Sexual health innovations in undergraduate medical education.

Recent national and global initiatives have drawn attention to the importance of sexual health to individuals' well-being. These initiatives advocate enhancement of efforts to address this under-represented topic in health professions curricula. University of Massachusetts Medical School (UMMS) has undertaken a comprehensive effort to develop an integrated curriculum in sexual health. The UMMS project draws upon the expertise of a multidisciplinary faculty of clinicians, basic scientists, a medical ethicist, and educators. This article describes the project's genesis and development at UMMS, and reports on three innovations in sexual health education implemented as part of this endeavor.

Oxalate-induced changes in the viability and growth of human renal epithelial cells.

Previous studies on the porcine renal epithelial LLC-PK1 cell line demonstrated that oxalate exposure produces concentration-dependent effects on renal cell growth and viability via process(es) involving free radicals. The present studies were conducted to determine whether these findings could be extended to a renal proximal tubular epithelial cell line derived from the human kidney. These studies examined oxalate-induced changes in membrane integrity after short-term exposure (4 h) and changes in cell survival after longer-term exposure (24 to 72 h). Oxalate-induced changes were also assessed in the expression of two genes: egr-1, a zinc-finger transcription factor, and osteopontin, a protein associated with tissue remodeling. The present studies also determined whether oxalate-induced changes in either cell viability or gene expression depended on free radicals. Oxalate at a concentration > or = 175 microM (free) produced membrane damage within 4 h. This effect was inhibited by Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP), a superoxide dismutase mimetic, but not by N-acetyl cysteine, a glutathione precursor, or by deferoxamine, an iron chelator. Acute oxalate-induced injury was followed by cell loss within 24 h, an effect maintained at 48 and 72 h at high concentrations of oxalate. Oxalate also promoted DNA synthesis. This mitogenic effect offset cell loss at lower oxalate concentrations (88 microM) leading to a small but significant increase in cell number at 72 h. Treatment with oxalate also increased expression of egr-1 mRNA within 1 h, a response that was attenuated by MnTMPyP; oxalate treatment for 8 h also increased abundance of osteopontin mRNA. These studies suggest that oxalate exposure produces changes in human renal cell growth and viability via a process(es) dependent on reactive oxygen intermediates. Such changes may play a role in the development and/or progression of renal disease via generation of reactive oxygen intermediates.

The effect of a domestic violence interclerkship on the knowledge, attitudes, and skills of third-year medical students.

PURPOSE: To determine whether participation in an intensive domestic violence interclerkship (DVI) improved the knowledge, attitudes, and skills of two successive cohorts of students at the University of Massachusetts Medical School. METHOD: The authors measured the knowledge, attitudes, and skills pertaining to domestic violence of third-year students in the classes of 1997 and 1998 using a validated written examination administered before, immediately after, and six months after participation in a 3.5-day or two-day DVI, respectively; they compared the scores using paired t-tests. Nine months after the DVI, the students' domestic violence screening skills were measured by a performance-based assessment (OSCE); using unpaired t-tests, the authors compared the OSCE scores with those of a previous third-year class that had not participated in a DVI. Immediately after the OSCE, the students reported their levels of confidence in domestic violence screening and their satisfaction with the domestic violence curriculum; using chi-square analysis, those self-reports were compared with those of the class with no DVI. RESULTS: The students who participated in the DVIs immediately and significantly improved their knowledge, attitudes, and skills (p < .001), and fully or partially sustained those improvements six months later (p < .001). Nine months after the DVI, the students performed domestic violence screening more effectively (p < .001), expressed greater comfort with domestic violence screening (p < .001), and felt better-prepared by the curriculum to address domestic violence issues (p < .001) than did the students with no DVI. CONCLUSION: Participation in a short, focused DVI curriculum produced sustainable improvements in knowledge, attitudes, and skills that were successfully applied by third-year medical students to effective domestic violence screening. Interclerkships are an effective way to fit into the clinical curriculum those subjects that transcend the traditional biomedical domain and intersect all areas of medical practice.

