Alessandro Gambera

Management of Hirsutism

This review reports our own experience with, and literature studies of, the pharmacological management of hirsutism in women with hyperandrogenism (polycystic ovary syndrome) or with normal serum androgen levels and regular ovulatory menstrual cycles (idiopathic hirsutism). Treatment consists of suppressing ovarian or adrenal androgen secretion, or blocking androgen actions in the skin. The major drugs used are gonadotropinreleasing hormone (GnRH) agonists, combined oral contraceptives (COCs), and steroidal (cyproterone acetate and spironolactone) or nonsteroidal (flutamide and finasteride) antiandrogens.GnRH agonists, suppressing the pituitary, decrease androgen and estradiol secretion and improve severe hirsutism. To avoid estrogen deficiency problems, ‘add back’ therapy with estrogen-progestogen or COCs is advisable. This method of treatment is complicated and expensive, limiting its use to severe forms of ovarian hyperandrogenism with hyperinsulinemia.The third-generation COCs, containing new progestogens or cyproterone, have very restricted effectiveness in the short term (6 cycles), but their long term use (>12 cycles) cures mild-to-moderate hirsutism and improves severe hirsutism. As well as suppressing gonadotropins and ovarian androgen steroidogenesis, these formulations decrease free testosterone levels and may also decrease adrenal androgen production. In women being treated with antiandrogens, COCs are important to provide control of the menstrual cycle and contraception.Cyproterone, a progestational agent, inhibits gonadotropin secretion and blocks androgen action. It is used in COCs or in a reverse sequential regimen. In the latter, it is very effective in the short term treatment of hirsutism.Spironolactone blocks androgen receptors. Its effectiveness in hirsutism is dosage-dependent: low dosages are less active than other antiandrogens, whereas high dosages (200 mg/day) are very effective at the cost of several adverse effects (particularly dysfunctional uterine bleeding), but the concomitant use of a COC may prevent these.Flutamide is a pure antiandrogen that blocks androgen receptors and inhibits hair growth. It is very effective in treating hirsutism within 6 to 12 months. Dry skin is very frequent during treatment with flutamide, and hepatotoxicity is possible at high dosages. Finasteride, a 5α-reductase type 2 inhibitor, is the least effective antiandrogen, but a dosage of 5 mg/day decreases hirsutism without adverse effects. Pregnancy must be avoided during therapy with antiandrogens because of the possible risk of abnormal development of a male fetus.Antiandrogens, especially flutamide (250 to 500 mg/day) and cyproterone (12.5 to 50 mg/day in a reverse sequential regimen), alone or in association with COCs, seem to be the most effective agents for the treatment of hirsutism.

Comparison of finasteride and flutamide in the treatment of idiopathic hirsutism

OBJECTIVE To compare the effectiveness of finasteride and flutamide in the treatment of idiopathic hirsutism. DESIGN Randomized study. SETTING Department of Gynecological Endocrinology, University of Brescia, Italy. PATIENT(S) Forty-six women with idiopathic hirsutism were selected. INTERVENTION(S) Patients were assigned randomly to receive 5 mg of finasteride once daily or 250 mg of flutamide twice daily for 12 consecutive months. MAIN OUTCOME MEASURE(S) Hirsutism was evaluated at 6 and 12 months of therapy by measuring the Ferriman-Gallwey score and the terminal-hair diameters (microm) taken from different body areas. Blood samples were taken and side effects were monitored during the treatment. RESULT(S) Both finasteride and flutamide induced a statistically significant decrease in hirsutism scores and hair diameters at the end of 12 months. Finasteride reduced the Ferriman-Gallwey score by 20.5% at 6 months and by 34.2% at 12 months, and hair diameter by 18.9%-23.6% at 6 months and by 29.6%-37.9% at 12 months. Flutamide reduced the Ferriman-Gallwey score by 26.6% at 6 months and by 50.9% at 12 months, and hair diameter by 22.3%-28.2% at 6 months and by 47.7%-56.5% at 12 months. Flutamide did not induce hormonal variations, whereas finasteride increased T levels by 60% and decreased 3alpha-androstanediol glucuronide by 69.5% at 12 months. CONCLUSION(S) Both drugs were effective in the treatment of idiopathic hirsutism, but flutamide was more effective than finasteride.

