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BACKGROUND: The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause. METHODS: Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone. RESULTS: The mean (+/-SD) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter (4.2+/-2.8 pmol per liter) during placebo treatment to 3.9+/-2.4 pg per milliliter (13.5+/-8.3 pmol per liter) and 5.9+/-4.8 pg per milliliter (20.5+/-16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day, respectively (normal range, 1.3 to 6.8 pg per milliliter [4.5 to 23.6 pmol per liter]). Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women (P=0.03 for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo), but the scores on the telephone-based diary did not increase significantly. CONCLUSIONS: In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.

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Female sexual function, as well as sexual dysfunction often seen during menopause, is assumed to be closedly related to the hormonal milieu of the body, particularly that of the target organs of the sex steroids. Estrogen as the hormone associated with female reproductive functioning is given first consideration in treating complaints of dysfunction, especially dyspareunia. However, simply restoring some, or all, of the estrogenization of the premenopausal years does not always lead to improvement in overall sexual functioning. Decreased libido is often still present in situations that appear to be anatomically satisfactory. Thus, exogenous testosterone, in a number of dosage forms, is often used adjunctively. Although the results are often gratifying, side effects may be a problem for some women. Treated women should be monitored for increased facial oiliness, acne, hirsutism, and alopecia.

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Androgenic disorders are those conditions in women characterized by excessive androgen action. They are the most common endocrinopathy of women, affecting from 10% to 20%. Signs are: persistent acne, hirsutism and androgenic alopecia, which is the female equivalent of male pattern baldness. A subgroup, those traditionally labeled as having polycystic ovary syndrome (PCOS), additionally have anovulation, as well as menstrual abnormalities and, often, obesity. Although women with androgenic disorders usually present themselves for help with the skin or menstrual changes, there are other important implications regarding their health. Women with PCOS have varying degrees of insulin resistance, and an increased incidence of Type II diabetes mellitus, as well as unfavorable lipid patterns. The presence of these risk factors is suggested by upper segment obesity, darkening of the skin, and the other skin changes that make up acanthosis nigricans. Diagnosis involves measurement of circulating androgens (of which free testosterone is most important), together with prolactin and FSH when menstrual dysfunction is present. Many women with androgenic skin changes have normal serum androgen levels, suggesting increased end organ sensitivity to androgens. Others have hyperandrogenism (of ovarian or adrenal origin). Treatment is usually successful in controlling acne, reducing hirsutism and stabilizing, or partially reversing, androgenic alopecia. Pharmacological approaches involve suppressing androgen levels, for example, the use of an appropriate oral contraceptive, or antagonizing androgen action with several medications that have this activity. Unfortunately, most women with androgenic disorders are frustrated in their efforts to obtain medical help. Understanding androgenic disorders will enable the physician to significantly help the majority of women with these conditions.

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OBJECTIVE: To evaluate the efficacy of a triphasic, combination oral contraceptive (OC), (norgestimate-ethinyl estradiol), in comparison with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty women were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the effectiveness of norgestimate-ethinyl estradiol in the treatment of acne vulgaris. Subjects were 15-49 years old and had moderate acne vulgaris. Each month for 6 months, subjects received either 3 consecutive weeks of active OC treatment followed by 1 week of inactive drug, or 4 consecutive weeks of color-matched placebo tablets. Efficacy was assessed by facial acne lesion counts, the investigator's global assessment, and the subject's self-assessment. Hormone levels were also measured. RESULTS: Despite the large placebo effect inherent in an acne trial (due to, for example, careful skin care, frequent office visits, regression to the mean), of the 164 subjects who completed the study without major protocol deviations, the OC group was significantly better than the placebo group for all primary efficacy measures: inflammatory lesions (mean reduction, 51.4% compared to 34.6%; P = .01), total lesions (mean reduction, 46.4% compared to 33.9%; P = .001); investigator's global assessment (83.3% compared to 62.5%; P = .001). Free testosterone decreased significantly and sex hormone-binding globulin increased significantly in the OC group, but remained unchanged in the placebo group. CONCLUSION: A triphasic combination of norgestimate and ethinyl estradiol is an effective treatment for moderate acne vulgaris in women with no known contraindication to OC therapy.

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The use of growth hormone (GH) has been implicated as a possible risk factor for leukemia. We present data from six patients that support a working hypothesis that an increased risk of leukemia may exist in patients with GH deficiency not related to exogenous use of GH.

