John Defazio

Acute ovarian responses to a long-acting agonist of gonadotropin-releasing hormone in ovulatory women and women with polycystic ovarian disease.

A long-acting agonist of gonadotropin-releasing hormone (GnRH-a, 100 micrograms/day) was administered daily for 14 days in four patients with polycystic ovarian disease (PCOD) and eight ovulatory women (OW) to determine acute hormone responses. Initiation of GnRH-a treatment in OW on day 5 of their menstrual cycles (OW-day 5) stimulated a greater acute rise of serum follicle-stimulating hormone (FSH) than that seen in OW beginning treatment on day 2 (OW-day 2) or PCOD patients. FSH levels fell to baseline values with repeated injections, whereas luteinizing hormone levels remained elevated in all patients. An acute rise and progressive fall of estradiol (E2) was found in all groups. The OW-day 5 group demonstrated a secondary increase, which by day 14 was clearly greater than that found in the other groups. This secondary increase of E2 in the OW-day 5 group was associated with lower abdominal pain, whereas OW-day 2 and PCOD patients were asymptomatic. For comparison, human menopausal gonadotropin (150 IU/day for 3 days) stimulated a significantly greater increase of E2 in OW-day 5 than in PCOD patients. These studies indicate that daily GnRH-a administration induced variable effects on ovarian function, which depended on when it was begun during the menstrual cycle and whether it was given to ovulatory or PCOD subjects. In addition, abdominal discomfort associated with GnRH-a use in regularly OW can be avoided by commencing agonist administration earlier in their menstrual cycles.

Direct action of androgen on hot flushes in the human male

Hot flushes (HF) were demonstrated definitively in a hypogonadal man by continuous recordings of finger temperature, skin resistance and subjective symptoms. The magnitudes and temporal interrelationships of these physiological changes were similar to those previously observed in oophorectomized women. HF were abolished by injections of methyl testosterone (MT) and during oral administration of fluoxymesterone (FM), a non-aromatizable androgen. Increases of the non-SHBG bound fractions of T and E2 were noted during MT therapy, either of which may have been responsible for suppression of HF. No significant changes of the non-SHBG bound levels of E2 were observed during FM ingestion. These data confirm that typical HF occur in the male and support the concept that androgen acts directly on the central nervous system without requiring aromatization to estrogen in the brain or other tissues.

Impermeability of the Rat Blood-Brain Barrier to Exogenously Administered Gonadotropin-Releasing Hormone

To assess the permeability of the blood-brain barrier (BBB) to exogenously administered gondatrophin-releasing hormone (GnRH), a study was performed in male-rats using the double isotope, intracarotid, single injection technique of Oldendorf. The mean (+/- SEM) brain uptake indices (BUI) of 3H-GnRH in comparison to a freely diffusible reference compound, 14C-butanol, were 1.1 +/- 0.2, 3.5 +/- 0.7 and 3.0 +/- 0.6 when the injection vehicles were Ringers lactate, rat serum and human serum, respectively. The BUI of 3H-GnRH was similar to that of 3H-inulin, a nondiffusible compound. With different concentrations, the BUI of 3H-GnRH did not change significantly. These data indicate that the BBB of the male rat is impermeable to exogenously administered GnRH.

Effects of the (imBzl)D-His6, DES-GLY analog of GnRH on gonadotropin and estradiol secretion in normal women

The acute gonadotropin and estradiol responses following single subcutaneous injections of 10, 50, 100 and 200 micrograms of [(imBzl)]D-His6,Pro9-NEt]-GnRH were compared to those after 100 micrograms of [D-Trp6, Pro9-NEt]-GnRH. The gonadotropin responses after 50-100 micrograms of the D-His analog of GnRH were equivalent to those following 100 micrograms of the D-Trp analog. The ovarian E2 response, a reflection of the total cumulative secretion of gonadotropins, was similar at 100 micrograms of each analog. The estradiol response paralleled the increasing gonadotropin response accompanying the graded doses of the D-His analog, indicating the lack of a direct inhibitory action of this GnRH agonist on the ovary. Assessment of both gonadotropin and estradiol responses appears to be satisfactory for assessing relative potency among GnRH agonistic analogs.

Origin of Serum Progestins in Polycystic Ovarian Disease

The glandular origin of excess circulating steroid hormones in women with polycystic ovarian disease has been difficult to establish with previously described perturbation techniques. Recently it was demonstrated that daily administration of a potent gonadotropin-releasing hormone agonist achieves complete and reversible suppression of ovarian steroid secretion. To examine the source of C-21 steroid hormones, circulating levels were measured before and after administration of the same agonist in polycystic ovarian disease subjects and normal control subjects. Serum levels of these hormones were also determined after administration of dexamethasone and adrenocorticotropic hormone (ACTH) as well as bilateral oophorectomy. Subjects with polycystic ovarian disease exhibited significant elevations of serum pregnenolone, 17OH-pregnenolone, and 17OH-progesterone by comparison with normal control subjects. The glandular origins of the excess levels of pregnenolone and 17OH-pregnenolone were more difficult to determine and appear to be different from that of 17OH-progesterone.