A comparative randomized trial on the impact of two low-dose oral contraceptives on ovarian activity, cervical permeability, and endometrial receptivity.

In a double-blind randomized study, the suppression of ovarian activity and anti-conceptive effects on the cervix and endometrium were assessed during administration of two low-dose monophasic oral contraceptives (20 micrograms ethinyl estradiol [EE], 500 micrograms norethisterone--Eve 20 [Grünenthal, Aachen, Germany]; 20 micrograms EE, 150 micrograms desogestrel --Lovelle [Organon, Munich, Germany]). One hundred eighteen healthy women (ages: 18-35 years) were studied in 10 investigation centers during medication with either Eve 20 (n = 59) or Lovelle (n = 59). During three treatment cycles, ovarian activity was evaluated by sonographic determination of follicle-like structures (FLS) and by simultaneous assessment of serum endocrine profiles (gonadotropins LH and FSH, ovarian steroids estradiol [E2] and progesterone [P]). While on either treatment, no ovarian activity (as judged by no FLS and/or reduced sex steroid levels) was found in 90.8% (Eve 20) and 97.2% (Lovelle) of all investigated cycles. Follicular activity or cyst formation were detected in 18 of 173 cycles (Eve 20) and in 5 of 175 cycles (Lovelle), respectively. Gonadotropin levels were suppressed (LH < 6 IU/L, FSH < 8 IU/L) in most treatment cycles (Eve 20 76.6% vs. Lovelle: 84.8%). Serum E2 concentrations exceeding 0.1 nmol/L indicated residual follicular activity in 19.3% (Eve 20) versus 12.2% (Lovelle) of all cycles. An estimated by serum P levels over 5 nmol/L, ovulation had presumably occurred in 4.1% (Eve 20) versus 2.9% (Lovelle) of treatment cycles. However, when the sonographical and endocrinological data were combined, no ovulation was documented in any pill cycle. The quality and quantity of the cervical mucus was found to be minimal in the majority of women. Moreover, the endometrial layer was determined to be low by ultrasound during most pill cycles, indicating equally strong suppressive effects on endometrial receptivity by the two contraceptives. These observations suggest that ovarian activity is suppressed in the majority of cycles during use of low-dose contraceptives. This effect may mainly be medicated by pronounced suppression of serum gonadotropin levels. Strong anti-conceptive effects of these formulations on both cervical permeability and endometrial receptivity are additional factors ensuring the contraceptive efficacy of these formulations.

PIP: The impact of two low-dose monophasic oral contraceptives (OCs) on suppression of ovarian activity, cervical permeability, and endometrial receptivity was investigated in a randomized double-blind study involving 118 healthy women 18-35 years of age recruited from 10 study centers in Germany. 59 women received Eve (20 mcg of ethinyl estradiol and 500 mcg of norethisterone) and 59 were given Lovelle (20 mcg of ethinyl estradiol and 150 mcg of desogestrel) for a total of 3 cycles. No ovarian activity, as assessed by sonographic determinations of follicle-like structures and serum endocrine profiles, was detected in 90.8% of cycles of Eve users and 97.2% of cycles in the Lovelle group. Follicular activity or cyst formation was found in 18 of 173 cycles of Eve users and 5 of 175 cycles of Lovelle users. Gonadotropin levels were suppressed (luteinizing hormone under 6 IU/L and follicle-stimulating hormone less than 8 IU/L) in 76.6% of treatment cycles in the Eve group and 84.8% of cycles in the Lovelle group. Serum estradiol concentrations exceeding 0.1 nmol/L, indicative of follicular activity, were recorded in 19.3% of cycles of Eve users and 12.2% of cycles in the Lovelle group. Although serum progesterone levels were over 5 nmol/L in 4.1% of cycles in the Eve group and 2.9% of those in the Lovelle group, consolidation of sonographic and endocrinologic data failed to document ovulation in any treatment cycles. The quantity and quality of cervical mucus was minimal in most women in both groups. Finally, the endometrial layer was determined to be low by ultrasonography during most pill cycles, confirming the OCs' equally strong suppressive effects on endometrial receptivity.