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Women with androgenic disorders usually seek medical attention to ameliorate the effects of androgens on appearance or on fertility, less commonly for oligomenorrhea or for prevention of metabolic complications. These conditions affect at least 5-10% of women and can be very disturbing to the affected woman. Careful attention to possible androgenic changes is necessary when performing physical examination because changes are often concealed. Treatment for skin and hair changes depends less on the nature of the changes than on the underlying endocrine causation. The two endocrine factors are androgen levels and receptor sensitivity. The latter is a factor in all androgenic changes, and therapy is rarely successful without use of medication to block androgen receptors. If androgen levels are even minimally elevated, suppression of the source gland--ovary or adrenal--is appropriate. Ovarian suppression is usually by means of an oral contraceptive; for adrenal suppression, a glucocorticoid is effective. Response to medical therapy of androgenic disorders is slow; physicians and patients must be willing to wait weeks, or months, for the beginning of improvement. Endocrine therapy does not seem to help associated diabetes or dyslipidemia. Overall, medical therapy of androgenic disorders is more effective than generally recognized. The principal pitfalls are failing to select medication based on the specific endocrine disturbance and failing to wait long enough for improvement to appear. Side effects do occur but are generally uncomfortable or inconvenient rather than dangerous. Treatment is highly rewarding, however, for there are few situations in medicine in which treatment is so appreciated by the patient.

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Sixty-nine growth hormone-deficient patients were treated for 1 year with somatotropin (recombinant DNA-derived human growth hormone) produced in mouse cells. The growth velocity of the 50 patients (72%) in whom the effectiveness of this growth hormone could be evaluated increased from a mean (+/- SD) of 3.5 +/- 1.1 to 8.7 +/- 1.6. cm/y. An enhanced rate of weight gain was also observed. Bone age was not unduly accelerated. One of 66 patients developed antibodies to recombinant growth hormone, which did not affect the response to therapy. No patient developed antibodies to host cell proteins. An increased insulin response to a standard glucose load, without any change in glucose tolerance, was observed after 1 year of treatment. This authentic sequence human growth hormone preparation produced in mammalian cells is both effective and safe in the treatment of children with growth hormone deficiency.

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The most common signs of androgen excess in women are acne, alopecia, and hirsutism. Less common manifestations include android obesity, virilization, and acanthosis nigricans. These changes appear to be the result of excessive androgen production or increased target organ sensitivity. To evaluate excessive androgen production, an androgen screening protocol is recommended that includes measurement of dehydroepiandrosterone sulfate, testosterone, androstenedione, prolactin, follicular stimulating hormone, and luteinizing hormone. When androgen excess is confirmed, dexamethasone suppression is recommended to determine the source of the androgen(s). Once excessive androgen production is confirmed, more specific therapies can be administered.

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Androgen excess disorders--acne, alopecia, and hirsutism--can be treated effectively with endocrine therapy such as androgen receptor blockers or antagonists, or with androgen suppression. Spironolactone, estrogen, and dexamethasone are considered the most effective approaches to treatment. Whatever the modality, careful planning is key to success, with recognition that response rates vary from patient to patient. A treatment regimen generally continues for at least 2 years.

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Hirsutism in women is frequently associated with increased levels of androgens. Studies of biochemical changes, however, have yielded conflicting results. This study compares the findings in 30 hirsute women with normal menses and those of 30 hirsute women with abnormal cycles. Of the women with abnormal menstruation, 73% had oligoamenorrhea only and the others had dysfunctional uterine bleeding. The abnormally menstruating group had a similar mean age but tended to have heavier body weights than those with normal cycles. Free and total testosterone levels were significantly higher in the abnormal group (total testosterone, 54 +/- 35 ng/dl vs 35 +/- 12 ng/dl, p = 0.004; free testosterone, 7.8 +/- 4.9 pg/ml vs 4.2 +/- 1.4 pg/ml, p = 0.002). The abnormal group tended to have higher levels of androstenedione than the normal group (227 +/- 116 ng/dl vs 139 +/- 59 ng/dl) but dehydroepiandrosterone sulfate (DHEAS) levels were similar (320 +/- 142 mg/dl vs 298 +/- 169 pg/dl). Levels of thyroxin, thyrotropin, and prolactin were comparable in the two groups. Among hirsute women those with abnormal menses tended to be heavier and to have higher levels of total testosterone, free testosterone, and androstenedione. This is consistent with the clinical impression, not previously documented, that of hirsute women, those with abnormal menses have more severe endocrine abnormalities than those with normal cycles.

