An Update on Contraception in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women, characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology. Combined oral contraceptives (COCs), along with lifestyle modifications, represent the first-line medical treatment for the long-term management of PCOS. Containing low doses of estrogen and different types of progestin, COCs restore menstrual cyclicity, improve hyperandrogenism, and provide additional benefits such as reducing the risk of endometrial cancer. However, potential cardiometabolic risk associated with these agents has been a concern. COCs increase the risk of venous thromboembolism (VTE), related both to the dose of estrogen and the type of progestin involved. Arterial thrombotic events related to COC use occur much less frequently, and usually not a concern for young patients. All patients diagnosed with PCOS should be carefully evaluated for cardiometabolic risk factors at baseline, before initiating a COC. Age, smoking, obesity, glucose intolerance or diabetes, hypertension, dyslipidemia, thrombophilia, and family history of VTE should be recorded. Patients should be re-assessed at consecutive visits, more closely if any baseline cardiometabolic risk factor is present. Individual risk assessment is the key in order to avoid unfavorable outcomes related to COC use in women with PCOS.

The role of estrogen receptor subtypes for induction of delayed effects on the estrous cycle and female reproductive organs in rats.

It has been reported that neonatal exposure to estrogens at relatively low doses can induce early onset anovulation as a delayed effect in female rats. Dysfunction of kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) was proposed to be a trigger for this effect. To determine the roles of estrogen receptor (ER) subtypes in the induction of delayed effects, we conducted a series of experiments using Donryu rats to examine whether neonatal injection of an ERα agonist (PPT), an ERß agonist (DPN) or an ERα antagonist (ICI) could induce delayed effects. Also, involvement of the kisspeptin neurons in the AVPV for induction of delayed effect by PPT and DPN was investigated. We observed that neonatal exposure to PPT, DPN and ICI induced the early onset of abnormal estrous cyclicity after sexual maturation, suggesting that the compounds capable of inducing delayed effects are not limited to ERα agonists. On the other hand, the data suggested the possibility that DPN and ICI functioned partially as ERα agonists in the neonatal brain. Regardless of the agents used, there is a possibility that dysfunction of kisspeptin neurons in the AVPV might contribute to induction of early onset anovulation.

Dose-dependent acceleration in the delayed effects of neonatal oral exposure to low-dose 17α-ethynylestradiol on reproductive functions in female Sprague-Dawley rats.

Xenoestrogen exposure during the critical period of sexual differentiation of the brain causes delayed effects on female reproduction. We investigated the internal dose of orally administered ethynylestradiol (EE) during the critical period and its delayed effects by administering 0 (vehicle control), 0.4, or 2 µg/kg EE to female Sprague-Dawley rats for 5 days from postnatal day (PND) 1. Determination of serum EE level 24 hr after the initial dosing and 6 and 24 hr after the final dosing of 2 µg/kg indicated that the administered EE entered the circulation and cleared after every administration. Although the treatment did not affect physical development, including growth, eyelid opening, and vaginal opening, the estrous cycle was arrested from postnatal week (PNW) 12 even with 0.4 µg/kg EE, with an inverse correlation between doses and arresting ages. Although ovarian morphology at PNW 22-23 indicated that the treatment caused long-term anovulation and cystic follicle formation, the number of primordial follicles at PNW 22-23 was similar among the groups. Because this number was lower than that at PND 10 in all groups, primordial follicles may have been consumed under long-term anovulation. The treatment also caused other abnormalities, including mammary gland hyperplasia, increase in pituitary and liver weights, and decrease in the uterine weight. Because the highest circulating EE level in the 2 µg/kg-treated neonates is considered to be comparable to the physiological range of estradiol-17ß, we concluded that a slight increase in the circulating estrogens during the neonatal period exerts irreversible delayed effects.

Early indicators of delayed adverse effects in female reproductive organs in rats receiving neonatal exposure to 17alpha-ethynylestradiol.