Photoperiodic regulation of pulsatile luteinizing hormone secretion and adenohypophyseal gene expression in female golden hamsters.

LH concentrations were measured in serum collected at 10-min intervals from chronically ovariectomized female Syrian hamsters that had been maintained for 9 wk in stimulatory (long) or inhibitory (short) photoperiods. Short days reduced the number of detectable LH pulses during both the morning and the afternoon. Most short-day hamsters experienced a gradual afternoon rise in serum LH concentrations; this rise was not composed of multiple pulses. In separate groups of similarly treated hamsters, pituitary LH-beta mRNA abundance was significantly reduced by short-day exposure at both times of day even though serum LH concentrations rose in the afternoon. Estradiol treatment induced an afternoon surge of serum LH in both photoperiods, and eliminated the effect of photoperiod on LH-beta mRNA abundance in the afternoon. Serum prolactin (PRL) concentrations were not consistently influenced by day length in castrated hamsters with or without estrogen treatment, but PRL mRNA abundance was significantly suppressed by short-day exposure in all groups. The results indicate that day length exerts profound steroid-independent effects upon hypophyseal gene expression, and that the regulation of LH-beta mRNA abundance may be due to photoperiodic control of the neural GnRH pulse generator.

Regulation of adenohypophyseal messenger RNAs in female rats by age, hypothyroidism, estradiol and neonatal androgenization.

Hormonal regulation of adenohypophyseal messenger ribonucleic acids (mRNAs) encoding preprotachykinin (PPT), prolactin (PRL) and thyrotropin beta subunit (TSH beta) was examined in juvenile and pubertal female rats. Hypothyroidism, initiated on day 2 (d2) or 22 (d22) of life, increased PPT and TSH beta mRNAs but decreased PRL mRNA 17 days later. Exogenous estradiol given for 3 days reduced PPT mRNA in pubertal (d38) but not juvenile (d18) euthyroid females; conversely, estradiol increased PRL mRNA on d18 but not d38. In hypothyroid females however, estradiol decreased PPT and TSH beta mRNAs at both ages and increased PRL mRNA in pubertal but not juvenile females. Thus, regulation of adenohypophyseal mRNAs by estradiol varies with age and thyroid status. In previous studies, adenohypophyseal tachykinins increased in male, but not female rats at puberty. This sex difference was not reproduced here by neonatal androgenization of females, suggesting that it is not mediated by hypothalamic sexual differentiation. However, PRL mRNA increased in androgenized females; this increase was prevented by ovariectomy, suggesting its medication by estradiol.

Long-term hyperprolactinaemia reduces basal but not androgen-stimulated oestradiol production in small antral follicles of the rat ovary.

Hyperprolactinaemia disrupts fertility in many species, perhaps by inhibiting ovarian follicular steroidogenesis. The present studies measured oestradiol and progesterone secretion from isolated follicles from rats rendered hyperprolactinaemic in one of two ways. Sustained hyperprolactinaemia was induced by transplantation of two donor pituitary grafts under the renal capsule of adult female rats; grafts remained in place for 3 months. Transient hyperprolactinaemia was induced by pseudopregnancy initiated by cervical stimulation. Small antral follicles were isolated from both groups of rats 8-10 days after the previous vaginal oestrous smear and also from a control group of dioestrous female rats. Follicles were incubated for 3 h in the presence or absence of human chorionic gonadotrophin (hCG) or testosterone. Basal and hCG-stimulated oestradiol production were each reduced in follicles from both hyperprolactinaemic groups, relative to follicles from dioestrous control rats. In contrast, in the presence of testosterone, all groups of follicles produced comparable amounts of oestradiol. hCG stimulated comparable progesterone production by follicles from all three treatment groups. Testosterone elicited smaller increases in progesterone accumulation by follicles from all in-vivo groups. Reduced basal and gonadotrophin-stimulated, but not androgen-stimulated, oestradiol accumulation suggests that androgen production rather than aromatase activity in small antral follicles may be impaired by long-term hyperprolactinaemia.

