Beatrice Couzinet

Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone).

We studied the effects of the progesterone antagonist RU 486 in 100 women with early, unwanted pregnancy (within 10 days of the expected onset of the missed menstrual period). Thirty-four women received oral doses of 400 mg (in four days), 26 received 600 mg (in four days), and 40 received 800 mg (in two days). Uterine bleeding occurred in all patients within four days of the first dose and continued for 5 to 17 days. In 85 of the women, a dramatic decrease in the plasma chorionic gonadotropin level was observed on day 6, and an empty uterus was confirmed by ultrasonography on day 13. Hence, these women were considered to have had a complete abortion. Fifteen subjects had persistently elevated plasma chorionic gonadotropin levels on day 6 and were considered not to have responded to RU 486. They all had uterine evacuation, which was facilitated by a softening of the cervix. The percentage of women with complete abortion was similar in all dosage groups. Furthermore, plasma levels of immunoreactive RU 486 were similar in subjects with and without complete abortion. The only important side effect observed in the responders was prolonged uterine bleeding in 18 percent, but neither blood transfusion nor curettage was required. We conclude that RU 486 is an effective and safe method for termination of very early pregnancy but that it should be used only under close medical supervision.

Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin deficiency of nutritional origin.

Functional hypothalamic amenorrhoea (FHA) is a consequence of low dietary intake as observed in two major pathophysiological conditions, anorexia nervosa and/or intensive physical exercise. The aim of the present study was to assess in women with FHA and normal body mass index (BMI) and apparently normal daily activities, the degree of impairment of GnRH secretion, its nutritional origin and its reversibility.

The impact of a pure anti-androgen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism

OBJECTIVES We assessed in women the effects of androgen suppression on gonadotrophin secretion and the therapeutic efficacy of the pure anti‐androgen flutamide (2‐methyl‐N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]‐propanamide).

Percutaneous dihydrotestosterone treatment

Various forms of androgen replacement therapy are readily available for the treatment of hypogonadism in men (Cantril et al. 1984). The commonly used long-acting, injected, testosterone esters produce wide variations of serum androgen concentrations with high levels soon after the injection and subnormal levels after 15 days (Snyder et al. 1980). In addition, an elevation in the estradioltestosterone ratio can cause gynecomastia in some men. Oral therapy requires the administration of multiple daily doses of testosterone. Some of the preparations which are 17α-alkylated androgens such as fluoxymesterone and methyltestosterone produce severe hepatotoxicity and should not be used on a long-term basis. Testosterone undecanoate produces only short-lived testosterone peaks and thus requires repeated doses. Testosterone incorporated into microspheres may be slowly and steadily released from the intramuscular site over extended periods of time. Finally, a transdermal testosterone delivery system, when applied at the appropriate dose and on the appropriate part of the body, has been shown to be an effective and new modality for the treatment of male hypogonadism. Daily application of a patch, containing 10 mg of testosterone, applied to the scrotal skin brings the serum testosterone levels in the normal range, increases the DHT levels into the supranormal range while the estradiol levels remain low (Bals-Pratsch et al. 1986 and 1988; Ahmed et al. 1988).

Primary adrenal and thyroid insufficiencies associated with hypopituitarism: a diagnostic challenge.

Polyglandular syndromes have been described for many years but only one case of panhypopituitarism with adrenal and thyroid insufficiencies has been documented. We present a 69‐year‐old woman with the initial diagnosis of idiopathic primary hypopituitarism. An associated primary adrenal disease was suspected on low plasma aldosterone and increased plasma renin values during unjustified withdrawal of treatment. The complete absence of cortisol response to long‐term ACTH administration confirmed the diagnosis. In addition, primary hypothyroidism was demonstrated by the absence of radioiodine uptake by the thyroid gland and the inability to increase T4 secretion after repeated TSH injections. The pattern of hypopituitarism and the coexistence of both adrenal and thyroid deficiencies provide strong evidence for the diagnosis of autoimmune polyglandular syndrome with hypophysitis.

