Biomedical subjects
H S Jacobs
Publications and source records attributed to H S Jacobs.
Ovarian failure after total body irradiation.
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Regulation of testicular function by insulin and transforming growth factor-beta.
Hyperinsulinism is associated with disorders of androgen production in humans. We have studied the effects of insulin and insulin-like growth factor-1 on androgen production in vitro using a crude preparation of mouse Leydig cells incubated with luteinizing hormone in a serum-free medium. We found a positive correlation between testosterone production and the luteinizing hormone dose over 3 hours. Exposure of the cells for 1 hour to insulin (1 micrograms/ml) prior to the addition of luteinizing hormone significantly augmented the amount of testosterone produced in response to the gonadotropin when added after this preincubation. In contrast, prior exposure of the cells to proinsulin (30 micrograms/ml), insulin-like growth factor-1 (30 ng/ml), or epidermal growth factor-1 (1 micrograms/ml) did not influence the testosterone response to luteinizing hormone. Transforming growth factor-beta reduced the testosterone response to luteinizing hormone. Transforming growth factor-beta (1,000 pg/ml) blocked the insulin augmentation of luteinizing hormone-stimulated testosterone production. We conclude that insulin has an endocrine effect on testosterone production by mouse Leydig cells in vitro. Furthermore, the Leydig cell response to insulin is itself sensitive to interaction with transforming growth factor-beta which may operate as part of the paracrine control of Leydig cell function.
Laparoscopic ovarian diathermy in the management of anovulatory infertility in women with polycystic ovaries: endocrine changes and clinical outcome.
Twenty-one nulliparous oligomenorrheic women with polycystic ovaries, complaining of infertility (mean duration 6 years) refractory to medical treatment, underwent laparoscopic ovarian diathermy. Eleven had adhesions and/or endometriosis. Regular ovulatory cycles ensued in 17 women (81%). In 9 responders there was a transient rise in mean follicle-stimulating hormone from 5.0 +/- 0.4 (standard error of the mean [SEM]) to 6.7 +/- 0.5 mIU/mL on postoperative day 1 and a fall in testosterone from 2.6 +/- 0.2 to 1.9 +/- 0.2 nmol/L by day 8. Luteinizing hormone fell from 19 +/- 1.2 to 10.4 +/- 1.2 mIU/mL by the follicular phase of the next cycle. Eleven women have conceived 13 pregnancies; 3 miscarried, 7 were delivered at term and 3 are ongoing. Ovarian diathermy is a useful option in women with polycystic ovaries complaining of refractory anovulatory infertility.
Cotreatment with human growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial.
A randomized, double-blind, placebo-controlled trial of cotreatment with biosynthetic, human sequence, growth hormone (GH), and human menopausal gonadotropins (hMG) for induction of ovulation was performed in 16 women with amenorrhea and anovulatory infertility. Patients were randomly allocated to treatment with hMG + GH (24 IU on alternate days, total dose 144 IU) or hMG + placebo. Those who received placebo were given GH in a subsequent course of treatment. On cotreatment with GH compared with placebo, there was a significant reduction in the required dose of hMG, duration of treatment, and the daily effective dose of gonadotropins. Serum insulin-like growth factor-I (IGF-I) rose during treatment with GH but not with placebo. We conclude that growth hormone augments the response of the human ovary to stimulation by gonadotropins. These results suggest a role for the use of GH in induction of ovulation.
Comparative trial of luteinizing hormone-releasing hormone analog/human menopausal gonadotropin and clomiphene citrate/human menopausal gonadotropin in an assisted conception program.