Influences of photoperiod on sexual behaviour, neuroendocrine steroid receptors and adenohypophysial hormone secretion and gene expression in female golden hamsters.

Exposure to short daylengths arrests the oestrous cycle, provokes daily gonadotrophin surges and reduces the ability of exogenous oestradiol to trigger behavioural receptivity in golden hamsters. In order to examine neuroendocrine effects of photoperiod which might underlie these responses, ovariectomized hamsters were maintained under long or short photoperiods for 54 days before treatment with cholesterol or various doses of oestradiol-17 beta. Short days reduced the ability of low doses of oestrogen to prime hamsters for the induction of oestrus by progesterone. Upon repetition of oestrogen priming 2 weeks later, photoperiod was without significant influence on the concentrations of nuclear oestrogen receptors or cytosolic progestin receptors in a block of tissue containing the hypothalamus and preoptic area. Oestradiol treatment provoked significant increases in serum concentrations of LH and prolactin in the afternoon, but photoperiod did not alter the positive-feedback efficacy of this gonadal steroid hormone. Adenohypophysial LH-beta subunit and prolactin mRNAs were suppressed by short days in ovariectomized hamsters not treated with oestradiol. Oestradiol decreased expression of the LH-beta subunit gene in both stimulatory and inhibitory photoperiods, but increased prolactin mRNA abundance in both long and short days. Photoperiod therefore exerts pronounced steroid-independent effects on phasic LH and prolactin secretion, but regulation of adenohypophysial abundance of LH-beta subunit and prolactin mRNAs by oestradiol is not markedly influenced by daylength. Photoperiodic regulation of the priming effects of oestradiol on behavioural receptivity may result from modulation of events occurring subsequent to steroid-receptor interactions, or involve changes in receptor populations not detectable by the present methods.

Pituitary hormone gene expression in male golden hamsters: interactions between photoperiod and testosterone.

Abstract Daylength regulates neuroendocrine function in male golden hamsters. Exposure to short days triggers gonadal regression and decreases serum luteinizing hormone (LH), prolactin and testosterone concentrations. Inhibitory photoperiods also amplify the negative feedback actions of androgens upon gonadotropin secretion. To examine whether these changes arise from altered adenohypophyseal gene expression, we measured the abundance of the messenger ribonucleic acids (mRNAs) encoding beta-LH, prolactin and proopiomelanocortin in anterior pituitaries of male golden hamsters which were either left intact, castrated, castrated and implanted with testosterone, or pinealectomized and maintained in either long (14 h light/10 h dark) or short (5 h light/19 h dark) days. Short days caused testicular atrophy in intact male hamsters and reduced serum LH in intact and castrated, testosterone-replaced hamsters. The relative abundance of beta-LH mRNA was suppressed by exposure to short days only in castrated hamsters. Serum prolactin was decreased by short days regardless of circulating testosterone concentrations. Prolactin mRNA abundance was decreased by short days in all pineal-intact groups. Castration reduced proopiomelanocortin mRNA abundance in long days and testosterone replacement reversed this effect. In the presence of testosterone, photoperiod influenced serum LH concentrations without altering hypophyseal abundance of beta-LH mRNA. In contrast, photoperiodic influences on prolactin secretion were correlated with alterations in steady-state mRNA abundance.

Localization of vasoactive intestinal peptide and peptide histidine isoleucine immunoreactivity and mRNA within the rat suprachiasmatic nucleus.

The distribution of vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) mRNA within the suprachiasmatic nucleus (SCN) of rats was evaluated by immunocytochemistry and in situ hybridization. The pattern of VIP and PHI immunoreactivity corresponded closely to the distribution of VIP/PHI mRNA within the ventrolateral SCN. Clear hybridization signal was observed within the SCN of rats killed 5 h after light onset and in rats killed 2 h after the onset of the dark phase of the light-dark cycle. Visual examination of the grain density within the autoradiographs suggested that VIP/PHI mRNA may occur in higher concentrations shortly after the onset of darkness than 5 h after the onset of the light phase.

