Santen, F. J., Sofsky, J., Bilic, N., & Lippert, R. (1975). Mechanism of action of narcotics in the production of menstrual dysfunction in women. Fertility and Sterility, 26(6), 538-548. https://doi.org/10.1016/s0015-0282(16)41173-8
Santen FJ, Sofsky J, Bilic N, Lippert R. Mechanism of action of narcotics in the production of menstrual dysfunction in women. Fertil Steril. 1975;26(6):538-548. doi:10.1016/s0015-0282(16)41173-8
Santen, F. J., et al. "Mechanism of action of narcotics in the production of menstrual dysfunction in women." Fertility and sterility, vol. 26, no. 6, 1975, pp. 538-548.
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Abstract
The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.
AMENORRHEA and sterility are frequent accompaniments of morphine addiction in the human female (Menninger-Lerchenthal, 1934; Pescor, 1938). The mechanisms by which these effects are induced, however, are not clearly understood. In experimental animals results are contradictory. Myers and Flynn (1928, 1931) failed to observe any disturbance of estrous cycles, ovulation or fertility despite 132 days of chronic morphine treatment in rats, and their results were confirmed by Forster (1928). In contrast, treatment of mice daily for a two-month period with morphine has been reported to suppress estrus and induce atrophy of the ovary and uterus (Ko, 1934). Similar observations were noted in the rabbit (Bun, 1937).
The finding by Everett and Sawyer (1950) that “spontaneous” ovulation in the rat involves a neurogenic timing factor with a 24-hour rhythmicity offers a new approach to the study of the control of ovulation.
In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin-releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post-naloxone. The LH response to naloxone in individual subjects showed a significant (P less than 0.01) quadratic (U-shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.
To test the postulate that endogenous opioid peptides may be involved in the neuroendocrine mechanisms controlling the frequency and amplitude of LH pulses, saline and an opioid receptor antagonist, naloxone, were infused sequentially, each for 6-h intervals, in six normal cycling women during the luteal phase of the menstrual cycle. During naloxone infusion (1.6 mg/h), there was a significant (P less than 0.01) increase in both the frequency and amplitude of LH pulses compared to those in saline controls. FSH pulses were not discernible in individual subjects; however, a significant increment in FSH levels occurred concomitantly with the increase in LH. These data strongly suggest that endogenous opiates, through an inhibition of hypothalamic LRF, participate in the endocrine events leading to the low frequency of episodic LH secretion characteristic of the luteal phase of the human menstrual cycle.
A study was made of the effects on the preovulatory surges of LH and FSH exerted by morphine sulfate (M) administered at 1400 h on proestrus, the beginning of the critical period for gonadotropin release in cycling rats in our colony. Various doses of M were given ip and jugular venous blood was collected under ether anesthesia for radioimmunoassay of plasma levels of LH and FSH. To verify ovulation, oviducts were examined the following day for the presence of ova. A high dose of M (60 mg/kg) totally abolished the LH surge and partially prevented the FSH surge while completely blocking ovulation. With intermediate doses of M (20-30 mg/kg) about half of the rats showed undiminished elevations of plasma LH at 1800 h and complete ovulation the next morning, whereas the other half revealed almost total blockade of LH release and no ovulation. Following a low dose of M (10 mg/kg) a small but significant (P < 0.05) augmentation of LH levels was observed in two of three experiments and all animals receiving this dose ovulated. Pretreatment with naloxone (10 mg/kg) did not itself affect LH or FSH release or ovulation but reversed the effect of the high dose of M and permitted complete ovulation. At 1800 h the pituitaries of control and Mblocked rats responded about equally to exogenous LHRH (100 ng iv) in 15 min increments of plasma LH and FSH and all of the rats ovulated. A timecourse study indicates that the onset of the LH surge may be somewhat delayed but the amplitude was undiminished following administration of a low dose of M. These findings indicate that M exerts dose-dependent effects on the preovulatory discharge of pituitary gonadotropins in the cycling rat.
PMID 236938 236938 DOI 10.1016/s0015-0282(16)41173-8 10.1016/s0015-0282(16)41173-8 Santen et al. 1975, Santen 1975
Cite this article
Santen, F. J., Sofsky, J., Bilic, N., & Lippert, R. (1975). Mechanism of action of narcotics in the production of menstrual dysfunction in women. Fertility and Sterility, 26(6), 538-548. https://doi.org/10.1016/s0015-0282(16)41173-8
Santen FJ, Sofsky J, Bilic N, Lippert R. Mechanism of action of narcotics in the production of menstrual dysfunction in women. Fertil Steril. 1975;26(6):538-548. doi:10.1016/s0015-0282(16)41173-8
Santen, F. J., et al. "Mechanism of action of narcotics in the production of menstrual dysfunction in women." Fertility and sterility, vol. 26, no. 6, 1975, pp. 538-548.