Uwe Goebelsmann

Hypergonadotropic Hypogonadism in Female Patients with Galactosemia

Abstract We evaluated gonadal function in 18 female and eight male patients with galactosemia due to transferase deficiency; it was normal in the males, but 12 females had signs of hypergonadotropi...

Serum testosterone concentrations in women throughout the menstrual cycle and following HCG administration.

Abstract Serum testosterone (T) concentrations, measured by a specific, precise, and sensitive radioimmunoassay in 40 women with apparently normal menstrual cycles averaged 34.6 ± 10.3 (S.D.) ng. per cent and ranged from 14 to 59 ng. per cent. Mean serum T concentrations, assayed daily in eight women throughout an entire ovulatory cycle, were highest around the midcycle LH peak and higher during the follicular than during the luteal phase of the cycles. Averages of daily serum T concentrations, when determined for each individual woman for the entire cycle, varied significantly among the eight subjects studied, ranging from 23.1 to 39.0 ng. per cent. Coefficients of variation of serum T levels in these eight individual cycles averaged 22 per cent. HCG administration to three of these eight women during the luteal phase of their subsequent cycle resulted in a significant rise of serum T concentrations in only one subject. These data indicate that mean serum T concentrations in normal women are subject to small but significant changes during the course of the menstrual cycle. Despite these cyclic changes, as well as day-to-day variations, serum T concentrations in normal women largely fall into a relatively narrow range. Repeated serum T concentrations which consistently exceed 55 ng. per cent (2 S.D. above the mean) may be regarded as documentation of androgen excess.

Adult manifestation of congenital adrenal hyperplasia due to incomplete 21-hydroxylase deficiency mimicking polycystic ovarian disease

This study was carried out to document the postpubertal presentation of congenital adrenal hyperplasia (CAH), to elaborate the diagnostic criteria for it, and to investigate family members of CAH patients. Serum 17-hydroxyprogesterone (17OHP) was measured in normal women and 25 hirsute oligomenorrheic patients, five of whom were shown to have CAH. These five CAH patients, as a group, had significantly elevated levels of 17OHP when compared to normal and hirsute women, although the other 20 hirsute oligomenorrheic women also had higher levels of 17OHP than the follicular phase control subjects. A single intravenous bolus of 0.25 mg of adrenocorticotropic hormone (ACTH) caused much larger increased in 17OHP in all five CAH patients than in the control and hirsute women. The five CAH patients had decreased cortisol but normal 11-deoxycortisol responses to ACTH, thus indicating 21-hydroxylase deficiency (21HD). Clinically, they were indistinguishable from women with polycystic ovarian disease (PCO) and had basal serum levels of androgens and urinary 17-ketosteroids which were similar to those found in 47 other women presenting with the complaint of hirsutism. However, the androstenedione levels and androstenedione/cortisol ratios in response to ACTH were significantly higher in the five CAH patients than in both the normal and hirsute women. Of seven family members tested, two fathers and one mother had an intermediate 17OHP response to ACTH, thus suggesting heterozygosity. Human lymphocyte antigen (HLA) typing on family members indicated that the inheritance of the disorder may be linked to B antigens. Two siblings of one of the CAH patients had normal 17OHP responses to ACTH and also had a different HLA-B complement. These data document the existence of adult manifestation of CAH, due to 21 HD. This disorder presents with androgen excess and oligomenorrhea or amenorrhea and mimicks PCO. The diagnosis of it hinges upon the post-ACTH rise in 17OHP, whereas the levels of serum androgens and urinary 17-ketosteroids may be inconclusive.

Clinical and laboratory predictors of clomiphene response

A prospective study was carried out on 158 anovulatory women for the purpose of finding parameters that might predict the clomiphene dose at which ovulation would occur. Both body weight and obesity were positively correlated with the dose required to achieve ovulation (P less than 0.05). Once ovulation occurred, obesity did not affect the ability to conceive. Fifty-eight women who ovulated with various doses of clomiphene, including six women who failed to ovulate, had hormonal measurements performed prior to treatment. Compared with normally ovulating controls, serum luteinizing hormone (LH), the ratio of LH to follicle-stimulating hormone (FSH), serum androgens, unbound testosterone, and unbound estradiol were elevated and sex hormone binding globulin-binding capacity (SHBG-BC) significantly lower in women receiving clomiphene. Although the ovulatory dose of clomiphene was positively correlated with both weight and obesity, neither weight nor any laboratory parameter could accurately predict the clomiphene response.