We previously reported that neonatal exposure to 17α-ethynylestradiol (EE) led to delayed adverse effects in which age-related anovulation after sexual maturation was accelerated. To identify early indicators of these adverse effects, female Wistar Hannover GALAS rats received a single EE injection (0, 0.02, 0.2, 2, 20, or 200 µg/kg) within 24 hr of birth. Histopathological changes in ovarian and uterine development were investigated from postnatal day (PND) 14 to 10 weeks of age. Immunohistochemical expression of estrogen receptor alpha (ERα) in the uterus, serum levels of sex-related hormones and gene expression in the hypothalamus were examined. Although neonatal exposure to EE did not affect body growth or ovarian development, serum FSH tended to decrease at doses ≥ 2 µg/kg, and Kiss1 mRNA level in the whole hypothalamus was significantly decreased in all EE-treated groups at PND14.The number of uterine glands at PND21 was suppressed at doses ≥ 20 µg/kg, and ERα expression in the uterine epithelium at estrus stage decreased in a dose-dependent manner at 10 weeks of age. These results demonstrated that the various identified changes that occurred before the appearance of delayed adverse effects could be candidate early indicators.

Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies.

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content). DESIGN: Pooled pharmacokinetic and pharmacodynamic analyses of phase II and III studies. SETTING: Randomized, open-label, multicenter studies. PATIENT(S): Nulliparous and parous women. INTERVENTION(S): Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 µg/24 h (total content 52 mg). MAIN OUTCOME MEASURE(S): Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects. RESULT(S): The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 µg/24 h after 24 days, declining progressively to 5 µg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 µg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 µg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups. CONCLUSION(S): Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in alower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 µg/24 h.

Delayed effects of neonatal exposure to 17alpha-ethynylestradiol on the estrous cycle and uterine carcinogenesis in Wistar Hannover GALAS rats.

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 µg/kg) within 24h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 µg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 µg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis.

Cadmium, lead, and mercury in relation to reproductive hormones and anovulation in premenopausal women.

BACKGROUND: Metals can interfere with hormonal functioning by binding at the receptor site and through indirect mechanisms; thus, they may be associated with hormonal changes in premenopausal women. OBJECTIVES: We examined the associations between cadmium, lead, and mercury, and anovulation and patterns of reproductive hormones [estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone] among 252 premenopausal women 18-44 years of age who were enrolled in the BioCycle Study in Buffalo, New York. METHODS: Women were followed for up to two menstrual cycles, with serum samples collected up to eight times per cycle. Metal concentrations were determined at baseline in whole blood by inductively coupled mass spectroscopy. Marginal structural models with stabilized inverse probability weights and nonlinear mixed models with harmonic terms were used to estimate the effects of cadmium, lead, and mercury on reproductive hormone levels during the menstrual cycle and anovulation. RESULTS: Geometric mean (interquartile range) cadmium, lead, and mercury levels were 0.29 (0.19-0.43) µg/L, 0.93 (0.68-1.20) µg/dL, and 1.03 (0.58-2.10) µg/L, respectively. We observed decreases in mean FSH with increasing cadmium [second vs. first tertile: -10.0%; 95% confidence interval (CI), -17.3% to -2.5%; third vs. first tertile: -8.3%; 95% CI, -16.0% to 0.1%] and increases in mean progesterone with increasing lead level (second vs. first tertile: 7.5%; 95% CI, 0.1-15.4%; third vs. first tertile: 6.8%; 95% CI, -0.8% to 14.9%). Metals were not significantly associated with anovulation. CONCLUSIONS: Our findings support the hypothesis that environmentally relevant levels of metals are associated with modest changes in reproductive hormone levels in healthy, premenopausal women.

Prevention of paclitaxel and cisplatin induced ovarian damage in rats by a gonadotropin-releasing hormone agonist.