To establish the usefulness of a new drug regimen in an assisted conception program, a trial was performed comparing clomiphene citrate (CC) plus human menopausal gonadotropins (hMG) with a new regimen of intranasal luteinizing hormone-releasing hormone (LH-RH) analog plus hMG. One hundred two patient cycles received treatment with CC and hMG and 118 patient cycles received treatment with LH-RH analog and hMG. Fifteen percent of cycles were canceled in the CC group and 8% in the analog group. Four percent of cycles in the CC group were canceled due to premature ovulation. The number of oocytes collected in the analog group was significantly higher than in the CC group (8.5 versus 5.5), as was the number of mature oocytes (3.5 versus 2.7). However, the percentage of mature oocytes was higher in the CC group (54.2% versus 42.3%). The number of embryos resulting from in vitro fertilization as well as the number of cleaving embryos were significantly higher in the analog group (5.2 versus 2.8 and 4.6 versus 2.3, respectively). The pregnancy rate in the analog group was significantly higher than in the CC group (30.6% versus 16.1%), as was the live birth rate (21% versus 8%). Early pregnancy loss was significantly higher in the CC group than in the analog group (35% versus 9%); and the serum level of LH on the day of human chorionic gonadotropin (hCG) administration was also significantly elevated in the CC group when compared with the analog group (8.1 versus 4.1).(ABSTRACT TRUNCATED AT 250 WORDS)
Treatment with pulsatile luteinizing hormone-releasing hormone modulates folliculogenesis in response to ovarian stimulation with exogenous gonadotropins in patients with polycystic ovaries.
Combined treatment with pulsatile LH-RH and hMG, given to eight patients who had anovulation associated with PCO and resistant to CC, significantly reduced the number of large follicles induced by hMG alone. A direct effect of pulsatile LH-RH on the ovary is postulated. This combined treatment eased the problems of multifollicular development, thereby increasing efficiency and reducing complications in patients with PCO stimulated by gonadotropins.
The endocrinology of conception.
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Induction of ovulation with pulsatile GnRH.
The use of pulsatile GnRH to treat infertile women who do not ovulate has been shown to be safe, simple, and effective and the preferred method of inducing ovulation in appropriately selected patients who are resistant to treatment with clomiphene citrate. Treatment with GnRH is particularly effective for restoring ovulation in patients with idiopathic hypogonadotrophic hypogonadism and partially recovered weight-related amenorrhoea, but less successful in patients with polycystic ovary syndrome and organic hypothalamic pituitary disease. Based on personal experience, we advocate routine use of the subcutaneous route, using 15 micrograms per pulse every 90 min, and we monitor the patient's progress by serial ultrasound scanning and measurement of serum gonadotrophin and oestradiol concentrations. If the patient does not respond we recommend adding treatment with clomiphene citrate (Homburg et al, 1988b). Treatment with intravenous GnRH is reserved for women who do not respond to the above combination of drugs. We do not treat patients with GnRH until their body mass index is in the normal range (between 20-25) and we avoid GnRH treatment in patients with hypersecretion of LH during the follicular phase. If LH concentrations are raised, an alternative method of treatment is recommended, such as ovarian diathermy (Armar et al, 1990). Finally, the question of whether GnRH deficiency in patients with hypogonadotrophic hypogonadism is caused by a specific genetic lesion is not yet fully resolved. Yang-Feng et al (1986) used a cDNA clone encoding the human GnRH precursor molecule in order to assign the GnRH gene to a particular human chromosome. They found a single site for GnRH sequences in the human genome and that the gene coding for GnRH is located on the short arm of chromosome 8. Experiments in the congenitally hypogonadal mouse have shown that it is possible to restore gonadal development and gametogenesis by gene transfer (Mason et al, 1987). Clearly an abnormality at the level of the genome may be responsible for the secretory defect in patients with hypogonadotrophic hypogonadism, but it has yet to be defined (Weiss et al, 1989). Presumably elucidation awaits the development of more refined methods because both the genetics and the clinical associations of GnRH deficiency are most persuasive. Meanwhile replacement treatment with GnRH provides a simple and safe form of treatment for managing the clinical syndromes of GnRH deficiency.
Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries.
