Alcoholic women may have several disorders of menstrual cycle function, including amenorrhea, luteal phase dysfunction, anovulation, and, in some instances, early menopause. Most available information about alcohol effects on reproductive function has been derived from clinical studies of alcoholic women during sobriety. Evidence of menstrual cycle dysfunctions is based on clinical history information and endocrine evaluations at the time of admission for treatment of alcohol-related medical problems. Disorders such as liver disease and pancreatitis, often complicated by malnutrition or other infectious disorders, are observed clinically. Since these medical disorders can also contribute to reproductive system dysfunctions, it is not possible to attribute abnormal menstrual cycles to alcohol alone. However, recent replications of these reproductive disorders in animal models under controlled conditions and in healthy social drinkers increase confidence in the validity of the clinical observations.
Amenorrhea refers to the complete cessation of menses. Amenorrhea has been consistently reported by alcoholic women, and this condition may persist for several months or for many years. Data from two clinical case reports suggest that alcoholic women, amenorrheic for 3 and 4 years, can resume menses after abstinence from alcohol, but recovery menstrual cycles were not evaluated for normalcy. In one woman, menstrual cycles continued during a 3-year follow-up, and in the other women, persistent amenorrhea (2 years) occurred after 7 months of menses despite continued sobriety. To date, there have been no systematic endocrine studies of resumption of normal menses in recovered alcoholic women. However, it is not unreasonable to assume that remission of alcoholism may be associated with recovery of reproductive function.
A number of factors may contribute to the development of amenorrhea in nonalcoholic women. Weight reduction, and/or jogging or professional athletic pursuits in women of normal weight, may be accompanied by amenorrhea in otherwise healthy normal women. Clinical disorders involving severe weight loss, such as anorexia nervosa, are also associated with persistent amenorrhea. Since alcoholic women are often malnourished, it is likely that this factor combines with alcohol to increase risk for cessation of menstruation. However, obesity may also disrupt the menstrual cycle and lead to amenorrhea.
The largest number of alcoholic women studied to date were citizens of Yugoslavia. Data were obtained from outpatients at a gynecological-obstetrical hospital in Belgrade. Of a total of 321 chronic alcoholic women, 21, or 10.6%, of the sample reported amenorrhea. Sixty percent of that sample were under 35 years old, and 94% of the sample reported a history of alcoholism of 5-15 years’ duration. Specific patterns of reproductive dysfunction were not described in relation to age or drinking history, and no information about clinical status, liver, or pancreatic disease was reported.
Nine amenorrheic alcoholic women aged 24-40 were studied in Finland. All women were admitted for treatment of liver diseases; seven women had cirrhosis and two had alcoholic fatty liver. All women were drinking heavily just before hospital admission and reported a 4- to 15-year history of alcoholism. Basal levels of pituitary and gonadal hormones were measured during the first 5 days after admission to the hospital and compared with nine pre-menopausal and ten postmenopausal normal controls. Plasma estrogen and progesterone levels were significantly lower in the amenorrheic alcoholic women than normal controls of reproductive age. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were somewhat higher and prolactin was somewhat lower in the amenorrheic alcoholic women than in normal controls, but these differences were not significant.
Similar findings were reported in 13 amenorrheic alcoholic women studied in Paris. Seven alcoholic amenorrheic women had cirrhosis of the liver and six had chronic pancreatitis. The average age of these women was 42-46 years, and all had been chronic alcoholics for at least 10 years. Five amenorrheic alcoholic women had a similar endocrine profile (low estrogens, elevated gonadotropins) and were diagnosed as having hypothalamic amenorrhea. However, eight alcoholic amenorrheic women had normal estrogen levels and a positive estradiol response to stimulation with clomiphene or human chorionic gonadotropin (hCG).
Synthetic luteinizing-hormone-releasing-hormone (LHRH) (100 µg) was used to evaluate pituitary function in both clinical samples of amenorrheic alcoholic women. There were no significant differences in the magnitude of the LH and FSH response to LHRH stimulation in amenorrheic alcoholic women and normal controls. The normal gonadotropin response to synthetic LHRH stimulation led both investigators to conclude that the pituitary was not the primary site of alcohol’s disruptive actions in amenorrheic alcoholic women.
Although estrogen levels were low in each group of amenorrheic alcoholic women, gonadotropin levels were not elevated to the extent seen in post-menopausal women following decline of ovarian steroid modulation of gonadotropin secretion. These observations led Valimaki and co-workers to conclude that alcohol-induced disruptions of gonadotropin secretion leading to amenorrhea probably reflected a hypothalamic rather than a pituitary dysfunction. Moreover, since women were of normal weight, malnutrition and weight loss probably did not contribute to amenorrhea. The possible role of impaired liver function and associated elevations in estrone were discussed, but data obtained were considered insufficient for definitive conclusions.
The possibility that the estrogen deficiency observed in some amenorrheic alcoholic women might reflect impairment of ovarian function as well as disruption of gonadotropin secretory activity was considered. Valimaki and co-workers concluded that data obtained did not rule out an alcohol- or liver-disease-related ovarian dysfunction, whereas Hugues and co-workers considered a primary alcohol-induced ovarian dysfunction unlikely because of the ovarian responsivity to provocative tests. However, there are reports that ovaries of alcoholic women and alcohol-dependent female rhesus monkeys and rats are abnormally small as well as devoid of corpus lutea. Moskovic attributed amenorrhea in alcoholic women to ovarian dysfunction but did not discuss alternative hypotheses.
