Michel Ferin

The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides

Publisher Summary This chapter presents a study involving a rhesus monkey that demonstrates changes in the arcuate oscillator caused by ovarian steroids during the menstrual cycle. The chapter discusses the role of endogenous opioid peptides in the central modulation of gonadotropin secretion by ovarian steroids. The modulation of gonadotropin-releasing hormone (GnRH) and consequently luteinizing hormone (LH) pulsatile secretion by ovarian steroids involves to a certain degree an interaction with the hypothalamic opioid peptide network. β-endorphin secretion into the hypophyseal portal circulation—a reflection of hypothalamic β-endorphin secretory activity—fluctuates cyclically and in accordance with the endocrine milieu. The stimulatory action of naloxone on GnRH and LH release parallels that of endogenous opioid secretion. The sequential acceleration and deceleration of the GnRH oscillator during the menstrual cycle, brought about by cyclic β-endorphin variations, are important determinants of menstrual cyclicity as experimental disturbance of this sequence results in acyclicity for a prolonged period of time.

Predictors of ovulatory failure in women with epilepsy.

Women with epilepsy (WWE) are at increased risk for reproductive disorders. This study was designed to evaluate whether WWE are more likely to have anovulatory cycles and to assess the relative association of the epilepsy syndrome category and antiepileptic drugs (AEDs) to ovulatory dysfunction. Subjects included women aged 18 to 40 years not receiving hormones. Women without epilepsy (23 controls) and women with localization‐related epilepsy (LRE, n = 59) or idiopathic (primary) generalized epilepsy (IGE, n = 35) receiving either a cytochrome P450 enzyme (cP450) inducing AED (carbamazepine, phenytoin, and phenobarbital), a cP450 inhibiting AED (valproate), or an AED that does not alter cP450 enzymes (lamotrigine and gabapentin) in monotherapy for 6 months or more were followed for three menstrual cycles. A transvaginal ovarian ultrasound was obtained. Endocrine and metabolic variables were measured and luteinizing hormone sampled over 8 hours on days 2 to 5 of one cycle. Anovulatory cycles occurred in 10.9% of cycles in controls, 14.3% of cycles with LRE, and 27.1% of cycles with IGE. Of women using valproate currently or within the preceding 3 years, 38.1% had at least one anovulatory cycle in contrast with 10.7% of women not using valproate within the preceding 3 years. Predictors of ovulatory failure included IGE syndrome, use of valproate currently or within 3 years, high free testosterone, and fewer numbers of luteinizing hormone pulses, but not polycystic‐appearing ovaries. WWE are more likely to experience anovulatory menstrual cycles and the effects of epilepsy syndrome, and AED therapy may be additive. Women with IGE receiving valproate were at highest risk for anovulatory cycles, polycystic‐appearing ovaries, elevated body mass index, and hyperandrogynism. WWE with anovulatory cycles may have no other signs of reproductive dysfunction. Therefore, clinicians must be alert to this potential complication of epilepsy.

Circulating levels of adipose products and differences in fat distribution in the ovulatory and anovulatory phenotypes of polycystic ovary syndrome.

Central fat distribution is increased in anovulatory women with polycystic ovary syndrome (PCOS) compared with ovulatory PCOS and matched controls. Among secreted adipocytokines, this is reflected mainly in lower levels of adiponectin.

Onset of dementia is associated with age at menopause in women with Down's syndrome.

Women with Downs syndrome experience early onset of both menopause and Alzheimers disease. This timing provides an opportunity to examine the influence of endogenous estrogen deficiency, indicated by age at menopause, on risk of Alzheimers disease. A community‐based sample of 163 postmenopausal women with Downs syndrome, 40 to 60 years of age, was ascertained through the New York State Developmental Disability service system. Information from cognitive assessments, medical record review, neurological evaluation, and caregiver interviews was used to establish ages for onset of menopause and dementia. We used survival and multivariate regression analyses to determine the relation of age at menopause to age at onset of Alzheimers disease, adjusting for age, level of mental retardation, body mass index, and history of hypothyroidism or depression. Women with early onset of menopause (46 years or younger) had earlier onset and increased risk of Alzheimers disease (AD) compared with women with onset of menopause after 46 years (rate ratio, 2.7; 95% confidence interval [CI], 1.2–5.9). Demented women had higher mean serum sex hormone binding globulin levels than nondemented women (86.4 vs 56.6 nmol/L, p = 0.02), but similar levels of total estradiol, suggesting that bioavailable estradiol, rather than total estradiol, is associated with dementia. Our findings support the hypothesis that reductions in estrogens after menopause contribute to the cascade of pathological processes leading to AD.

Gonadotropin-releasing hormone neurons in the rhesus macaque are not immunoreactive for the estrogen receptor.

The issue of whether gonadotropin-releasing hormone (GnRH) neurons in the primate contain the estrogen receptor was examined by immunocytochemistry using prepubertal and adult (intact and ovariectomized) female rhesus macaques. No GnRH neurons were found to contain nuclei that were immunoreactive for the estrogen receptor. These results confirm in primates what has been reported in other species and leave open the question of how the effects of gonadal steroids on GnRH neurons are mediated.