[Ovarian activity, cycle behavior and tolerance of low dosage oral contraceptives: a comparative study]. / Ovarielle Aktivität, Zyklusverhalten und Verträglichkeit bei niedrigdosierten oralen Kontrazeptiva: Eine Vergleichsstudie.

In a double-blind randomized study, the suppression of ovarian activity, the effects on the cervix and endometrium, menstrual bleeding patterns and overall tolerance were assessed during administration of two low-dose oral contraceptives (20 micrograms ethinylestradiol EE, 500 micrograms norethisterone--Eve 20, Grünenthal, Aachen; 20 micrograms EE, 150 micrograms Desogestrel--Lovelle, Organon, Munich), 118 healthy women (ages: 18 to 35 years) with comparable bioprofiles (height, weight, menstrual cycle patterns) were studied in 10 investigation centres during medication with either Eve 20 (n = 59) or Lovelle (n = 59). During 3 treatment cycles, ovarian activity was evaluated by sonographic determination of follicular size and by simultaneous assessment of serum endocrine profiles (gonadotropins LH and FSH, ovarian steroids estradiol [E2] and progesterone [P]). Treatment cycles 4 to 6 served to evaluate the patterns of menstrual bleeding and the overall subjective tolerance on each contraceptive. While on the preparations, no ovarian activity (as judged by a lack of follicular growth and suppressed sex steroid levels) was found in over 90% of all investigated cycles. Follicular activity and/or cyst formation were detected in 18 of 173 cycles (Eve 20) and in 5 of 175 cycles (Lovelle) respectively. Gonadotropin levels were suppressed (LH < 6 IU/l, FSH < 8 IU/l) in most treatment cycles (Eve 20: 76.6% vs. Lovelle: 84.8%). Serum E2 concentrations exceeding 0.1 nmol/l indicated residual follicular activity in 19.3% (Eve 20) vs. 12.2% (Lovelle) of all cycles. As estimated by serum P levels over 5 nmol/l, ovulation had presumably occurred in 4.1% (Eve 20) vs. 2.9% (Lovelle) of treatments respectively. However, when the sonographic and endocrinological data were combined, no ovulation was documented in any treatment cycle. In addition, the quality of the cervical mucus was minimal and a low endometrial thickness was found in the majority of women, indicating strong progestogen effects of both contraceptives. Menstrual irregularities (intermenstrual spotting, break-through bleeding) occurred initially on each preparation, but were mostly resolved when the pills were continued. The acceptance of each investigated drug was rated as very good or good by most subjects. These observations allow us to conclude that the rate of ovarian suppression with inhibition of follicular activity is high under low-dose oral contraceptives. The different progestogens as components of these contraceptive pills display equally good anti-conceptive effects on both the cervix and the endometrium. Furthermore, the rate of irregular menstrual bleeding is acceptable for these low-dose contraceptives. The high acceptance of each preparation suggests that such agents will have a high rate of acceptability in clinical use.

Galanin gene expression in hypothalamic GnRH-containing neurons of the rat: a model for autocrine regulation.

Increasing experimental evidence has accumulated to suggest that galanin may be one of the essential regulators in the reproductive system of the rat. Galanin is a polypeptide which has been found in hypothalamic neurons, where it is colocalized with GnRH. GnRH-containing cells begin to express detectable levels of galanin mRNA at the onset of puberty, and this process is dependent on the presence of the gonads. This indicates that the induction of galanin expression in GnRH neurons is an important requirement for the maturation of the reproductive axis. The pattern of co-expression of galanin and GnRH in hypothalamic neurons is sexually dimorphic, with much greater galanin mRNA content in the GnRH neurons of females compared to males. The role of galanin may therefore be important in reproductive processes unique to the female, such as the LH surge and ovulation. During the estrous cycle, galanin mRNA levels are enhanced in GnRH neurons at the time of the LH surge. This suggests a tight coupling of galanin biosynthesis and release to the activity state of the GnRH neurons. Expression of the galanin gene in GnRH neurons is regulated by ovarian sex steroids: estradiol appears to support the basal expression of galanin mRNA in GnRH neurons. In addition, estradiol is capable of dramatically increasing galanin gene expression, either when administered alone or in conjunction with progesterone. Nevertheless, neuronal activation with concomitant induction of galanin gene expression requires transsynaptic signals by afferent inputs impinging on the GnRH cells. Galanin may serve as a critical autocrine regulator for the activity of GnRH cells, in that it may be co-released with GnRH and act presynaptically on the GnRH neuron, helping to shape GnRH release into distinct pulses. Collectively, these observations indicate that galanin gene expression in GnRH neurons may represent a pivotal signal for the activation of the neuroendocrine reproductive axis.