Stimulation of pituitary luteinizing hormone secretion by gonadotropin-releasing hormone is not coupled to beta-luteinizing hormone gene transcription.

The physiological stimulation and inhibition of release of several peptide and protein hormones appears to be associated with transcription of the respective peptide- and protein hormone-encoding genes. In the current studies we investigated whether this was also true for the rat pituitary LH system. Using an anterior pituitary primary tissue culture system, we have analyzed the effects of 10(-9) M GnRH on beta LH gene transcription using a transcription run-on assay, and on nuclear beta LH RNA levels using a highly sensitive solution hybridization-S1-nuclease protection assay. GnRH-stimulated release of LH does not appear to be coupled to a significant change in the rate of beta LH gene transcription, but is associated with both a 2- to 3-fold increase in levels of the beta LH primary transcript and processing intermediates and a rapid decrease in the levels of fully processed beta LH mRNA in the nucleus. No significant change in beta LH cytoplasmic mRNA levels, however, was associated with GnRH-stimulated release of LH, in vitro. Our findings suggest that unlike several other peptide and protein hormone systems, stimulated release of beta LH by GnRH in vitro is not associated with an increase in beta LH gene transcription or cytoplasmic mRNA levels.

Complex transcriptional regulation by glucocorticoids and corticotropin-releasing hormone of proopiomelanocortin gene expression in rat pituitary cultures.

Proopiomelanocortin (POMC) peptide secretion from rat anterior pituitary corticotrophs and intermediate pituitary melanotrophs is stimulated by corticotropin-releasing hormone (CRH). CRH-stimulated secretion in the corticotrophs is inhibited by glucocorticoids in a complex fashion, involving both a fast, direct blockade of POMC secretion (minutes to hours) and a longer inhibitory action (hours to days) that decreases the amount of POMC peptide available for release. The current studies tested the ability of CRH to stimulate beta-endorphin (a peptide derived from POMC) secretion and POMC gene transcription in cultured anterior and neurointermediate lobe pituitary cells, and examined interactions between CRH and glucocorticoids in regulating POMC gene expression using an in vitro nuclear transcription run-on assay. In both tissues, CRH elicited a time-dependent stimulation of POMC gene transcription that was maximal at 60 min and remained elevated for at least 18 hr. Glucocorticoids rapidly inhibited POMC gene transcription fourfold in the anterior lobe with maximal effects within 20 min. Glucocorticoids also blocked CRH-stimulated POMC gene transcription in anterior pituitary cultures in a temporal manner paralleling their inhibitory effects on CRH-stimulated beta-endorphin secretion. In neurointermediate lobe cultures, the effects of glucocorticoids and CRH on POMC gene transcription were qualitatively similar to, but of lesser magnitude than those observed in the anterior lobe. These studies indicate that the regulation of POMC gene transcription by glucocorticoids and CRH is complex and that the two modulators do not function independently.

Thyroid hormone status regulates preprotachykinin-A gene expression in male rat anterior pituitary.

Substance P (SP) and substance K (SK) are mammalian tachykinin peptides derived from a single preprotachykinin-A (PPT-A) gene and are widely but selectively distributed in neural and endocrine tissues. SP is present in the rat anterior pituitary, and its content there varies with the thyroid status of the animal. The present studies were undertaken to determine whether the PPT-A gene is expressed in the anterior pituitary and if so, whether PPT-A messenger RNA (mRNA) abundance is regulated by thyroid hormone status. Male rats were surgically or chemically thyroidectomized or made hyperthyroid by thyroid hormone (T3) injection. Total RNA was isolated from individual anterior pituitaries, and PPT-A mRNA abundance was determined by dot blot procedures. In parallel groups of rats, anterior pituitaries were extracted for measurement of SP and SK by specific RIAs. Surgical or chemical thyroidectomy increased PPT-A mRNA abundance 4 to 6-fold and increased both SP and SK content in the anterior pituitary. Administration of T3 to thyroidectomized rats reversed the increase in both PPT-A mRNA abundance and SP and SK content in the adenohypophysis. T3 administration to euthyroid rats also decreased PPT-A mRNA abundance and SP and SK content in the anterior pituitary. The coordinate presence of PPT-A mRNA with SP and SK in the anterior pituitary strongly suggests that these peptides are synthesized within this gland.

