Lorna A. Marshall

Use of an agonistic analog of gonadotropin-releasing hormone (nafarelin) to treat leiomyomas: assessment by magnetic resonance imaging.

The purposes of this study were to investigate the effect of a superactive agonistic analog of gonadotropin-releasing hormone, nafarelin, on uterine leiomyomas and to assess the use of magnetic resonance imaging in monitoring uterine and myoma size. Eleven women with uterine leiomyomas were treated with 800 micrograms of nafarelin per day for 6 months. Serum gonadotropin and estradiol concentrations were suppressed during treatment. The mean +/- SEM serum luteinizing hormone level decreased from 11.1 +/- 1.4 to 5.6 +/- 0.42 mlU/ml and follicle-stimulating hormone from 9.5 +/- 0.66 to 7.5 +/- 0.72 mlU/ml by 3 months of treatment (p less than 0.01). The estradiol level decreased from a pretreatment follicular phase mean +/- SEM of 43 +/- 8.3 to 19.8 +/- 3.1 (p less than 0.05) and 14.8 +/- 2.2 pg/ml (p less than 0.01) at 3 and 6 months of treatment, respectively. Mean pretreatment androgen levels (testosterone, androstenedione, and dehydroepiandrosterone sulfate) were low in these women and did not change significantly during treatment. Ten women had magnetic resonance imaging, which provided excellent resolution of individual uterine myomas. As assessed by magnetic resonance imaging, the largest myoma decreased in size in nine of 10 women; the mean decrease was 46% +/- 9%. Uterine volume decreased in all 10 patients; the mean decrease was 57% +/- 7%. In several women myomas reenlarged after discontinuance of nafarelin treatment. Posttreatment myomectomy was carried out in four women; there was minimal blood loss and no surgical complications. These data indicate that suppression of ovarian estrogen production with nafarelin is associated with a decrease in uterine myoma size in many women but that myomas may regrow with reinstitution of ovarian function. Magnetic resonance imaging is an excellent method by which to monitor treatment as changes in the size of the uterus, as well as individual myomas, can be assessed. The optimal use of gonadotropin-releasing hormone analogs may be in perimenopausal women or as presurgical treatment to decrease uterine and myoma size to facilitate myomectomy.

Therapeutic uses of gonadotropin-releasing hormone analogs.

Since the discovery and synthesis of gonadotropin-releasing hormone (GnRH) in 1971, numerous long-acting agonistic and antagonistic analogs have been synthesized. Agonistic analogs were found to desensitize pituitary GnRH receptors with chronic use, resulting in decreased gonadotropin secretion and a hypogonadal state. These analogs are being investigated as potential contraceptives and in the treatment of several conditions in which decreased gonadal steroid production is desired. Substantial progress has been made in these areas. The purpose of this review is to provide the clinician with data regarding the potential clinical utility of this class of peptides.

Luteinization of human granulosa cells in vivo is associated with expression of MHC class II antigens

SummaryWe previously described the presence of MHC class II (HLA-DR) antigens, structurally similar to those on lymphoid cells and bearing the genetically-appropriate allotypic determinants, on human adrenocortical cells in the zona reticularis of normal glands. We now report a similar expression by granulosa-lutein cells (GLC) in corpora lutea (CL) of normal ovaries, as detected by indirect immunofluorescence techniques with the use of mouse monoclonal antibodies (MAb). In some cases, GLC were also positive for HLA-DQ and-DP antigen expression. Neither granulosa nor theca interna cells in large antral follicles of the same ovaries showed any detectable expression of MHC class II antigens. Moreover, theca-lutein (paralutein) cells, identified by their reactivity with specific human autoantibodies in 5 of the 7 human CL examined, were also negative. Similarly, GLC, but not paralutein cells, in rhesus monkey CL showed significant cross-reactivity with anti-HLA-DR MAb. In contrast, lutein cells in ovaries from either cycling or 7-day-pregnant rats were negative for MHC class II (Ia) antigen expression. Expression of MHC class II antigens by human granulosa cells after their luteal transformation confirms the normal inducibility of certain human steroidogenic cells at the time of their further functional differentiation and enhanced biosynthetic activity, and suggests that these molecules, may have additional functions beyond serving as restriction elements in the immune response.