OBJECTIVE: To evaluate the protective effect of GnRH agonist for the prevention of ovarian reserve during treatment with paclitaxel and cisplatin. DESIGN: Experimental study. SETTINGS: University-based research laboratory. ANIMAL(S): Seventy female Wistar-Albino rats. INTERVENTION(S): Each group consisted of 10 rats. Group 1 served as controls. Groups without GnRH agonist (groups 2, 3, and 4) were administered paclitaxel and cisplatin, respectively; the remaining groups (groups 5, 6, and 7) were given the same regimens with GnRH agonist. The GnRH agonist (leuprolide acetate; 2.5 microg/d subcutaneously for 5 weeks) was started four weeks before chemotherapy to achieve anovulation. Paclitaxel (7.5 mg/kg) and cisplatin (5 mg/kg) were administered intraperitoneally on the 28th day as a single dose. MAIN OUTCOME MEASURE(S): One week after the chemotherapy, the animals were euthanized and primordial, primary, secondary, and tertiary follicle counts were evaluated. RESULT(S): Primordial, primary, and tertiary follicle counts in group 5 (paclitaxel plus GnRH agonist) and tertiary follicles in groups 2 and 3 had not decreased, but there was a significant decrease in other treatment groups compared with controls (P < 0.05). Binary comparison between all groups demonstrated that the primordial follicle count in group 5 was comparable to those of the controls. CONCLUSION(S): Paclitaxel plus GnRH agonist treatment may be an appropriate option for patients deserving further fertility in the preservation of primordial follicles.

The estrogen-injected female mouse: new insight into the etiology of PCOS.

BACKGROUND: Female mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland. METHODS, RESULTS AND CONCLUSION: A putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS) was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 microg estrogen at 5-7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naïve mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We propose that in utero exposure to excessive levels of steroids such as estrogen has a long-term effect on the ability of the thymus to produce regulatory T cells. In female offspring this can lead to PCOS.

Effect of ethanol extract of whole plant of Trichosanthes cucumerina var. cucumerina L. on gonadotropins, ovarian follicular kinetics and estrous cycle for screening of antifertility activity in Albino Rats / Efectos del etanol extraído de la planta completa de Trichosanthes cucumerina var. cucumerina L. sobre gonadotropinas, cinética folicular ovárica y ciclo para screening de actividad antifertilidad en Ratas Albinas

Ethanol extract of whole plant of Trichosanthes cucumerina L. var. cucumerina was evaluated for antiovulatory activity in adult rats. The ethanol extract at the doses 200 and 400mg/kg body weight (orally) affected the normal estrous cycle showing a significant increase in estrus and metestrus phases and decrease in diestras and proestrus phases. The extract also significantly reduced the number of healthy follicles (Class I-Class VI) and corpora lutea and increased the number of regressing follicles (Stage IA, Stage IB, Stage IIA, and Stage IIB). The protein and glycogen content in the ovaries were significantly reduced in treated rats. The cholesterol level was significantly increased, whereas, the enzyme activities like 3b-HSD and 17b-HSD were significantly inhibited in the ovary of treated rats. Serum FSH and LH levels were significantly reduced in the treated groups were measured by RIA. In acute toxicity test, neither mortality nor change in the behavior or any other physiological activities in mice were observed in the treated groups. In chronic toxicity studies, no mortality was recorded and there were no significant differences in the body and organ weights were observed between controls and treated rats. Hematological analysis showed no significant differences in any of the parameters examined (RBC, WBC count and Hemoglobin estimation). These observations showed the antiovulatory activity of ethanol extract of whole plant of Trichosanthes cucumerina L. var. cucumerina in female albino rats.