Considerably more research will be required to determine the primary site or site(s) of alcohol’s toxic actions on the hypothalamic-pituitary-gonadal axis. It is likely that persistent amenorrhea reflects a disruption of the balance between ovarian steroid regulation by the hypothalamus and pituitary and suppression of gonadotropin stimulation by ovarian steroid feedback. Several disorders of reproductive function in women, including hypothalamic amenorrhea, have been shown to be associated with abnormal patterns of LH secretory activity (). A low frequency of LH pulses was most commonly associated with secondary hypothalamic amenorrhea. Treatment with pulsatile administration of synthetic LHRH restored normal ovulatory menstrual cycles in women with hypothalamic amenorrhea. These data suggest that amenorrhea in alcoholic women reflects aberrant gonadotropin secretory patterns; however, no systematic pulse frequency analysis of gonadotropin activity has been reported to date.
The importance of pulsatile gonadotropin secretion for normal reproductive function was discovered through the systematic studies of Knobil and co-workers (). Lesions of the arcuate nucleus and median eminence in the hypothalamus of ovariectomized rhesus monkeys disrupted hypothalamic release of endogenous LHRH and abolished LH and FSH secretory activity. Pulsatile administration of synthetic LHRH restored LH and FSH secretory patterns, whereas continuous administration of LHRH did not. This fundamental discovery has changed contemporary understanding of the neuroendocrine regulation of the menstrual cycle and opened many new opportunities for analysis and treatment of reproductive disorders.
Anovulation and Luteal Phase Dysfunction
Among alcoholic women who continue to menstruate, two other disorders of reproductive function, anovulation and luteal phase dysfunction, are reported. Anovulation refers to a failure to ovulate and is diagnosed by the absence of a midcycle LH, FSH, and estradiol surge and by low progesterone levels during the luteal phase of the menstrual cycle. Luteal phase dysfunction is defined either as a short luteal phase defect (8 days or less from ovulation to menses) or an inadequate luteal phase when progesterone levels are abnormally low but the interval from ovulation to menstruation is normal.
Only one endocrine evaluation of alcoholic women with anovulation or luteal phase inadequacy has been reported. Each of the four anovulatory women had severe oligomenorrhea, or scanty menses, and also had intermittent amenorrhea. The women classified as anovulatory had almost undetectable plasma progesterone concentrations during the 40th and 50th days of their cycles, but androgen levels were normal. Administration of clomiphene induced a significant rise in LH and estradiol followed by withdrawal bleeding. Three women had pancreatitis and one had cirrhosis.
The six women classified as having luteal phase inadequacy had menstrual cycles of normal length and mild oligomenorrhea. These women had normal gonadotropin and estradiol levels during the late foUicular phase but low plasma progesterone levels during the luteal phase. The response to synthetic LHRH stimulation was adequate. Three of six women responded to hCG stimulation during the luteal phase with an increased level of progesterone exceeding 10 ng/ml. Two women with luteal phase inadequacy had cirrhosis and four had pancreatitis.
The mechanisms accounting for anovulation and luteal phase abnormalities are poorly understood. However, there is increasing evidence that disruption of the hormonal milieu essential for normal folliculogenesis during the follicular phase may result in anovulation and/or luteal phase dysfunction. Suppression of FSH and a low FSH/LH ratio during the early follicular phase can compromise development of the preovulatory follicle. Extensive studies by Hodgen and co-workers on folliculogenesis in the primate ovarian cycle suggest that recruitment of the dominant follicle occurs during menstrual cycle days 1-4; a single follicle is selected during days 5-7; and that follicle achieves dominance during cycle days 8-12. The determinants of the selection and dominance of a single ovulatory follicle are unclear, but Goodman and Hodgen postulate that nonsteroidal ovarian pep-tides, inhibins, critically affect this process through titration of FSH levels during folliculogenesis.
There is considerable evidence that suppression of FSH during the early follicular phase by porcine follicular fluid (pFF) leads to follicle atresia or to abnormal or delayed follicle development. Moreover, if FSH is suppressed by pFF throughout the follicular phase (cycle days 1-14.5), anovulation or a prolonged follicular phase and luteal phase abnormalities may occur. Reversal of pFF-induced FSH suppression by administration of FSH (human menopausal gonadotropin; FSH:LH ratio of 3:1) during cycle days 1-3 results in normal ovulation and normal luteal phase progesterone.
Porcine follicular fluid is derived from the granulosa cell of the porcine ovarian follicle. Tissue culture studies indicate that inhibin is secreted by the granulosa cells, but not by the thecal tissue or the stroma. Unequivocal demonstration of the physiological significance of ovarian inhibin has occurred recently (). Inhibin was first isolated and synthesized in 1984, and a reliable radioimmunoassay for measurement of inhibin in human plasma was reported in 1986. Recent studies of women given exogenous FSH to induce ovarian hyperstimulation for in vitro fertilization showed that inhibin levels increased as the number of follicles and plasma estradiol levels increased. McLachlan and co-workers concluded that increased production of ovarian inhibin following FSH stimulation is consistent with its proposed role in FSH regulation.
If alcohol directly suppressed FSH or stimulated inhibin to down-regulate FSH secretory activity, this could produce aberrations in folliculogenesis which culminate in anovulation or luteal phase dysfunctions in alcoholic women. Direct evidence of an alcohol-induced suppression of FSH during the follicular phase has been reported in a primate model and is described later in this chapter.