Neuromodulatory regulation of gonadotropin-releasing hormone pulsatile discharge in women

The pulsatile release of gonadotropin-releasing hormone and the consequent secretion of gonadotropins are regulated by a complex interplay of steroids, neuropeptides, catecholamines, and environmental factors. Estrogen and progesterone influence the amplitude and frequency of luteinizing hormone pulsatile secretion. These effects lead to both a diurnal variation in pulse frequency, with a lower frequency at night, and variation during the menstrual cycle, with a lower frequency and increased amplitude during the luteal phase. Opioid peptides inhibit the pulsatile discharge of gonadotropin-releasing hormone and luteinizing hormone. The opioid antagonist, naloxone, causes an increase in luteinizing hormone secretion, particularly during the luteal phase. The administration of opioid receptor agonists, such as beta-endorphin, results in a decline in serum luteinizing hormone during the early follicular phase. Corticotropin-releasing factor, which is increased during stress, inhibits pulsatile luteinizing hormone secretion, and this effect can be blocked by the simultaneous administration of naloxone. These observations suggest that corticotropin-releasing factor exerts its effects on luteinizing hormone through an opioidergic intermediary. Endogenous catecholamines such as dopamine inhibit pulsatile luteinizing hormone release; however, the mechanism involved is not clear.

Intergenerational gamete donation: Ethical and societal implications☆☆☆★

Cases of daughter-to-mother oocyte donation, niece-to-aunt oocyte donation, and father-to-son sperm donation are presented. Comparisons to sibling gamete donation and organ donation, potential ethical conflicts, and societal implications are examined in an attempt to aid decision making when these procedures are requested.

Contrasting effects of a gonadotropin-releasing hormone agonist and antagonist on the secretion of free α subunit

Gonadotropin-releasing hormone agonists and antagonists have initial divergent effects on the pituitary secretion of intact biologically active gonadotropins and long-term divergent effects on the secretion of free alpha-subunit. The antagonists appear to function as true competitive inhibitors, blocking the stimulatory effects of endogenous GnRH without evoking any known postreceptor activity. The agonists, in contrast, initially stimulate pituitary secretion and then incompletely desensitize the gonadotrope, resulting in suppression of intact gonadotropin, but not free alpha-subunit, secretion. The mechanisms by which GnRH-a produce this incomplete gonadotrope desensitization and facilitate limited postreceptor activity remain to be elucidated.

Influence of preovulatory estradiol concentration on diurnal and pulsatile prolactin secretion patterns

We evaluated the effect of preovulatory concentrations of estradiol on the 24-hour profile of prolactin secretion in women with regular menstrual cycles. An estradiol preparation was chosen to allow comparison with physiologic events. Estradiol benzoate, 1 mg intramuscularly, was administered for 7 days to achieve estradiol concentrations just above preovulatory levels (424 +/- 54 pg/ml); 24-hour mean prolactin concentrations increased threefold (14.0 +/- 2.1 to 40.6 +/- 7.1 ng/ml). Prolactin pulse frequency increased significantly (p less than 0.001) during waking hours after estradiol benzoate administration. The diurnal pattern of prolactin secretion was maintained with estradiol benzoate, although the sleep acrophase often reached high concentrations (86 +/- 11 ng/ml). These results suggest in women with regular menstrual cycles: (1) that estrogen administration that achieves slightly greater than preovulatory estradiol concentrations can stimulate prolactin release, (2) that estradiol may elevate prolactin by increasing its pulsatile secretion, (3) that estradiol does not alter the diurnal pattern of prolactin secretion, (4) that estradiol concentrations just above preovulatory levels can be associated with markedly elevated prolactin concentrations.

Effect of preovulatory estradiol concentrations on luteinizing hormone diurnal secretory patterns: A hypothesis for the timing of the luteinizing hormone surge

The effect of preovulatory estradiol concentrations on 24-hour patterns of luteinizing hormone secretion was studied in six women with normal menstrual cycles. Blood samples were collected every 15 minutes for 24 hours before and after 7 days of estradiol benzoate administration, which achieved mean (+/- SE) estradiol concentrations of 424 +/- 54 pg/ml. The luteinizing hormone pulse frequency decreased significantly during sleeping hours both before (p less than 0.05) and after (p less than 0.005) estradiol benzoate administration. After estradiol benzoate, there also was diurnal variation in overall mean luteinizing hormone concentrations, which markedly increased secretion in the morning hours. The diurnal changes in luteinizing hormone secretion varied inversely with those of prolactin. These findings are consonant with the observation that the onset of the preovulatory luteinizing hormone surge in women occurs most frequently in the early morning hours.