Identification of a new mutation in the SRY gene in a 46,XY woman with Swyer syndrome

OBJECTIVE To determine the genetic cause of primary amenorrhea in a 46,XY woman. DESIGN Case report. SETTING Centre of Gynecological Endocrinology and Cytogenetics and Molecular Genetics Laboratory of university medical school. PATIENT(S) A 19-year-old woman referred for primary amenorrhea. INTERVENTION(S) Clinical, endocrinologic, and ultrasonographic investigation and SRY mutation analysis. MAIN OUTCOME MEASURE(S) Hormone profile (LH, FSH, PRL, leptin, E(2), 17alpha-hydroxyprogesterone, 3alpha-androstanediol glucuronide), ultrasonographic evaluation, clinical follow-up. RESULT(S) A new SRY sporadic mutation due to a single nucleotide insertion at codon 13 position 38 (38-39insA) was found in a 46,XY woman with sex reversal. This mutation determined a frameshift of the reading frame sequence and a protein truncation at codon 16. Clinical and endocrinologic data are reported. CONCLUSION(S) This is a new rare case of a single nucleotide insertion affecting the SRY gene in 46,XY females with sex reversal. This new mutation should be considered in genetic counseling.

Psychopathological traits of adolescents with functional hypothalamic amenorrhea: a comparison with anorexia nervosa

BackgroundFunctional hypothalamic amenorrhea (FHA) is a form of anovulation, due to the suppression of hypothalamic–pituitary–ovarian axis, not related to identifiable organic causes. Like adolescents with anorexia nervosa (AN), subjects with FHA show dysfunctional attitudes, low self-esteem, depressive mood, anxiety and inability to cope with daily stress. The aim of the study is to examine similarities and differences between FHA and AN in terms of clinical profiles and psychological variables.Methods21 adolescents with FHA, 21 adolescents with anorexia nervosa, and 21 healthy adolescents were included in the study. All the teenagers completed a battery of self-administered psychological tests for the detection of behaviors and symptoms attributable to the presence of an eating disorder (EDI-2), depression (CDI), and alexithymia (TAS-20).ResultsDifferent from healthy controls, subjects with FHA and with AN shared common psychopathological aspects, such as maturity issues, social insecurity and introversion, a tendency to depression, excessive concerns with dieting, and fear of gaining weight. Nevertheless, adolescents with AN presented a more profound psychopathological disorder as observed at test comparisons with subjects with FHA.ConclusionsResults show a clinical spectrum that includes AN and FHA and suggest the necessity to treat FHA with a multidisciplinary approach for both organic and psychological aspects.

Heart rate variability in adolescents with functional hypothalamic amenorrhea and anorexia nervosa

Aim of this study consisted in assessing the 24-h heart rate variability (HRV), a measure of autonomic nervous system (ANS) imbalance, in 21 adolescents with functional hypothalamic amenorrhea (FHA, 11 normogonadotropic, N-FHA, and 10 hypogonadotropic, Hy-FHA) compared to 21 patients with anorexia nervosa (AN) and 21 controls. As expected, subjects with AN showed a significant dysregulation in multiple HRV parameters, while Hy-FHA patients presented with a dysregulation in a few domains (SDNN, HFr), which was not present in girls with N-FHA, who showed values largely similar to controls. FHA might represent part of the AN biological spectrum, and a link between these two conditions might exist, possibly related to the degree of psychological and/or hormonal dysfunction.

