydroxysteroid dehydrogenase deficiency. After 100 micrograms of nafarelin was given subcutaneously, serum follicle-stimulating hormone and luteinizing hormone increased rapidly to peak levels within four hours. The women with polycystic ovary syndrome had a pattern similar to that of the men, with greater early luteinizing-hormone responses (30 minutes to 1 hour) and lower peak follicle-stimulating-hormone responses than normal women (P less than 0.05). Patients with polycystic ovary syndrome responded to gonadotropin stimulation with normal to increased production of plasma estrogens and increased levels of androstenedione at 16 to 24 hours (P less than 0.05). Elevated production of 17 alpha-hydroxyprogesterone was found in all the women with polycystic ovary syndrome and in the men. These abnormal responses were unchanged by pretreatment with dexamethasone to suppress adrenal function. In the patient with the 3 beta-hydroxysteroid dehydrogenase deficiency, both basal and stimulated plasma levels of delta 5-3 beta-hydroxysteroids before the enzymatic block were elevated, whereas plasma levels of 17 alpha-hydroxyprogesterone and androstenedione--the steroids immediately beyond the block--were low. We conclude that women with polycystic ovary syndrome have masculinized pituitary and ovarian responses to stimulation by nafarelin. Our findings suggest that the regulation of the ovarian 17-hydroxylase and C-17,20-lyase activities is abnormal in such women.

Dysregulation of cytochrome P450c17α as the cause of polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) appears to be due to a previously unrecognized type of steroidogenic abnormality, one in which hyperandrogenism arises from a regulatory abnormality (dysregulation) rather than from enzyme deficiency. It appears that PCOS typically arises from masculinized regulation of the androgen-forming enzyme (cytochrome P450c17 α ) within ovarian thecal cells. This may arise by either excessive stimulation by luteinizing hormone (LH) or by escape from desensitization to LH. We review evidence which is compatible with the concept that the latter situation may result from an intrinsic intraovarian flaw in the paracrine feedback mechanism by which thecal androgen biosynthesis is inhibited and that coexistent adrenal 17-ketosteroid hyper-responsiveness to corticotropin (ACTH) may be due to a similar type of dysregulation of adrenocortical P450c17 α .

The Polycystic Ovary Syndrome: Pathogenesis and Treatment

PURPOSE To propose a theory for the pathogenesis of the polycystic ovary syndrome that explains the endocrinologic abnormalities of the syndrome and provides a rational approach to therapy. DATA IDENTIFICATION An English-language literature search using MEDLINE (1975 to 1988) and extensive bibliographic reviews of identified articles. STUDY SELECTION We reviewed the literature and selected 169 articles considered most relevant for the definition of the endocrinologic abnormalities, elucidation of pathogenic mechanisms, or delineation of therapeutic interventions. DATA EXTRACTION The authors independently assessed study quality and data concerning endocrinologic abnormalities, pathogenic mechanisms, and therapy of the polycystic ovary syndrome. RESULTS OF DATA SYNTHESIS The polycystic ovary syndrome may be best defined as functional, gonadotropin-dependent ovarian hyperandrogenism. The polycystic ovary syndrome results when a primary defect increases one of three variables: the ratio of the serum concentrations of luteinizing hormone to follicle stimulating hormone, the ratio of the intraovarian concentrations of androgen to estrogen, or follicular atresia. An increase in one of these variables can then induce successive abnormalities in one or more of the remaining two variables in a to-and-fro manner. CONCLUSIONS Evidence suggests that several causes exist, each of which can produce the clinical syndrome by a to-and-fro interaction among pathogenic mechanisms. Treatment objectives for the syndrome include amelioration of hirsutism, induction of ovulation, and weight reduction.