Reduced ovarian follicular development as a consequence of low body condition in ewes.

The effect of body condition on ovarian follicular development was investigated in Scottish Blackface ewes in high and low body condition. Follicles were dissected from ovaries on days 11 and 12 of the luteal phase and 24 h after prostaglandin-induced luteal regression. Ewes in low body condition had a lower ovulation rate (low: 0.9; high: 1.8 P less than 0.05) and lower mean plasma levels of FSH during both the luteal (low: 54; high: 72 micrograms/l) and follicular (low: 34; high: 43 micrograms/l) phases of the cycle. Low body condition was associated with a reduced number of large (greater than or equal to 4 mm) follicles in both the luteal and follicular phases, and in low condition a lower proportion of these follicles was oestrogenic and potentially ovulatory as assessed by follicular fluid levels of oestradiol. However, within the different oestrogenic classifications of these large follicles there were no significant differences in the steroidogenic capacity as assessed by the concentrations of either oestradiol or testosterone in follicular fluid, basal and hCG-stimulated testosterone production, thecal 125I hCG binding or basal and testosterone-stimulated oestradiol production by granulosa cells in relation to body condition. These results suggest that body condition influences ovulation rate by altering the concentration of FSH in blood, which in turn affects the number of potentially ovulatory follicles growing beyond 4 mm.

Suppression of follicular development after chronic LHRH immunoneutralization in the ewe.

Active immunization of 6 Damline ewes against LHRH during seasonal anoestrus resulted in an inhibition of ovarian cyclicity throughout 2 subsequent breeding seasons. This was associated with a significant suppression of plasma LH and FSH concentrations but no significant effect on prolactin. The ovaries of LHRH-immunized ewes 30 months after primary immunization contained no follicles greater than 2.5 mm in diameter and a greater proportion of follicles between 1 and 2 mm were atretic than in control ewes (N = 8). In-vitro production of testosterone and androstenedione were similar in follicles 1-2 mm in both control and LHRH-immunized ewes (N = 6) and all had little or no ability to secrete oestradiol. However, basal and hCG-stimulated progesterone secretion was suppressed in the follicles from LHRH-immunized ewes. These results show that follicular development beyond 2.5 mm in the ewe is dependent on adequate stimulation by both LH and FSH.

Prolactin effects on basal and gonadotrophin-stimulated progesterone accumulation by PMSG-primed mouse ovaries in vitro.

To examine the effects of prolactin (Prl) and human chorionic gonadotrophin (hCG) on progesterone production by murine ovarian explants, immature female mice were injected with 4 IU pregnant mare's serum gonadotrophin (PMSG) to induce follicular maturation. After 24 or 40 h mice were killed, ovaries removed, cut into fragments and maintained as explants for 24 h in the presence or absence of ovine or human Prl (25-2500 ng/ml). None of these doses of Prl affected basal progesterone accumulation into media over 24 h. To determine if Prl could modify the capacity of ovarian explants to respond to gonadotrophin, ovaries were incubated with 25 IU/ml hCG for 3 h after an initial 24 h incubation period with or without Prl. Prl had no effect on basal progesterone accumulation but significantly enhanced hCG-stimulated progesterone accumulation during the 3 h incubation period. We conclude that Prl does not inhibit but may enhance progesterone secretion by pre-ovulatory follicles in the mouse.