British Medical Bulletin (1979) Vol. 35, No. 2, pp. 151-154
EFFECTS OF LACTATION ON FERTILITY A S McNeilly
EFFECTS OF LACTATION ON FERTILITY ALAN S McNEILLY PhD Medical Research Council Reproductive Biology Unit Edinburgh 1
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Epidemiological studies a Lactation and the birth interval b Ovulation and menstruation post partum Endocrinology of lactational amenorrhoea a Endocrinology of lactation b Gonadotrophins during lactation c Ovarian activity in lactation Pathological hyperprolactinaemia Mechanism of lactational amenorrhoea References
It has long been recognized that the return of menstruation and fertility is delayed in women who suckle their babies, and it has been suggested that breast feeding acts as a natural birth spacer—Nature's own contraceptive (Short, 1976). In societies where breast milk is the sole nutrition for the baby lactational amenorrhoea may last for two to three years, giving a birth interval of three to four years. Our understanding of the mechanisms underlying lactational amenorrhoea has advanced rapidly in the last few years, owing mainly to the recognition and purification of human prolactin and the establishment of specific and sensitive radioimmunoassay methods for its detection in blood. This paper reviews our present knowledge of the mechanisms underlying the maintenance of infertility associated with lactation. 1
b Ovulation and Menstruation post Partum While in many cases the duration of amenorrhoea parallels the period of full lactation this is certainly not always the case. Several studies have shown that there may be no intervening menstruation between two successive conceptions, clearly showing that menstruation is an unreliable indicator of fertility. Many of the difficulties in giving a reliable estimate of the period of lactational infertility lie in the definition of full lactation. In many western societies babies are fed on a rigid time regimen and it is often the practice to eliminate night-time feeds early in the course of lactation. While the amount of milk taken by the baby fed according to a time regimen may well be comparable to that taken by a baby who is fed on demand, even where the baby sleeps with the mother, the consequence in terms of the influence of breast feeding on fertility may be very different Few studies have related the period of lactational infertility to the number of suckling episodes each day, although there are several studies of the duration of amenorrhoea itself, and of the time at which ovulation recommences. During breast feeding the first ovulation post partum has been detected as early as day 33 and sporadic ovulations between day 34 and day 42 have been demonstrated by either meastirement of basal body temperature or endometrial biopsy (Chartier & GiUain, 1964; Sharman, 1967; Kava et al. 1968; Perez et al. 1972). The
Epidemiological Studies
a Lactation and the Birth Interval In many societies the newborn infant is totally reliant on breast milk for its survival. Thus breast feeding is of fundamental importance for the growth and development of the offspring. It is now clear that, associated with the production of milk, lactation also inhibits reproductive activity. It should be emphasized that the relationship between lactation and lactational amenorrhoea is not through the process of milk secretion but is related to the endocrine consequences of the continual application of the suckling stimulus. That breast feeding plays a profound role in the control of fertility is illustrated by a comparison between the length of the infertile period and alterations in the mode of breast feeding, particularly in societies moving from a rural to an urban way of life. In the nomadic IKung hunter-gatherers of the Kalahari, babies are breast fed with minimal supplementation for three to four years. This is related to a prolonged period of infertility associated with the period of lactation and results, in the total absence of contraception, in a birth interval of approximately four years, i.e., an average period of lactational infertility of over 151
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three years. When the IKung forsake the nomadic way of life and settle in agricultural communities where breast feeding is supplemented with grain meal and cows' milk the birth interval is reduced to under three years, a decrease associated primarily with the reduced intensity of breast feeding (Kolata, 1974). An obvious consequence of the decreased birth interval is an increase in the number of children born in the reproductive lifespan of the women and a consequent increase in population growth. A similar situation has been documented in Rwandese women (Bonte et al. 1974), where in the rural areas babies are breast fed on demand and 50% of women had conceived within 23 months post partum. In the urban areas where breast feeding was confined to a more rigid timetable, with a consequent reduction in the number of suckling episodes, the interval to conception post partum for 50% of women had dropped to nine months, only five months longer than if the women had not breast fed at all. It is important to recognize that one consequence of the move from a rural to an urban way of life may be an improvement of the nutritional status of the mother. Thus while the decrease in the intensity of breast feeding may well be directly related to the decrease in the infertile period associated with lactation, it may also be related to the better nutritional status of the mother. However, in North American Hutterite communities where mothers breast feed their babies on demand, have a high standard of health and nutrition and use no form of contraception, the average birth interval was still 21.7 months (Eaton & Mayer, 1953). This gave an average period of lactational infertility of 12-13 months even when nutrition was presumably optimal. Similar studies have been carried out in Eskimos and South American communities with the same conclusions. Lactation by maintaining a prolonged period of infertility reduces the possible number of children born during the reproductive life-span of a woman and as a consequence acts as a natural contraceptive and a limiter of population growth. Thus Short (1976) has concluded that, throughout the world as a whole, more births are prevented by lactation than by all other forms of contraception put together.