El extracto de etanol de toda la planta de Trichosanthes cucumerina var. cucumerina (L.) se evaluó en cuanto a su actividad antiovulatoria en ratas adultas. El extracto de etanol en dosis de 200 y 400mg/kg de peso corporal (oral) afectó el ciclo normal estral, mostrando un aumentó significativo en las fases de estro y metaestro y la disminución de las fases de diestro y proestro. El extracto también redujo significativamente el número de folículos sanos (Clase I=Clase VI) y cuerpo lúteo y aumentó el número de folículos en regresión (etapa I, etapa IB, etapa II y etapa IIB). La proteína y el contenido de glucógeno en los ovarios se redujeron significativamente en las ratas tratadas. El nivel de colesterol aumentó significativamente, mientras que, actividad de las enzimas 3b-HSD y 17b-HSD se inhibió significativamente en el ovario de ratas tratadas. FSH sérico y los niveles de LH se redujeron significativamente en los grupos tratados y medidos por RÍA. En la prueba de toxicidad aguda, no hubo mortalidad ni cambio en el comportamiento fisiológico o de cualquier otra actividad en los grupos tratados de ratas. En estudios de toxicidad crónica, no se registró mortalidad y no hubo diferencias significativas en el peso corporal o el peso de los órganos entre los controles y las ratas tratadas. Los análisis hematológicos no mostraron diferencias significativas en ninguno de los parámetros examinados (eritrocitos, recuento de glóbulos blancos y estimación de hemoglobina). Estas observaciones mostraron la actividad antiovulatoria del extracto de etanol de toda la planta de Trichosanthes cucumerina var. cucumerina en ratas albinas hembras.

Interruption of the canine estrous cycle with a low and a high dose of the GnRH antagonist, acyline.

To test the efficacy and clinical safety of a low and high dose of the GnRH antagonist, acyline, on estrous cycle interruption and anovulation in female dogs, 20 proestrous (<3d) bitches were randomly assigned to one of the following pharmacological protocols (given sc): acyline 110 microg/kg (ACY-L; n=6); acyline 330 microg/kg (ACY-H; n=8); or placebo (PLACE, n=6). The animals were monitored (clinical and vaginal cytology examinations) daily for 60d. Blood samples for serum progesterone serum concentrations were collected 14d after treatment to determine if ovulation had occurred. Appearance of side effects and days to the onset of the first spontaneous estrous cycle after treatment were also recorded. In both ACY groups, but not the PLACE group, estrous cycles were interrupted after treatment (P<0.05). The interval from treatment to estrus interruption in ACY-L and ACY-H groups was 3.0+/-0.6 and 3.2+/-0.2d, respectively (LSM+/-SEM; P>0.05). In the PLACE bitches, physical, behavioral and cytological proestrus slowly progressed to estrus and diestrus. Ovulation was absent in all ACY, but not in PLACE bitches (P<0.05). None of the females manifested side effects related to the treatments (P>0.05). Spontaneous return to a normal estrous cycle during the study period occurred in all ACY (ACY-L 19.5+/-2.7d vs ACY-H 24.8+/-2.0d; P>0.05), but in none of the PLACE bitches (P<0.05). In conclusion, acyline efficiently, safely and reversibly interrupted an early phase of the estrous cycle in bitches by preventing ovulation.

Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine.

OBJECTIVE: To evaluate development of components of polycystic ovary syndrome (PCOS) and PCOS in women with epilepsy initiating valproate or lamotrigine therapy. METHODS: Female individuals with epilepsy and regular menstrual cycles were eligible for this prospective study. Participants were randomized to 12 months of valproate (n = 225) or lamotrigine (n = 222) therapy. Serum androgen levels were measured every 3 months. Urinary pregnanediol glucuronide levels were measured weekly for two 3-month periods. The primary end point was development of PCOS components (ie, hyperandrogenism or ovulatory dysfunction). A post hoc analysis was conducted in women more than 2 years after menarche (177 lamotrigine, (HA) 186 valproate) to exclude OD the confounding effect of puberty. RESULTS: More women in the valproate group than the lamotrigine group developed (OD) in the prospective (54% valproate, 38% lamotrigine; p = 0.010) and the post hoc (HA) analyses (36% valproate, 23% lamotrigine; p = 0.007). More women in the valproate group than the lamotrigine group developed PCOS (9 vs 2%; p = 0.007). Development of HA was more frequent with OD valproate than lamotrigine among those initiating treatment at age younger than 26 years (44% valproate, 23% lamotrigine; p = 0.002) but was similar if treatment was started at age 26 years or older (24% valproate, 22% lamotrigine). INTERPRETATION: Development of HA occurred more frequently with valproate than lamotrigine, especially if medication was started at age younger than 26 years.