Treatment of Hyperandrogenic States in Women

Hyperandrogenic states have to be treated according to their etiology. But, idiopathic hirsutism represents the majority of observed cases. Its pathophysiology is still under discussion. The ovary and/or adrenal origin has led to various treatments with corticoids or combined estrogen-progestogen preparations. However, practical problems are different. After ruling out a tumoral process or mild congenital adrenal hyperplasia, a rational and efficient treatment must be proposed. It has now become possible with the use of both antiandrogen and antigonadotropin drugs. Cyproterone acetate is the best therapeutic agent because of its antiandrogen, antigonadotropin and progestogen properties. Because of its antiestrogen effects, cyproterone acetate must be used in combination with estrogens as a substitutive therapy to permit regular bleeding.

The postmenopausal ovary is not a major androgen-producing gland

There is much reason to believe that androgens are a quality-of-life factor in postmenopausal women, and it presently is thought that the ovaries are a major site of androgen production. This study focused on the steroidogenic potential and gonadotropin responsiveness of postmenopausal ovaries. Ten postmenopausal women 50 to 71 years of age with complete adrenal insufficiency were studied to exclude a contribution by adrenal androgens. Levels of testosterone and androstenedione (Adione) were measured directly in homogenates of ovarian tissue from 17 postmenopausal women at the time of hysterectomy/ salpingo-oophorectomy. Eight other samples were taken from normally cycling women having unilateral oophorectomy for benign disorders. Steroidogenic enzymes and gonadotropin receptors were identified immunocytochemically. Five of the study women had Addisons disease, had five had Cushings disease treated 20 to 30 years earlier by bilateral adrenalectomy. Three women with adrenal insufficiency who previously underwent ovariectomy for benign conditions also were studied. Fifteen ovariectomized women and 15 postmenopausal women, all with intact adrenal function, made up a control group. Total and free testosterone were undetectable in postmenopausal women with adrenal insufficiency and also in ovariectomized women with this condition (Fig. 1). Total testosterone levels of 16 to 18 ng/dl were found in postmenopausal and ovariectomized women with intact adrenals. Plasma Adione also was undetectable in adrenal-insufficient women. Plasma dehydroepiandrosterone was not detected in adrenal-insufficient women, and only low levels were found in control women with intact adrenals. Neither plasma testosterone nor Adione increased after chorionic gonadotropin injection in postmenopausal adrenal-insufficient women. Dexamethasone markedly lowered levels of testosterone and Adione in postmenopausal women with intact adrenals (Fig. 2). Samples of postmenopausal ovarian tissue had negligible levels of testosterone and Adione. P-450 was invariably absent from the ovaries, and enzymes promoting androgen synthesis were absent or at most present in very low amounts. No gonadotropin receptors could be identified in postmenopausal ovaries. Androgens circulating in postmenopausal women arise not from the ovaries but from the adrenal glands. Furthermore, the climacteric ovary lacks full capacity to synthesize androgens and is not activated by high levels of luteinizing hormone. Because androgen deficiency may impair sexual function and bring about adverse psychological changes, postmenopausal women may well benefit if androgen is added to classic hormone replacement therapy.

The Impact of a Pure Anti-Androgen (Flutamide) on LH, FSH, Androgens and Clinical Status in Idiopathic Hirsutism