EFFECTS OF LACTATION ON FERTILITY A S McNeilly
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to two years) in women studied in Zaire and the degree of elevation was directly related to the number of suckling episodes. Prolactin concentrations remained at least three times the normal basal values for more than one year, when breast feeding occurred more than six times each day. If breast feeding took place only one to three times each day, prolactic concentrations returned to normal basal values within six months post partum (Delvoye et al. 1977). Since high concentrations of prolactin may be implicated in the maintenance of lactational amenorrhoea it is clearly necessary to relate all observations on the onset of ovarian activity to the number of daily suckling episodes during lactation. b Gonadotrophins during Lactation i Follicle-stimulating hormone (FSH). As a result of the high concentrations of placental oestrogens and progesterone, blood concentrations of FSH are suppressed during pregnancy and at term are low normal or undetectable. In all women, whether breast feeding or not, blood concentrations increase post partum until by 15-20 days post partum they are within the normal range of the follicular phase. Thereafter in lactating women FSH remains in the upper normal range during the first year of lactation (Reyes et al. 1972; Bonnar et al. 1975; Rolland et al. 1975; Keye & Jaffe, 1976). During the second year post partum FSH concentrations decline to normal concentrations of the early follicular phase (Delvoye et al. 1978). ii Luteinizing hormone {Lit). Blood concentrations of LH are not measurable immediately post partum because of the cross-reaction of human chorionic gonadotrophin in the radioimmunoassays used. It is probable, however, that concentrations are extremely low, as the pituitary content of LH during late pregnancy is less than 1% of that of normally cyclic women (de la Lastra & Llados, 1977). By 15-20 days post partum LH concentrations have increased and are low normal (Reyes et al. 1972; Bonnar et al. 1975; Rolland et al. 1975; Keye & Jaffe, 1976). Despite the return to low normal basal levels of LH, no pulsatility of LH secretion (a feature of normally cyclic women) occurs during lactation (Bonnet & Schneider, 1977); this indicates a reduced hypothalamic secretion of gonadotrophin-releasing hormone (GnRH). LH concentrations increase when prolactin concentrations fall to normal at the time of weaning (Rolland et al. 1975). In non-lactating women LH concentrations remain low during the early puerperium, with a return to normal cyclic concentrations during the third to fifth week when prolactin concentrations return to normal (Bonnar et al. 1975). ill Gonadotrophin response to GnRH and oestrogen. The secretion of both LH and FSH is under the control of GnRH released from the hypothalamus (see Fink, 1979). To determine whether the low concentrations of LH seen during lactational amenorrhoea were due to a decreased ability of the pituitary to release LH and FSH, the sensitivity of the pituitary to GnRH stimulation has been assessed by several groups of workers. During the first seven days post partum the FSH and LH response is absent or low both in breast-feeding and nonbreast-feeding mothers. In fully breast-feeding mothers a diminished LH response but normal FSH response to GnRH was seen at six to eight weeks of lactation (Jeppsson et al. 1974; LeMaire et al. 1974; Andreessen & Tyson, 1976; Keye & Jaffe, 1976). In long-term lactation of one to two years' duration, the FSH increase in response to GnRH remains exaggerated, while the LH increase is similar to that seen in the normal luteal phase (Delvoye et al. 1978). This situation is similar to that seen in
