Khalid M. Ataya

Bone density and reproductive hormones in patients with neuroleptic-induced hyperprolactinemia

To study the prevalence of osteoporosis and hyperandrogenism in neuroleptic-induced hyperprolactinemia, the authors evaluated 10 patients. Three were amenorrheic, while seven had oligomenorrhea. Nine patients had galactorrhea. The Ferriman-Gallway hirsutism score was 12 +/- 2. Vaginal smear maturation value was 53 +/- 8. Bone density, measured by dual photon absorptionometry in the spine, femoral neck, Wards triangle, and trochanteric region, was 98 +/- 1.5, 92.7 +/- 3, 88.5 +/- 4.2, and 92.6 +/- 3.3 percentile of controls matched for age, sex, weight, and ethnicity, respectively. Serum prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), total testosterone, and free testosterone were 82 +/- 10 ng/ml, 8.5 +/- 1.1 mIU/ml, 11.1 +/- 2.6 mIU/ml, 4695 +/- 594 ng/ml, 90 +/- 17 ng%, and 2.36% +/- 0.3%, respectively. Serum thyroid-stimulating hormone (TSH) and free thyroxine index were normal. Bone density strongly correlated with vaginal maturation value (r = 0.904, P less than 0.01). It is concluded that (1) neuroleptic-induced hyperprolactinemia is associated with hirsutism and androgen excess primarily of adrenal origin and (2) a subset of these patients is at an increased risk of developing osteoporosis. It may be possible to identify patients at risk of osteoporosis by examining vaginal smears for maturation value. Early detection and management are imperative in this group of patients.

The effect of "activated" cyclophosphamide on rat granulosa cells in vitro

We investigated the mechanism of cyclophosphamide (CTX)-induced ovarian toxicity by studying the effect of an activated form, 4-hydroperoxycyclophosphamide (PCTX), on rat granulosa cells in vitro. Cells were obtained from PMSG-primed immature rats and incubated with PCTX at concentrations of 1, 10, 100, and 500 micrograms/mL. Ovine LH (10 ng/mL) was added in selected tubes. Cell viability before and after seven hours incubation was determined. Progesterone and prostaglandin E accumulation were measured by radioimmunoassay. Granulosa cell viability was significantly decreased at PCTX concentrations of 10 micrograms/mL or higher in a dose-related manner. PCTX at concentrations of 100 micrograms/mL and 500 micrograms/mL significantly decreased basal and LH-induced progesterone and prostaglandin E accumulation. The above findings demonstrate that cyclophosphamide metabolites decrease granulosa cell survival and function in vitro. These direct effects suggest a possible mechanism for CTX-induced premature ovarian failure.

The effect of "activated" cyclophosphamide on human and rat ovarian granulosa cells in vitro.

We investigated the mechanism of cyclophosphamide (CTX) induced ovarian toxicity by studying the effect of an activated form, 4-hydroperoxycyclophosphamide (PCTX), on human and rat granulosa cell function in vitro. In previous experiments we demonstrated that in short-term incubations with rat granulosa cells, high (greater than or equal to 100 micrograms/mL) but not low (less than or equal to 10 micrograms/mL) PCTX concentrations inhibited progesterone accumulation in vitro. In this study, human granulosa cells were obtained from patients undergoing follicle puncture for in vitro fertilization. PCTX at 10, 100, and 500 micrograms/mL, but not at 1 micrograms/mL, resulted in a dose-related reduction in progesterone accumulation in short-term human granulosa cell cultures. Rat granulosa cells were obtained from PMSG-primed immature rats and incubated for 24 h with PCTX concentrations of 1, 5, and 10 micrograms/mL. Ovine LH (10 ng/mL) was added in selected tubes. In comparison to control, progesterone accumulation was significantly reduced by PCTX concentration of 10 micrograms/mL. The above findings demonstrate that cyclophosphamide metabolites, at concentrations achievable in vivo during CTX therapy, decrease rat and human granulosa cell function in vitro. The effect of PCTX on granulosa cells is dependent on PCTX concentration and duration of exposure, as well as the species from which granulosa cells are obtained.

Clinical value of prolactin bioassay in euprolactinemic reproductive disorders

To examine the disparity between clinical presentation and prolactin (PRL) measured by radioimmunoassay (RIA), serum samples from 128 patients with galactorrhea and/or reproductive disorders were evaluated by RIA for immunoassayable PRL (RIA-PRL) and by Nb2 lymphoma cell proliferation assay for bioassayable PRL (bioassay-PRL). One hundred fifteen patients had normal RIA-PRL and 13 patients had high RIA-PRL (greater than 25 ng/ml). Twenty patients had galactorrhea, two of whom had hyperprolactinemia. The reproductive disorders in female patients included infertility, amenorrhea, oligomenorrhea, irregular menstrual cycles, and luteal phase defects. Six oligospermic males also were studied. Twenty-three male and female volunteers with no evidence of reproductive disorders served as controls. Appropriate comparisons showed that PRL bioassay/RIA ratio, an index of agreement between the two assay systems, did not differ for the various patient groups compared with controls. It is concluded that Nb2 lymphoma bioassay does not provide additional diagnostic value to RIA in defining the cause of euprolactinemic galactorrhea and/or reproductive disorders.