Gonadotropin secretion during aging in women: review article.

Biological aging during the postmenopause markedly affects the neuroendocrine control of gonadotropin release. The determination of the age-related dynamics on gonadotropin secretion in postmenopausal women have proven to be a valid approach for delineating changes as a function of progressive age. As a result, major functional derangements, primarily at a hypothalamic rather than a pituitary site, have been determined as concomitants of aging in women. Furthermore, aging may impair the negative feedback sensitivity to ovarian sex steroids, and interfere with the central neurotransmitter activity governing gonadotropin secretion. The data reviewed on gonadotropin secretion in postmenopausal women support the view that the age-related processes are related to a hypothalamic rather than to a pituitary hypofunction.

Serotoninergic control of gonadotrophin and prolactin secretion in women.

OBJECTIVE: Due to conflicting observations from previous investigations, the role of serotonin (5-HT) in the regulation of the human menstrual cycle has not been clearly established. We have therefore investigated the possible participation of 5-HR in the control of gonadotrophin and PRL secretion in women, using the potent 5-HT3 receptor antagonist ondansetron as a pharmacological probe. DESIGN: Serum profiles of LH, FSH and PRL were obtained in 9 normally cycling women during a control and a treatment cycle, during which ondansetron (8 mg orally) was administered daily. On day 10 of both cycles, the serum pulsatility of LH, FSH and PRL was assessed by frequent blood sampling (at 10-minute intervals for 10 hours). Pituitary responsiveness was tested by administration of a GnRH bolus (25 micrograms i.v. after 8 hours). MEASUREMENTS: LH, FSH and PRL were serially determined in all blood samples by immunofluorescence assays. The resulting hormone data arrays were searched for significant fluctuations by the Cluster pulse algorithm. RESULTS: Compared with control cycles, the temporal organization and the endocrine characteristics of the treatment cycles remained virtually unaltered. Serotonin antagonism did not noticeably affect the LH pulse attributes (frequencies, interpulse intervals, amplitudes). Although FSH amplitudes declined markedly (P < 0.05), the remaining pulse attributes were unchanged. A clear increase (P < 0.05) in the PRL pulse frequency was noted, while PRL pulse amplitudes tended to increase (P = 0.1). Gonadotrophin and PRL release in response to GnRH administration was unaltered by ondansetron treatment. CONCLUSIONS: Serotoninergic blockade by a selective 5-HT3 receptor antagonist failed to modify pulsatile LH secretion, but induced distinct changes in episodic FSH and PRL secretion. Since the pituitary gonadotrophin and PRL responsiveness remained unaltered during 5-HT3 receptor blockade, the observed alterations in the FSH and PRL secretion presumably relate to altered hypothalamic regulation of these pituitary hormones. Thus, the central regulation of pulsatile FSH and PRL release in women appears to involve 5-HT3 receptor-mediated processes.

Activation-dependent regulation of galanin gene expression in gonadotropin-releasing hormone neurons in the female rat.