This study was designed to compare the results of treatment with, firstly, exogenous gonadotrophins, with (57 cycles) and without (65 cycles) pretreatment with a superactive analogue of luteinizing hormone releasing hormone (LHRH) and, secondly, pure follicle stimulating hormone (FSH) (50 cycles) with those of human menopausal gonadotrophin (HMG) (72 cycles) in 46 women with clomiphene-citrate-resistant anovulation associated with polycystic ovaries. Patients randomly allocated to the analogue group received buserelin (Suprefact, Hoechst, UK, Ltd, Hounslow, Middlesex), 800 micrograms/day by nasal insufflation and when hypogonadism was achieved, patients were again randomly allocated for ovarian stimulation with either FSH or HMG. Controls received FSH or HMG alone. Patients pretreated with the analogue had similar pregnancy and ovulation rates, needed larger doses and more days of gonadotrophin therapy and had more ovarian overstimulation than those receiving no pretreatment. The role of superactive LHRH analogues for induction of a single ovulation for in-vivo fertilization is thus uncertain. Pure FSH had no advantages over HMG, the LH content of HMG having no deleterious effect on the ovary.
Oocyte donation: the role of endometrial receptivity.
Sixteen patients, 15 with primary ovarian failure and one carrier of chromosomal abnormality, received 21 embryo transfers following in-vitro fertilization of donated oocytes. Hormone replacement therapy was given to mimic a natural menstrual cycle. Five pregnancies were achieved (four infants delivered and one early pregnancy loss). All patients had endometrial biopsies taken in a preceding cycle of hormone replacement therapy. The majority (61%) showed delayed maturation compared with the expected appearances for the day of the cycle as assessed on light microscopy. Patients who conceived had a significantly better endometrial response than those who did not. Five out of seven patients (71%) conceived when the endometrium was 'in phase' (less than 2 days' delay). This suggests that endometrial receptivity is a key factor in conception. The implications for improving outcome from in-vitro fertilization treatment are discussed.
HLA associations in patients with polycystic ovaries and in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency.
Ninety-nine Caucasian patients with ultrasonically detected polycystic ovaries (PCO) were typed for human leucocyte (HLA) antigens. Fifty patients with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency were similarly typed. Among the patients with PCO, there was a significant increase in the frequency of HLA DRW6 (P = 0.0027) compared with that found in a control population, which remained significant (P = 0.027) when corrected for the number of antigens tested. This difference was reduced, but remained significant (P = 0.006), when the patients with CAH and PCO were added. There was also a significant decrease in the frequency of HLA DR7 (P = 0.017) among the patients with PCO compared with a control population, but there was no distortion of the frequencies of HLA A, B or Cw antigens. Among the patients with CAH, previously well documented associations of HLA B14 and DR1 with non-classical disease were confirmed. The frequency of HLA Bw47 was increased among the whole group of CAH patients (P = 0.05) but was not increased among those with classical salt-wasting (SW) or simple virilizing (SV) disease. Family studies were performed in close female relatives of 16 of the PCO patients and 21 of the CAH patients but no evidence for genetic linkage between HLA and PCO status could be found. These data suggest that there is no significant component of disturbed adrenal steroid 21-hydroxylase activity to account for the PCO morphology, although there may be some other genetic factor, more proximal to the centromere on chromosome 6, affecting the development of polycystic ovaries.
A double-blind study comparing a new non-ergot, long-acting dopamine agonist, CV 205-502, with bromocriptine in women with hyperprolactinaemia.
Twenty-two hyperprolactinaemic women were randomly allocated to two groups and treated with bromocriptine or the new, non-ergot, long-acting dopamine agonist, CV 205-502. The study was double-blind for 6 months. Four patients in the bromocriptine group, but none in the CV 205-502 group, discontinued the study because of adverse reactions. Adverse reactions in those receiving the new drug were milder and more transient than with bromocriptine. With once-daily doses of 0.075 mg CV 205-502, eight of 11 women achieved normal PRL concentrations after 8 weeks treatment (median (95% confidence limits), 352 (70-987) mU/l) compared with two of nine receiving a divided daily dose of 5 mg bromocriptine (1802 (1205-4438) mU/l) (P less than 0.002). With doses of 0.075-0.15 mg of CV 205-502, 10 of 11 women achieved normal PRL concentrations at 24 weeks compared with three of the remaining seven women on doses of 5-10 mg of bromocriptine. Regular menstrual bleeding was restored and galactorrhoea relieved in the majority of patients, with marginally greater efficacy with CV 205-502. CV 205-502 is highly effective for the long-term treatment of hyperprolactinaemia. It is better tolerated than bromocriptine, is effective in a once-daily dose, appears to be safe, and provides a valuable alternative to the dopamine agonist drugs in use today.