Food intake and the menstrual cycle in rhesus monkeys

Abstract Fourteen adult female rhesus monkeys were observed for 1 complete menstrual cycle, five of them for 2 cycles. Changes in LH, FSH, estrogens and progesterone were monitored daily. Mean hormonal concentrations followed patterns previously demonstrated in primates, with a typical late follicular phase estrogen peak preceeding the ovulatory LH and FSH surges. Maximal sexual skin color intensity paralleled the midcycle increase in estrogens. The results indicate that food intake fluctuated with changes in hormonal secretion. A significant decrease in the amount of food consumed correlated well with the midcycle estrogen and gonadotropin surges. The amount of food consumed during the luteal phase was greater than that of the early follicular phase.

Effects of Substance P on Anterior Pituitary Secretion in the Female Rhesus Monkey

The effects of substance P on anterior pituitary secretion were studied in 3 female rhesus monkeys. In nine experiments, 100 microgram substance P was injected intraventricularly, and the results were compared to those obtained following intraventricular injection of the control vehicle. In 7 out of 9 experiments, substance P induced a significant increase in prolactin secretion within 5 min. Peak levels at 10 min were approximately 15-20 times those of the baseline control. Substance P also induced a slight but significant decrease in GH secretion 20 min following injection, but at other times GH levels were not significantly changed. LH and FSH as well as cortisol concentrations remained unaltered. In 2 monkeys a decrease in systolic pressure of 40-70 mm Hg within 10-60 sec and lasting 180-300 sec was observed following the administration of substance P but not the control vehicle. The results indicate that substance P, which in the monkey has been shown to be associated with hypothalamic regions implicated in the control of anterior pituitary secretion, can alter prolactin and GH release.

Endogenous opioid peptides and the control of the menstrual cycle

This paper reviews recent experimental evidence which supports a role for endogenous opioid peptides in the control of gonadotropin function. In primates, cell bodies containing endogenous opioid peptides have been located within the hypothalamus in areas rich in gonadotropin-releasing hormone (GnRH) and dopamine. The release of beta-endorphin from these hypothalamic neurons is influenced by gonadal steroids, maximal release being observed when both estradiol and progesterone are present. beta-Endorphin has been shown to decrease LH secretion, and naloxone, an opiate antagonist, reverses this action. The LH-releasing activity of naloxone parallels variations in hypothalamic beta-endorphin secretory activity, so that maximal effects are seen during the luteal phase of the cycle. Present evidence indicates that opiates exert their effect on LH via a hypothalamic site. It is concluded that increased opioid inhibition of the GnRH-LH axis is responsible for the decline in LH pulse frequency during the luteal phase. The studies provide evidence for a chemical basis rationalizing relationships between reproductive function and stress, and have further implication on other forms of amenorrhea.

Section of the pituitary stalk in the rhesus monkey. I. Endocrine studies.

The effects of pituitary stalk section on anterior pituitary secretion were studied in 20 female rhesus monkeys. Vascular connections between the hypothalamus and the pituitary gland were permanently interrupted in all but 4 animals. Prolactin levels rose rapidly and remained significantly elevated in all effectively stalk-sectioned animals for as long as the observation period (up to 3 years). Only smaller and transient elevations of prolactin were seen in the animals in which revascularization of the anterior pituitary gland had occurred. Growth hormone and cortisol were significantly decreased after stalk section, and were not released by insulin. Radioimmunoassayable luteinizing hormone (LH) levels decreased following surgery and, by bioassay, LH became undetectable within 5 weeks after stalk section, indicating that gonadotropin-releasing hormone is essential for the viability of the gonadotrope. The results indicate that plasma prolactin concentrations can be used to monitor completeness of pituitary gland isolation from direct hypothalamic influence. Stalk-sectioned monkeys provide good models to study direct pituitary effects of various hormones or drugs.

Pulsatile administration of gonadotropin-releasing hormone for induction of ovulation

Chronic pulsatile administration of gonadotropin-releasing hormone (GnRH) was used to induce ovulation in 12 women with various ovulatory disorders. In the first group of eight patients with normal to low baseline levels of gonadotropin, seven responded favorably to the treatment. Follicular maturation was observed in 57% of the treated cycles, and normal ovulatory cycles were induced in 24% of the patients. Two patients became pregnant. The intravenous route of administration was more effective than the subcutaneous one, possibly in response to the GnRH profile after each pulse. (The amplitude of GnRH peaks after an intravenous pulse was four times that seen after a subcutaneous one.) In contrast, follicular maturation and ovulation could not be induced in four women of a second group of patients with normal baseline levels of follicle-stimulating hormone but with high and frequent pulses of luteinizing hormone. The conclusion reached was that pulsatile administration of GnRH can be a new therapeutic tool in the treatment of ovulatory disorders in women who have an insufficient endogenous release of GnRH.