Spermatogenic and Steroidogenic Impairment of the Testicle Characterizes the Hereditary Leucine-75-Proline Apolipoprotein A-I Amyloidosis

CONTEXT The leucine-75-proline variant of apolipoprotein A-I leads to a new hereditary systemic amyloidosis involving mostly the liver and kidney. OBJECTIVE The objective of the study was to examine the effects of this amyloidosis on testicular structure and function. DESIGN This was an observational study in which patients with testicular amyloidosis were characterized. SETTING The study was carried out at the Endocrinology Department of Brescia University. PATIENTS OR OTHER PARTICIPANTS Over a 13-yr period, 25 patients were found to be affected by leucine-75-proline apolipoprotein A-I testicular amyloidosis. Thirteen had the testicle as the first or only organ involved (group 1); in 12 testicular damage followed that of other organs (group 2). INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURE Hormone and lipidic profiles, semen analysis, echographic volume of testicles, testicular histology, and genetic analysis were carried out. RESULTS Group 1 patients were younger than those of group 2. In group 1, eight had hypergonadotropic hypogonadism and five were normogonadic with high gonadotropins; in group 2 all subjects were hypogonadic. All men had low high-density lipoprotein values. Group 1 patients were macroorchid, whereas the testicular volume was at the highest limit in group 2 (group 1 vs. group 2, P < 0.05). All men in the first group and six in the second group were azoospermic; the remaining had oligoposia. Biopsies showed the germinal epithelium replaced by amyloid. Leydig cells were essentially preserved in normogonadic but not hypogonadic patients. CONCLUSIONS This amyloidosis may determine infertility, macroorchidism, and hypogonadism. Endocrine impairment follows spermatogenic impairment.

Long-term follow-up of functional hypothalamic amenorrhea and prognostic factors

Functional hypothalamic amenorrhea (FHA), caused by deficient output of gonadotropin-releasing hormone, may present with an inadequate luteal phase, anovulation with menstrual irregularity, or actual amenorrhea. The underlying mechanisms remain uncertain but there appear to be numerous neuroendocrine abnormalities in FHA, including hyperfunction of the hypothalamic-pituitary-adrenal axis, leading to increased secretion of corticoids and opioids as well as heightened dopaminergic tone and increased nocturnal melatonin secretion. The investigators followed 93 women with FHA over 7 to 9 years (average, 8.1 years), at which time 65 patients (70.7%) had recovered. The FHA diagnosis was based on amenorrhea for 6 months or longer, the hormonal findings, and a radiologically normal sella turcica. In no case did 5 days of oral medroxyprogesterone acetate induce menstrual bleeding. Patients underwent transabdominal or transvaginal pelvic ultrasonography, which excluded polycystic ovary syndrome. Depending on their wish to conceive, patients received either estrogen replacement therapy or oral contraception. Compared with control women, those with FHA had significantly lower levels of gonadotropins, prolactin, estradiol, and thyrotropin, and higher levels of cortisol. The major historical factors associated with FHA were psychological stress and competitive athletic activity, but these factors did not correlate with the likelihood of recovery. Recovered women had higher baseline body mass indices, but age and the duration of amenorrhea were not factors. The only significant hormonal differences were higher androstenedione and lower cortisol levels in recovered women. Recovery did correlate with an increased body mass index at follow-up, but not with the ultrasonographic appearance of the ovaries (whether multifollicular or not). Recovery rates were 74% in women given hormone replacement therapy, 42% in those receiving oral contraception, and 80% in untreated patients. The respective mean recovery times were 25, 34, and 16.5 months. Twelve recovering women had 14 spontaneous pregnancies during follow-up, all but one of which occurred in the setting of hormone replacement therapy. On multivariate logistic regression analysis, baseline body mass index as well as baseline plasma cortisol and A levels predicted recovery from FHA (Fig. 1). FHA is frequently a result of psychological or physical stress, which, along with an inappropriate diet, may alter energy balance and reduce the body mass index. The disorder is reversible, as was the case in more than two thirds of the present patients. The role of various treatments remains unclear, but a stable or increasing body mass index does seem to be a factor in recovery.