A comparative study of single-dose growth hormone therapy as an adjuvant to gonadotrophin treatment for ovulation induction.
One intramuscular injection of biosynthetic human growth hormone (24 IU), administered on the first day of gonadotrophin treatment for ovulation induction, significantly augmented the ovarian response to gonadotrophic stimulation in seven patients. Compared with a protocol involving six injections of 24 IU of GH given on alternate days to the same patients, the smaller dose had an intermediate but highly significant effect in reducing the amount, duration of treatment and daily effective dose of hMG needed to induce ovulation. The difference between the effect of the one-dose and six-dose protocols was small. The action of growth hormone on the human ovary, probably mediated by insulin-like growth factor-1 (IGF-1), appears effective in enhancing the response to gonadotrophin therapy even when given in a single dose.
The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives.
Seventy-seven female patients (36 adults and 41 children aged under 16 years) with congenital adrenal hyperplasia (CAH) were assessed using pelvic ultrasound, as well as with standard endocrine tests and HLA typing. Forty-six close female relatives were also tested for ovarian morphology using ultrasound after assessment of their heterozygous state using HLA typing. The association of CAH with ultrasonically detected polycystic ovaries (PCO) was confirmed in 30/36 (83%) adult patients, 4/10 (40%) postpubertal girls and 1/31 (3%) pre and peripubertal girls: in all, 35/46 (76%) postmenarcheal patients. Six out of nine (67%) pre-menopausal mothers of patients with PCO, and 8/10 (80%) sisters of patients with PCO also had PCO. The proportions of both CAH patients and heterozygote subjects with PCO were significantly greater than that found in a normal population (P less than 0.0001). The finding, however, of two homozygous non-CAH-affected adult sisters with PCO and, conversely, of 10 heterozygous adult relatives and of 12 postmenarcheal CAH patients with normal ovaries, indicates that the ovarian morphological change may be independent of the adrenal lesion.
Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome.
This study explores the clinical and endocrine implications of hyperinsulinaemia in the polycystic ovary syndrome (PCOS). Oral glucose tolerance tests were performed on 34 lean and 19 obese women with PCOS and on 13 lean women with normal ovaries. Insulin measurements were compared with basal gonadotrophins, androgens, insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein 1 (IGFBP-1). Unselected lean women with PCOS were found to have fasting hyperinsulinaemia and the raised serum insulin concentrations were associated with menstrual disturbance and hyperandrogenaemia. In addition, serum insulin concentrations in lean women with PCOS correlated positively with serum IGF-I and negatively with serum IGFBP-1 concentrations. Ovarian stimulation by insulin appears to be independent of luteinizing hormone (LH) and is an important feature in 30% of lean women with PCOS.
Assessment of the effect of oral corticosteroids on bone mineral density in systemic lupus erythematosus: a preliminary study with dual energy x ray absorptiometry.
Dual energy x ray absorptiometry and a wide range of blood and urine tests were used to assess the propensity of patients with systemic lupus erythematosus to develop an impairment of bone mineral density. Surprisingly, in this preliminary study no significant differences in bone mineral density were found when patients taking 10 mg or more of prednisolone for six months or longer were compared with those who had never taken prednisolone.
Acanthosis nigricans in obese women with the polycystic ovary syndrome: disease spectrum not distinct entity.
Fasting and stimulated insulin concentrations in four patients with acanthosis nigricans and polycystic ovary syndrome were compared with four patients, matched for weight and ovarian morphology, without acanthosis. The median fasting serum insulin concentrations were 114.2 and 25.1 mU/l in the respective groups (P = 0.02). One additional patient was investigated before and after an 18% increase in weight which resulted in a 170% increase in fasting insulin concentrations and the development of acanthosis nigricans. These observations suggest that there is variation between individuals in the degree of obesity that results in the development of acanthosis and that obese patients with this skin condition represent the severe end of the spectrum of the polycystic ovary syndrome.