In rats, galanin is colocalized in GnRH neurons, and galanin mRNA in GnRH neurons is increased coincidentally with the preovulatory gonadotropin surge. Whether the induction of galanin mRNA in GnRH neurons at proestrus reflects the action of sex steroids is unknown. We tested this hypothesis by challenging ovariectomized rats (n = 7) with estrogen and progesterone (E/P) to induce a LH surge and measuring galanin mRNA in GnRH neurons to determine whether there was an associated induction of galanin message in these cells. We used single and double label in situ hybridization and image analysis to compare among groups the levels of both galanin mRNA and GnRH mRNA in GnRH neurons. We found that steroid-primed animals showed an approximately 400% induction of galanin mRNA signal in GnRH neurons over that in vehicle-treated animals. Second, we hypothesized that steroid-dependent events which induce the expression of galanin mRNA in GnRH neurons depend on transsynaptic input to GnRH neurons. We tested this hypothesis by examining the effect of a pharmacological blockade of the steroid-induced activation of GnRH neurons on levels of galanin mRNA in these cells. We killed groups of ovariectomized adult female rats at the peak of a E/P-primed LH surge (n = 7) and after steroid priming followed by blockade of the LH surge with either the general anesthetic pentobarbital (n = 7) or the specific alpha-adrenergic receptor blocker phenoxybenzamine (n = 7). When we examined signal levels representing galanin mRNA content in GnRH neurons, we observed a 4-fold increase in signal for galanin mRNA in the GnRH neurons of steroid-primed (E/P surge) animals compared with that in oil-treated controls (P < 0.0004). This increase in galanin mRNA was prevented when the LH surge was blocked by treatment with either pentobarbital or phenoxybenzamine (P < 0.03 and P < 0.0001 vs. E/P surge controls, respectively). Cellular levels of GnRH mRNA were not different among control, E/P, and E/P plus pentobarbital groups (P > 0.2). These observations suggest that an increase in galanin mRNA levels in GnRH neurons is tightly coupled to the occurrence of a LH surge. By inference, induction of galanin mRNA in GnRH neurons reflects their activation, possibly via afferent neurons that transduce the steroid signal to GnRH neurons.

The distribution of hypothalamic nitric oxide synthase mRNA in relation to gonadotrophin-releasing hormone neurons.

Using probes for rat neural nitric oxide synthase (NOS) mRNA and GnRH mRNA, we performed in situ hybridization to survey NOS mRNA distribution within the hypothalamus of the male and female rat and sought evidence for its expression in GnRH neurons. The NOS cRNA probe was radiolabelled with 35S, and a digoxigenin-labeled rat GnRH cRNA probe was used for double-label studies. NOS mRNA was localized in discrete hypothalamic areas, in grain clusters suggestive of individual neurons. NOS mRNA-positive cells were located mainly in the supraoptic and paraventricular nucleus, particularly overlying the magnocellular division. Rostrally, cells expressing NOS mRNA were especially prominent in the diagonal band of Broca, in a distribution very similar to GnRH neurons. Nevertheless, only one of 370 cells labeled for GnRH mRNA appeared to be positive for NOS mRNA. We conclude that NOS mRNA is located prominently in regions where CRH, AVP and oxytocin cells are located. NOS mRNA-positive cells are located in close proximity to GnRH neurons, but rarely do such neurons express NOS mRNA.

Acceleration of luteinizing hormone pulse frequency in functional hypothalamic amenorrhea by dopaminergic blockade.

A constellation of neuroendocrine secretory aberrations, including reduced LH pulse frequency and PRL concentrations, has been documented in women with functional hypothalamic amenorrhea (FHA). As pituitary function was preserved, these aberrations were attributed to an alteration in hypothalamic neuromodulation. To investigate the participation of the dopaminergic system in the genesis of the reduced LH pulse frequency and suppressed PRL levels in FHA, we studied six women with FHA and six cyclic women in the early follicular phase by obtaining blood samples at 15-min intervals for 48 h during sequential 24-h infusions of saline and a dopamine receptor blocker, metoclopramide (MCP). A hypothalamic vs. pituitary site of action was inferred from the pulsatility characteristics. MCP consistently elicited an increase in the LH pulse frequency in the women with FHA [7.3 +/- 1.2 (+/- SE) to 10.5 +/- 1.3 pulses/24 h; P less than 0.005]. In contrast, the eumenorrheic women did not show a significant change in LH pulse frequency in response to MCP (15.2 +/- 1.0 to 14.3 +/- 0.9 pulses/24 h). While the PRL concentrations were significantly lower in the FHA group during the infusion of saline (P less than 0.001) and MCP (P less than 0.005), the relative increases in PRL during MCP were similar in both groups. The acceleration of LH pulse frequency by blockade of dopamine receptors implies that there is increased hypothalamic dopaminergic inhibition of GnRH pulse frequency in women with FHA.