Endocrinology of Lactational Amenorrfaoca
Lactational amenorrhoea is a result of failure of ovarian activity associated with lactation. To understand the mechanisms that relate to this situation it is necessary to review the hormonal control of lactation, and the status of the hypothalamopituitary gonadal axis during the period of lactational amenorrhoea. a Endocrinology of Lactation It is not the purpose of this review to detail the endocrine events that lead to the onset and maintenance of milk secretion in women, since this has been reviewed recently (see McNeilly, 1977). However, a brief summary of these events is necessary to our understanding of the possible mechanisms involved in lactational amenorrhoea. It should first be pointed out that the secretion of prolactin from the pituitary is primarily under inhibitory control from the hypothalamus and the inhibitory substance is currently thought to be dopamine. During pregnancy the secretory alveolar tissue in the breast proliferates under the influence of placental steroids, placental lactogen and possibly prolactin. Blood concentrations of prolactin increase progressively throughout pregnancy under the influence of the increasing concentrations of placental steroids. During pregnancy, milk secretion is inhibited by a direct action of steroids on the breast At delivery, blood concentrations of prolactin are eight to 20 times the normal and remain high in the immediate seven days post partum even in the absence of suckling. Milk secretion begins two to three days post partum in response to the suckling of the baby and the time of onset of lactation is directly related to the withdrawal of the inhibitory influence of the placental steroids immediately post partum. In non-breastfeeding mothers prolactin concentrations decline and reach the normal concentrations of non-pregnant women 15-20 days post partum. In breast-feeding women blood concentrations of prolactin remain high for the duration of lactation, and prolactin is released at the majority of suckling episodes in response to tactile stimulation of the nipple. As lactation progresses the amount of prolactin released at each episode may decline but basal concentrations of prolactin remain high. The mechanism behind this is unknown. High basal concentrations of prolactin have been demonstrated in long-term lactation (eighteen months
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number of women ovulating at this time is very small. Perez et al. (1972) showed that of 170 subjects, 24 ovulated while fully nursing, 49 while partially nursing and 97 only after the baby had been weaned. In agreement with this El-Minawi & Foda (1971) showed by endometrial biopsy that 96% of the breastfeeding women investigated were anovulatory, an observation supported by Berman et al. (1972) in Alaskan Eskimos. In contrast with these findings, Kamal et al. (1969) reported an incidence of pregnancy during lactation in Egyptian women as high as 5 7%, of whom 44% were still amenorrhoeic. It is clear that there is considerable disagreement concerning the time of recurrence of ovarian function and obviously lactational amenorrhoea is not, in a proportion of women, a time when infertility can be guaranteed. As indicated however, full lactation does not adequately define the nature of the lactation and more attention should be paid to relating the onset of ovarian activity with the number of suckling episodes each day. Nevertheless, in a considerable number of women breast feeding does suppress ovarian activity and they remain infertile if not amenorrhoeic until breast feeding ceases.