A case of ovulatory cycle-dependent symptoms in woman with previous interferon beta therapy.

A woman with a menstrual cycle-dependent fever (more than 38 degrees C) and severe fatigue that disrupted her ability to work was referred to our hospital. Six years ago, the patient received interferon beta injections (6,000,000 IU day-1x48 days) for the treatment of hepatitis C virus. Although the treatment was successful against the virus, the symptomatic fever occurred monthly since the third year after receiving the treatment. The symptoms occurred a few days after ovulation in every menstrual cycle. When the ovarian function was suppressed by GnRH agonist (GnRHa), the symptoms disappeared. While in anovulation, the patient received estrogen followed by estrogen with progestogen, which resembles the sex hormone milieu of a normal menstrual cycle without the LH surge; this treatment did not induce the symptoms. When human CG (hCG) was injected on the beginning day of estrogen with progestogen following treatment with estrogen alone, the previous symptoms reappeared. However, the hCG injection without estrogen priming did not induce the symptoms. These studies indicated that the LH surge after estrogen priming induced the symptoms. Changes in serum inflammatory cytokine levels (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) were examined during the ovulatory cycle and the interleukin-1 levels during the treatment. There were no significant changes on these levels in the febrile period. The patient experienced normal menstrual cycles after finishing the five-month GnRHa treatment. Although her symptoms still occur, they are mild and do not require further medical treatment.

Neuroendocrine mechanisms of development of experimental hyperandrogen-induced anovulation.

An experimental model of hyperandrogen-induced anovulatory infertility (s.c. implantation of Silastic capsules containing testosterone into adult female rats) was used to study morphological, hormonal, and biochemical measures characterizing the state of the hypothalamo-hypophyseal-ovarian system. Impairments in functional androgen metabolism in the hypothalamus were seen, with decreases in the Luliberin sensitivity of the hypophysis, changes in the structure of estral cycles, and morphological changes in the ovaries; these findings are evidence for neuroendocrine disturbances in the control of ovulation. Flutamide, an experimental antiandrogen, led to partial normalization of the hormonal, biochemical, and morphological characteristics, as well as to recovery of fertility in females with anovulatory infertility.

The administration of cortisone to female B6A mice during their immune adaptive period causes anovulation and the formation of ovarian cysts.

PROBLEM: Female mice that are injected with estradiol-17beta (E2) and testosterone during the 7-day immune adaptive period are infertile at adulthood. To determine whether the resultant infertility can be caused by steroids other than estrogens/ androgens, this study examined the effect of injecting cortisone, alone, and in combination with E2 and testosterone, on reproductive function. METHOD OF STUDY: Neonatal (C57BL/6J x A/J)F1 B6A female mice were injected from 3 to 6 days of age with sesame oil:ethanol (9:1; v:v), alone, or containing 20 microgg cortisone acetate, 20 microg E2, or 20 microg testosterone. Two additional groups were given 20 microg cortisone acetate in combination with 20 microg E2 or 20 microg testosterone. At adulthood the animals were killed, the stage of vaginal estrus determined, the ovaries examined for the presence of corpora lutea and follicular cysts, and circulating levels of progesterone, E2, and testosterone were measured by radioimmunoassay (RIA). RESULTS: It was found that injections of cortisone seriously compromise reproductive development. For example, 11% of cortisone-injected animals had ovaries that lacked corpora lutea. In addition, 39% of cortisone-injected females had ovaries with follicular cysts. Cortisone-injected females also had low levels of circulating progesterone (18 ng/mL versus 30 ng/mL for the sesame oil-injected females). CONCLUSION: It is concluded that the deleterious effect of steroids on reproductive function, when administered during the immune adaptive period, is not restricted to estrogens and androgens. It is proposed that injections of cortisone alter T-lymphocyte subsets, which contributes to anovulation and the production of follicular cysts.