OVARIAN AND ADRENAL FUNCTION IN POLYCYSTIC OVARY SYNDROME

Androgens are secreted by both the ovaries and adrenal glands in response to their respective trophic hormones LH and ACTH. Androgens in women are not specifically under negative feedback control by these pituitary hormones because they are by-products of estradiol and cortisol secretion. Rather, androgen secretion seems to be regulated mostly by intraglandular mechanisms. Functional ovarian hyperandrogenism is found in about 70% of patients with PCOS. It is characterized by excessive secretion of 17-hydroxyprogesterone in response to GnRH agonist or hCG stimulation. Failure of dexamethasone to suppress plasma free testosterone normally in the presence of normal adrenocortical suppression is also typical. Functional adrenal hyperandrogenism is found in about half of patients with PCOS. It is most often characterized by moderately increased secretion of the 17-ketosteroid DHEA in response to ACTH. The most likely cause of the excessive androgen secretion by both glands seems to be abnormal regulation (dysregulation) of the 17-hydroxylase and 17,20-lyase activities of P-450c17, the rate-limiting step in androgen biosynthesis. There are also subtle generalized disturbances of steroid metabolism, including tendencies toward excessive estrogen and cortisol secretion. The cause of dysregulation of steroidogenesis is unknown. The hyperinsulinemia that is compensatory for resistance to the glucose-metabolic effect of insulin seems to have a role in many cases. In most cases, intrinsic intraovarian or intra-adrenal autocrine or paracrine regulatory mechanisms are most likely malfunctioning.

Growth hormone and insulin-like growth factors have different effects on sebaceous cell growth and differentiation.

Several observations suggest that GH stimulates sebaceous gland growth and development. Therefore, we studied the effects of GH and insulin-like growth factors (IGFs), alone and with androgen, on sebaceous epithelial cell (sebocyte) growth and differentiation in vitro. The rat preputial cell culture model system was used to judge differentiation (induction of lipid-forming colonies, LFCs) and DNA synthesis. GH increased sebocyte differentiation. At a dose of 10(-8) M in the presence of micromolar insulin, GH was 3.8 times more potent than IGF-I (38.1+/-4.2%, SEM, vs. 10+/-1.5% LFCs) and 6 times more potent than IGF-II (6+/-0.5% LFCs). IGF-I 10(-8) M alone stimulated a similar amount of differentiation as insulin 10(-6) M, although it was less effective than insulin in augmenting the effect of GH on differentiation. GH had no effect on sebocyte uptake of 3H-thymidine at doses up to 10(-6) M. On the other hand, IGF-I was the most potent stimulus of DNA synthesis (168% of control; P < 0.001 vs. all others). IGF-II 10(-8) M stimulated 3H-thymidine incorporation similarly to insulin 10(-6) M. In the presence of insulin, dihydrotestosterone (DHT) 10(-6) M induced 31.4+/-1.7% LFCs, and there was a tendency of DHT and GH to interact in promoting differentiation. When insulin was omitted from the system, differentiation was decreased overall, but GH +/- DHT slightly improved differentiation. The IGFs had no effect on the response to DHT. DHT decreased DNA synthesis by 40%, an effect unaltered by GH or IGFs. These results suggest that GH and IGFs have different functions in sebaceous cell growth and differentiation: GH stimulated differentiation beyond that found with IGFs or insulin, yet had no effect on DNA synthesis, a parameter stimulated most potently by IGF-I. While GH augmented the effect of DHT on differentiation, the IGFs had no effect on the response of DHT. These data indicate that GH may in part act directly on sebocytes rather than indirectly through IGF production. These data are consistent with the concept that increases in GH and IGF production contribute in complementary ways to the increase in sebum production during puberty and in acromegaly.

Mechanisms of Androgen Induction of Sebocyte Differentiation

It has been difficult to induce the expected sebocyte differentiation in vitro with dihydrotestosterone (DHT). We reasoned that our culture system lacks differentiating factors, and peroxisome proliferator-activated receptors (PPARs) were the prime candidates. We tested PPAR activators informative about diverse PPAR subtypes, with and without DHT (10–6 M): BRL-49653 (10–6 M, PPAR-γ), WY-14643 (10–6 M, PPAR-α), and linoleic acid (LIN, 10–4 M, PPAR-d). Treatments were added in serum-free medium to cultures of rat preputial sebocytes. Control, DHT, BRL and BRL + DHT treatments caused 11, 25, 66 and 80%, respectively, of preputial cell colonies to differentiate into lipid-forming colonies (LFCs) (p <0.001). WY induced 20% and LIN over 95% LFC formation. PPAR-γ mRNA was identified in preputial sebocytes by the RNase protection assay. These data suggest that differentiation of sebocytes is transduced by PPARs and have implications for the development of new treatments for acne.