Clinical experience with the amniotic fluid lecithin/sphingomyelin ratio

Abstract Amniotic fluid lecithin/sphingomyelin (L/S ratios were measured in 425 pregnancies and restrospectively correlated with neonatal pulmonary performance. L/S ratios of 2.0 and greater, a value reached at about 34 weeks of gestation, were associated with 3.7 per cent morbidity from idiopathic respiratory distress syndrome (RDS) and a 0.3 per cent mortality rate from hyaline membrane disease (HMD) among 347 newborn infants. A 63 per cent morbidity from RDS and 23 per cent mortality rate from HMD, however, were found among 48 newborn infants delivered within 72 hours of having an L/S ratio of less than 2.0. The association of an L/S ratio greater than 2.0 with a low incidence of RDS and virtual absence of HMD substantiates the value of this method as a predictor of fetal pulmonary maturity.

Prolactin modulation of dehydroepiandrosterone sulfate secretion

To clarify the controversy about the effect of prolactin (PRL) on dehydroepiandrosterone sulfate (DHEA-S), this study was undertaken to investigate the effects of alterations in plasma PRL on plasma DHEA-S concentrations in hyperprolactinemic women, as well as in normal male subjects. DHEA-S was measured in a group of 21 women with hyperprolactinemia, galactorrhea, and amenorrhea (PRL:257 +/- 89 ng/ml; mean +/- SEM). In these women, mean plasma concentrations of DHEA-S (2.54 +/- 0.2 microgram/ml) were significantly higher (p < 0.005) than those in 41 normal control women (1.78 z microgram/ml) and those in a group of 11 amenorrheic patients (1.77 +/- 0.2 microgram/ml). Eight women with hyperprolactinemia were given 5 mg of bromocriptine each day for 4 consecutive weeks. Within 1 week of medication, PRL levels fell by 60% (p < 0.05). To test whether lowering normal plasma levels of PRL would affect plasma concentrations of DHEA-S, five normal male subjects received a 48-hour infusion of dopamine at an average rate of 6 microgram/kg/min. Plasma levels of PRL fell by 60% (p < 0.01) after 8 hours of infusion, and DHEA-S decreased by 27% by 16 hours (p < 0.05). These data suggest that PRL modulates the secretion of DHEA-S: an increase in plasma levels of PRL is correlated with elevated concentrations of DHEA-S, whereas a decrease in PRL is followed by a fall in DHEA-S.

Radioimmunoassay of serum d-Norgestrel in women following oral and intravaginal administration

Serum level of dl-norgestrel (dl-Ng) were measured by a special radioimmunoassay method after oral and intravaginal administration. 3 women received .075 mg/day dl-Ng orally for 5 days, and 3 others received 50 or 100 mg dl-Ng via a polysiloxane elastomer placed in the vagina for 3 weeks. The radioimmunoassay method proved to be highly effective; cross reacting with less than .01% 1-Ng. Circulating levels of dl-Ng were detectable 30 minutes after oral ingestion, and reached peak values of 2, 1.7 and 1.5 ng/ml in 1 and 2-3 hours, respectively. Serum levels fell rapidly thereafter, reaching levels of .2-.4 ng/ml within 24 hours after injection. Serum dl-Ng levels rose rapidly after insertion of the intravaginal device, and reached peak values of 5 ng/ml and 7-11 ng/ml with 50 and 100 mg dl-Ng, respectively, within 24-48 hours after insertion. Serum dl-Ng levels then declined to about 30-40% of initial treatment concentrations. During subsequent cycles, serum dl-Ng levels remained relatively constant at 1-3 ng/ml. Concentrations declined rapidly to .2 ng/ml within 5-7 days after removal of the device. Preovulatory patterns of estradiol were observed, but ovulation did not occur, as evidenced by low progesterone values. During the 1st and 2nd treatment cycles, withdrawal bleeding began at times ranging from the day of removal to 5 days after removal. In the later treatment cycles, withdrawal bleeding began prior to removal of the device. The results indicate that the more constant release of dl-Ng with the intravaginal ring provides better control of irregular bleeding than orally administered dl-Ng.

Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol.