Mecanismos de acción de anticonceptivos orales: ¿cumplen los ACO de bajas dosis con el objetivo de inhibir la ovulación? / Mechanisms of action of oral contraceptives: they fulfill the ACO of low doses with the objective to inhibit the ovulation?

La inhibición de la ovulación es el principal mecanismo o efecto buscado en los casos de utilización terapéutica o contraceptiva de los anticonceptivos orales (ACO). Los mecanismos de acción secundarios postfertilización tienen reparos éticos para aquellas pacientes que consideran la concepción como el comienzo del desarrollo de la persona humana. Quisimos saber en qué medida se inhibe la ovulación mediante la administración de ACO de bajas dosis, como primera aproximación al problema ético planteado por los efectos postfertilización y para analizar la eficacia terapéutica de los anticonceptivos orales. Se revisa la literatura entre los años 1985 y 2001 y se seleccionan 3 trabajos comparables entre si de los cuales se desprenden los resultados. En un período de seguimiento de 3 meses, las mujeres que ingieren en forma adecuada ACO monofásicos combinados de bajas dosis que contienen 20 µg de etinilestradiol, presentan ovulación demostrada hormonal y ecográficamente en 2.35 por ciento a 8.3 por ciento de las mujeres. Existe una tendencia al aumento de la actividad ovárica y de los diámetros foliculares a medida que transcurre el tiempo de observación. Si el objetivo terapéutico es la anovulación, estas cifras permiten considerar los ACO como terapias adecuadas. Frente a la utilización individual de los ACO en contracepción, las cifras expuestas permitirán abordar en qué medida actúan los mecanismos secundarios y así considerar parámetros más objetivos en el análisis de los aspectos éticos a evaluar por el médico y la paciente

Oestrogenic effects of neonatal administration of raloxifene on hypothalamic-pituitary-gonadal axis in male and female rats.

Selective oestrogen receptor modulators constitute a family of drugs that are used increasingly in the management of oestrogen-associated pathology. Raloxifene is a selective oestrogen receptor modulator that is used to treat and prevent osteoporosis in post-menopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol concentrations have been widely analysed, but very few studies have investigated the possible actions of this drug on the central nervous system. The central nervous system of the newborn rat is very sensitive to oestrogen action. In this study a series of experiments was conducted to analyse the effects of different doses of raloxifene (50, 100, 250 or 500 microg per rat per day) administered to neonatal rats on days 1-5 of age. Female rats treated with raloxifene showed decreased gonadotrophin secretion, hyperprolactinaemia, advanced vaginal opening, decreased body weight, persistent presence of cornified epithelial cells in vaginal smears, anovulation, inhibition of positive feedback between oestradiol and LH, and infertility. Male rats showed delayed balanopreputial separation, reduced body weight and hyperprolactinaemia. All these changes resemble those obtained after neonatal administration of oestradiol benzoate, thus indicating, for the first time, that raloxifene exerts an oestrogenic action on the hypothalamic-pituitary structures controlling reproductive function in rats.

Effects of recombinant human FSH (rhFSH), urinary purified FSH (uFSH), and hMG on small preantral follicles and tertiary follicles from normal adult and androgen-sterilized female mice.