OBJECTIVES We assessed in women the effects of androgen suppression on gonadotrophin secretion and the therapeutic efficacy of the pure anti-androgen flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide). DESIGN AND SUBJECTS Ten women, aged 28-35 years, using an intrauterine device for contraception, were selected for this study. All women had idiopathic hirsutism with or without acne and seborrhoea. Flutamide was administered orally in a dose of 250 mg twice daily for 1 year. Basal body temperature was recorded and pelvic ultrasonography performed before and every 3 months during treatment. LH pulse frequency and amplitude (Cluster analysis) and basal and GnRH-stimulated plasma LH and FSH levels were determined on day 5 of the cycle prior to flutamide treatment, and after 6 and 12 months of therapy. Plasma total testosterone (T), non-SHBG bound T, androstenedione (A), dehydroepiandrosterone sulphate (DHEAS), androstanediol glucuronide (3 alpha-diol G) and sex hormone binding globulin (SHBG) levels were measured before and every 3 months during therapy, on day 5 of the cycle. Plasma oestradiol and progesterone levels were determined on day 22 of the studied cycles. RESULTS Disappearance of acne and seborrhoea occurred after 2 months with a marked improvement of hirsutism at 6 months. At 12 months, hirsutism had disappeared with a Ferriman and Gallwey score < 7. No adverse side-effects, apart from transient diarrhoea in two patients, were reported with this flutamide dose. None of the patients had any disturbance of menstrual cycles which remained ovulatory. The pure anti-androgen flutamide induced no significant change in LH pulsatile profile, nor in LH and FSH responsiveness to GnRH. Plasma concentrations of steroids were not altered. Plasma SHBG and 3 alpha-diol G levels did not change during flutamide treatment. CONCLUSION Flutamide, which interacts only with the androgen receptor, is effective for hirsutism, acne and seborrhoea, and does not disturb menstrual cyclicity or ovulation. It may represent a treatment of choice for essential hirsutism in women using safe contraceptive methods.

Stimulation of Ovarian Follicular Maturation with Pure Follicle-Stimulating Hormone in Women with Gonadotropin Deficiency

According to the 2-cell theory, ovarian steroidogenesis requires the coordinate action of both FSH and LH. To evaluate the relative importance of these hormones in follicular maturation, a randomized cross-over study was performed in 10 women with complete gonadotropin deficiency (absence of pulsatile LH secretion and no LH response to LHRH). Five women were treated with highly purified FSH (LH bioactivity, 0.09%) and 3 months later with human menopausal gonadotropin (hMG; LH bioactivity, 65%), each given for 10 days at a daily dose of 225 IU FSH, im. The sequence was reversed in the other 5 women. hCG (5000 IU) was administered im 24 h after the last injection of FSH or hMG. Plasma estradiol (E2), estrone (E1), androstenedione (A), testosterone, LH, and FSH concentrations and urinary LH and FSH were measured daily by RIA. Ultrasonography was performed during each treatment and 2 days after each hCG injection. After FSH treatment, mean plasma and urinary FSH levels increased, mean plasma LH did not change, and urinary LH increased slightly but not significantly from 91 +/- 32 (SE) to 164 +/- 55 mIU/24 h (10(-3) IU/24 h). After hMG treatment, mean plasma and urinary LH and FSH levels increased accordingly. The mean basal plasma E2 [11 +/- 1 pg/mL (40 +/- 4 pmol/L)] and E1 [14 +/- 4 pg/mL (52 +/- 15 pmol/L)] levels increased after FSH treatment to 207 +/- 69 pg/mL (760 +/- 253 pmol/L) and 82 +/- 21 pg/mL (303 +/- 78 pmol/L), respectively (P less than 0.01), but plasma A did not change. In response to hMG, the mean plasma E2, E1, A, and testosterone levels increased more than during FSH treatment. Ultrasonography revealed multiple preovulatory follicles (greater than or equal to 16 mm) in 2 women after hMG and 1 woman after FSH treatment; therefore, hCG was not administered. In 3 women given FSH, hCG did not induce ovulation. hCG induced ovulation in 8 women given hMG and in 6 women given FSH, based on ultrasonography and plasma progesterone levels. Thus, in the presence of profound gonadotropin deficiency pharmacological doses of FSH, with minute LH contamination, are capable of stimulating ovarian follicular maturation, underlining the key role of FSH in folliculogenesis.