The pronounced hepatic impact of oral ethinyl estradiol has been attributed by some to its so-called first-pass effect through the liver as only some 40% of ingested ethinyl estradiol reaches the systemic circulation. Others believe that ethinyl estradiol exerts its hepatic effects because of its chemical composition, specifically its 17 alpha-ethinyl group. In an attempt to resolve this controversy, a study was undertaken to determine whether vaginal administration of ethinyl estradiol can selectively reduce the hepatic effects of oral ethinyl estradiol. To compare the effects of oral and vaginal ethinyl estradiol, a group of postmenopausal subjects received either 5 micrograms of oral and 20 micrograms of vaginal ethinyl estradiol or 10 micrograms of oral and 50 micrograms of vaginal ethinyl estradiol in either sequence, respectively. Oral ethinyl estradiol was four to five times more potent than vaginal ethinyl estradiol. The potency ratios of the oral-vaginal ethinyl estradiol doses required to suppress follicle-stimulating hormone and luteinizing hormone were 4.4 and 3.2 and those to raise sex hormone-binding globulin binding capacity, corticosteroid-binding globulin binding capacity, and high-density lipoprotein cholesterol as well as lower low-density lipoprotein cholesterol were 3.5, 5.0, 4.2, and 4.2, respectively. These essentially equal oral-vaginal route potency ratios for both central nervous system and hepatic effects indicate that vaginal administration of ethinyl estradiol does not selectively reduce its hepatic impact in relation to its central nervous system effects. The pronounced hepatic effects of ethinyl estradiol are therefore attributed to its chemical composition.

Psychological stress and increases in urinary norepinephrine metabolites, platelet serotonin, and adrenal androgens in women with polycystic ovary syndrome

Twenty-three women with polycystic ovary syndrome, 10 women with hypothalamic-pituitary dysfunction, and 50 control subjects were studied in an attempt to investigate the prevalence of psychological stress and its possible relationship to various hormonal parameters. Norepinephrine (NE) excretion, as reflected by urinary 3-methoxy-4-hydroxyphenylglycol (MHPG), and urinary 3-methoxy-4-hydroxymandelic acid (VMA), platelet serotonin, plasma adrenocorticotrophic hormone (ACTH), urinary free cortisol, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione (Adione), dehydroepiandrosterone (DHEA), its sulfate (DHEA-S), delta 5-androstenediol (delta 5-Adiol), testosterone (T), and unbound estradiol (E2) were measured. In addition, psychological stress was assessed by means of questionnaires modified from the Schedule of Recent Experiences, in which a Life Events Inventory was scored between 1 and 100. Women with polycystic ovary syndrome had significantly elevated levels of serum LH, LH:FSH ratios, unbound E2, Adione, DHEA, delta 5-Adiol, T, and DHEA-S (p less than 0.01). The number of Major Life Events (events scored on the questionnaire above 60) was significantly higher in women with polycystic ovary syndrome than in control women and women with hypothalamic-pituitary dysfunction (p less than 0.05). Urinary MHPG and platelet serotonin levels were also significantly higher in women with polycystic ovary syndrome (p less than 0.05), whereas VMA was normal. Levels of plasma ACTH and urinary free cortisol were similar in all groups. There was a significant positive correlation between MHPG and DHEA-S, MHPG and LH, and LH and T levels in women with polycystic ovary syndrome and those with hypothalamic-pituitary dysfunction (p less than 0.01). VMA also correlated with DHEA-S (p less than 0.05). In conclusion, psychological stress may be more prevalent in women with polycystic ovary syndrome and may be associated with elevated levels of MHPG and platelet serotonin. Because we have found that MHPG, but not VMA, correlated with LH, and because both MHPG and VMA correlated with DHEA-S, we hypothesize here that psychological stress and neurotransmitter levels may be linked to some of the hormonal derangements, including inappropriate gonadotropin secretion and elevated adrenal androgen levels in women with polycystic ovary syndrome.

Direct radioimmunoassay of urinary estrogen and pregnanediol glucuronides during the menstrual cycle

Assays which measure immunoreactive metabolites of the major urinary estrogens directly are described, and their applicability to ovulation detection methods is discussed. The immunoreactive materials measured were estrone glucuronide (E1G), estradiol-3-glucuronide (E2-3G), estradiol-17beta-glucuronide (E2-17G), estriol-3-glucuronide (E3-3G), estriol-16alpha-glucuronide, and pregnanediol-3alpha-glucuronide (Pd-3G); these estrogen and pregnanediol glucuronide fractions were measured in portions of 24-hour and overnight samples of urine collected daily from 7 women throughout 1 menstrual cycle. The urinary excretions were correlated with daily serum levels of estradiol, progesterone, and luteinizing hormone. The usual serum changes were noted preovulatorily in all 7 women, who were therefore considered ovulatory. 24-hour and overnight urinary excretion patterns of the estrogen glucuronides were similar to the serum estradiol pattern, and of the 5 estrogen glucuronide fractions, E2-17G showed the earliest and steepest ascending slope of preovulatory estrogen surge. Therefore, E2-17G is most suitable estrogen fraction for predicting ovulation. Pd-3G rose in parallel with progesterone serum levels and was markedly elevated 2-3 days after the midcycle luteinizing hormone peak; therefore, because milligram quantities of Pd-3G are excreted daily in urine, measurements of this glucuronide are most useful for ovulation detection by a simple immunochemical or enzymatic technique (dipstick).