OBJECTIVE: To examine the stage-specific follicular response to recombinant human FSH (rhFSH), urinary FSH (uFSH), and hMG preparations. SETTING: In vitro follicle culture. INTERVENTION(S): Small preantral and tertiary follicles isolated from adult normal BDF-1 mice and androgen-sterilized mice were cultured with rhFSH, uFSH, and hMG for 4 days. MAIN OUTCOME MEASURE(S): Follicular diameter. Immunoreactive inhibin, E2, and progesterone concentrations in cultured medium. RESULT(S): The minimal effective dose of rhFSH, uFSH, and hMG for the follicular growth of small preantral follicles from normal mice was 10 mIU/mL, 1 mIU/mL, and 0.1 mIU/mL, respectively. For tertiary follicles from normal mice, the minimal effective dose of rhFSH, uFSH, and hMG was 10 mIU/mL, 10 mIU/mL, and 1 mIU/mL, respectively. The minimal effective dose of hMG for the follicular growth of small preantral follicles from androgen-sterilized mice was 0.01 mIU/mL, and that of rhFSH and uFSH on tertiary follicles from androgen-sterilized mice was 1 mIU/mL and 10 mIU/mL, respectively. No significant increase was found in the follicular diameter of the tertiary follicles from androgen-sterilized mice as a result of stimulation by hMG, but an hMG dose of >10 mIU/mL produced a significant increase in progesterone secretion. CONCLUSION(S): Human menopausal gonadotropin preparation acts detrimentally on follicles from androgen-sterilized mice by increasing the sensitivity of small preantral follicles to FSH and by inducing the luteinization of tertiary follicles.

New hyperprolactinemia and anovulation model in common marmoset (Callithrix jacchus) and effect of cabergoline.

We aimed to develop an anovulation model, using sulpiride-induced hyperprolactinemia in common marmosets. The serum prolactin level gradually increased during the twice-daily administration of sulpiride and reached a plateau after 4 days. Sulpiride produced as big a response at 10 mg kg(-1) as at 50 mg kg(-1). In this study, the length of the ovarian cycle was approximately 30 days in normal common marmosets. Serum progesterone and estradiol levels showed no consistent change during the first 2 months of treatment with sulpiride. When treatment with sulpiride had been continued for more than 2 months, serum progesterone and estradiol levels fell to within the range seen in the follicular phase of the normal cycle and absence of ovulation was recognized by laparoscopy. A single oral administration of cabergoline (at doses between 0.01 and 0.1 mg kg(-1)) dose dependently reduced the elevated serum prolactin level. Bromocriptine (at an oral dose of 10 mg kg(-1)) also reduced the serum prolactin level at 4 and 8 h after its administration. With bromocriptine, the prolactin level had recovered at 24 h, but with cabergoline at doses of 0.05 mg kg(-1) or more, it had still not recovered at 48 h. In anovulatory common marmosets, oral administration of cabergoline at a daily dose of 0.05 mg kg(-1) restored ovarian function and resulted in ovulation in 100% of the group (following a reduction in the serum prolactin level). Bromocriptine at a daily oral dose of 10 mg kg(-1) resulted in ovulation in 67% of the group, but this dose was about 200 times higher than the dose of cabergoline. We could produce an anovulatory model induced by sulpiride repeatedly administered over a long time period. It is suggested that, in this anovulatory model in common marmosets, cabergoline has a potent and long-lasting action as a dopamine D2 receptor agonist, and thus could be a useful drug for the treatment of galactorrhea and hyperprolactinemic amenorrhea and/or anovulation.

Birth of a foal after oocyte transfer to a nonovulating, hormone-treated recipient mare.

A nonovulating, hormone-treated mare was used successfully as an oocyte recipient. The mare's ovarian activity was suppressed using progesterone and estrogen treatment. This treatment was stopped, then estrogen was administered for 3 d prior to the transfer. An oocyte was recovered from the follicle of a donor mare and was transferred via flank laparotomy into the recipient's oviduct. The recipient mare was inseminated 7 h before transfer. The recipient was treated with intramuscular progesterone from the day after transfer until 47 d after transfer, and then with oral altrenogest until 150 d gestation. A normal colt was born at 321 d gestation, and was shown by DNA analysis to be the progeny of the donor mare. This is the first report of fertilization and embryo development to term after transfer of oocytes to a nonovulating mare, and, to our knowledge, the first of its kind in any domestic species.