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Glucocorticoids are effective in suppressing androgens in many women whose levels of these steroids are elevated. Their use has been controversial because of inconsistent reports about efficacy and concern about safety. We investigated the dose-response relationship for suppression of dehydroepiandrosterone sulfate (DHEAS) with the use of dexamethasone. Thirty women with an initial DHEAS value of greater than or equal to 300 micrograms/dl were studied. All had cystic or inflammatory acne, hirsutism, or androgenic alopecia. Dexamethasone was given as a single bedtime dosage of 0.125, 0.250, or 0.375 mg. Mean dosage required for suppression was 0.256 mg daily. Suppression of the DHEAS level to less than or equal to 200 micrograms/dl was achieved with 0.125 mg in 25% of women, 0.250 mg in an additional 50%, and 0.375 mg in a further 20%. Most patients were taking spironolactone when the study was performed. Effective suppression is attained with dexamethasone doses significantly lower than previously thought. Use of these doses was not associated with a significant incidence of adverse effects.

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Most patients who have a change in menstruation can be evaluated and treated on the basis of a brief history, a physical examination, and a few laboratory tests. Because menstrual dysfunction can cause worry and inconvenience, patients should be promptly treated. Pregnancy must be excluded as a cause of amenorrhea in the initial evaluation. Other possible causes that must be ruled out include hypothalamic or pituitary tumors and severe thyroid disease. Amenorrhea should be treated to avoid possible complications such as osteoporosis, cardiovascular disease, and uterine or endometrial cancer. Treatment methods depend on whether the lack of menstruation is caused by an excessive estrogen level or estrogen deficiency.

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Since skeletal muscle is an important source of precursor for gluconeogenesis, it would not be surprising if carbohydrate metabolism was altered in some muscle disorders. We report a 7-10/12-year-old white male with congenital muscular dystrophy whose recurrent episodes of vomiting and dehydration were due to fasting hypoglycemia. He was found to have a blood glucose of 21 mg/dl with an episode of vomiting and dehydration. Diagnostic fasting replicated the symptoms and hypoglycemia. Associated laboratory findings included hypoalaninemia, ketonemia, and acidosis. With use of frequent feedings, there were no further episodes over 1-9/12 years of observation. To our knowledge this is the first report of hypoglycemia complicating muscular dystrophy. However, hypoglycemia may not be diagnosed because of the nonspecific nature of the symptoms. Hypoglycemia should be considered when children with reduced muscle mass develop otherwise unexplained vomiting.

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Androgenic alopecia is a common and perplexing clinical problem in the female patient. In the past medical literature has offered little assistance in understanding or evaluating the balding woman. Recent advances in technology have better enabled the physician to evaluate and treat females with androgenic alopecia. This article presents the current evaluation and possible treatment modalities of androgenic alopecia.

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The androgen status of a hirsute woman can be diagnosed today by new techniques for measuring circulating androgens. Unfortunately, a battery of expensive tests is required to make this assessment. Two specific basic screening tests, DHEA-S and total free testosterone determinations, should be done. If the patient is interested in and can afford it, further testing can be done; it includes 17-hydroxyprogesterone, prolactin, compound S (serum 11-deoxycortisol) and cortisol measurements and a dexamethasone suppression test. Elevations of androgens, whereas elevations of testosterone can be due to ovarian or adrenal secretion. Establishing the site of androgen hypersecretion allows one to be more selective regarding the antiandrogen therapy. When excess androgen secretion is primarily adrenal in origin, adrenal suppression is effective with the use of such drugs as dexamethasone. If the excess androgen is primarily of ovarian origin, cyclic estrogens, for example, Demulen or Premarin with Provera, would be helpful. The evaluation of a hirsute patient takes time, interest, and knowledge of specific androgen-dependent cutaneous syndromes involving multiple possible enzymatic defects in the conversion of cholesterol to testosterone or intercellular pathways of androgen metabolism. If the dermatologist is not interested in or lacks the knowledge for such an evaluation, the patient is best referred to an interested endocrinologist.

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The decision when and how to treat a pregnant patient with drugs is difficult. The physician who prescribes a drug for the pregnant woman must make a rational decision in the absence of complete information on potential embryonic or fetal toxicity and on the contribution of drug or maternal disease to a fetal adverse effect as studies on propranolol have shown. Pharmacokinetic parameters change during pregnancy, with increases in plasma volume and estrogen stimulation of hepatic microsomal oxidation being two such changes which may have unpredictable effects. The placenta is not a general transfer barrier since most drugs cross the placenta readily and reach significant blood levels in the fetus. The timing of drug administration during the various stages of pregnancy is of major importance, since the conceptus has different vulnerabilities at different stages of development. Most anatomical malformations occur after drug exposure in the first trimester. However, the brain continues to develop throughout pregnancy and early infancy, so that subtle adverse effects, which require time to become evident, may occur with drugs acting on the central nervous system. Awareness of these special pharmacological features of the pregnant state and appreciation of the pitfalls of research in this area will aid the physician in evaluating published studies and in arriving at rational therapeutic decisions.

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