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EFFECTS OF LACTATION ON FERTILITY A S McNeilly
c Ovarian Activity in Lactation Following delivery, the placental steroids, including oestradiol and progesterone, are cleared rapidly from the blood and reach basal values within seven days. Progesterone concentrations do not increase until ovarian cyclicity resumes and a corpus luteum is formed. Oestradiol is secreted predominantly from the developing ovarian follicle and thus monitors follicular development. In non-lactating women a rise in basal oestradiol concentrations occurs at about 17 days post partum, indicating a resumption of follicular development at a time when prolactin concentrations have returned to normal (Bonnar et al. 1975; Rolland et al. 1975); and ovarian function together with ovulation can return as soon as 19-24 days post partum (Rolland et al. 1975). In lactating women oestradiol concentrations are significantly lower than in non-lactating women from day 17 onwards (Bonnar et al. 1975; Rolland et al. 1975; Baird et al. 1979) and remain so until the resumption of ovarian activity. In one study, urinary oestrogen output remained basal while prolactin concentrations were high in breast-feeding women for up to 250 days post partum, indicating absence of ovarian follicular development (Baird et al. 1979). Thus, despite circulating concentrations of FSH and LH within the normal early follicular phase range, no ovarian follicular development occurs during the period of lactation so long as the prolactin concentrations are high (Reyes et al. 1972; Bonnar et al. 1975; Rolland et al. 1975). These observations suggest that the ovary may be refractory to gonadotrophin stimulation when under the influence of prolactin. However, while gonadotrophin stimulation immediately post partum (7-15 days) failed to stimulate oestrogen secretion (Zarate et al. 1974; del Pozo et al. 1975), thereafter either exogenous gonadotrophin (Nakano et al. 1975; Andreassen & Tyson, 1976) or GnRH-induced increases in endogenous gonadotrophin (Zanartu et al. 1974; Andreassen & Tyson, 1976) did stimulate ovarian follicular development and oestro-
3
With the advent of radioimmunoassays for human prolactin it has become abundantly apparent that, in 15-20% of cases of secondary amenorrhoea, prolactin concentrations are high. In many cases hyperprolactinaemia results from increased secretion of prolactin from a tumour either within the pituitary or interfering with the median eminence. Galactorrhoea is not frequently associated with hyperprolactinaemia. As in lactation, pathologically high concentrations of prolactin are associated with normal or low blood concentrations of LH and FSH and adequate release in response to GnRH (see e.g., Thorner et al. 1974). Pulsatility of LH secretion is also absent and there is failure of positive feedback of LH secretion following administration of oestrogen (Glass et al. 1975). Suppression of prolactin concentrations to normal, either by surgical removal of a prolactin-secreting microadenoma (Hardy, 1973) or by treatment with Parlodel (bromocriptine mesylate; CB154, Sandoz) (e.g. Besser et al. 1972), leads to a resumption of normal menstrual cyclicity. These results clearly support the contention that high concentrations of prolactin are related to the lack of ovarian cyclicity. As in lactational amenorrhoea, in pathological hyperprolactinaemia the ovaries remain responsive to either gonadotrophin stimulation (Kemmann et al. 1977) or GnRH-stimulated LH and FSH secretion (Lachelin et al. 1977), and normal ovarian cyclicity can be maintained in the face of high prolactin concentrations provided an adequate dose of gonadotrophin is given (Kemmann et al. 1977). This short resume of pathological hyperprolactinaemia serves to illustrate the relationship between high prolactin concentrations and the absence of ovarian cyclicity and suggests that there may be a causal relationship between the two, as seems to be the case in lactational amenorrhoea. 153
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Pathological Hyperprolactinaemia
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gen secretion. Thus, as far as oestrogen secretion is concerned, the ovary remains responsive to gonadotrophin stimulation. These observations lead to the conclusion that high concentrations of prolactin, while being closely associated with ovarian inactivity, may not act directly on the ovary. It must be recognized, however, that maintenance of ovarian function by exogenous gonadotrophins may overcome any direct inhibitory effect of prolactin on the gonad. In vitro, high concentrations of prolactin, equivalent to those seen in lactation, inhibit progesterone production by human granulosa cells even in the presence of high concentrations of both LH and FSH (McNatty et al. 1974). Thus prolactin may alter the intrafollicular mechanisms whereby granulosa cells are programmed for their subsequent secretory activity as luteal cells following ovulation. To summarize the reproductive endocrine status in lactational amenorrhoea, prolactin concentrations are increased in response to the repeated suckling stimulus of breast feeding. Blood concentrations of FSH are high normal and of LH low normal without pulsatile secretion, and yet there is an absence of ovarian activity as judged by an absence of oestrogen secretion. Despite adequate releasable LH and FSH in the pituitary, oestrogen fails to induce a positive feedback release of LH and the hypothalamo-pituitary axis appears more sensitive to the negative feedback effects of oestrogen. Upon weaning there is an immediate drop in blood concentrations of prolactin and an increase in blood concentrations of LH and oestradiol, indicating prompt resumption of ovarian activity, and ovulation occurs within 14-30 days (Rolland et al. 1975).
prepubertal girls where the FSH response to GnRH is greater than the LH response, although in lactating women the LH response is much greater than it is before puberty. In non-breast-feeding women the LH and FSH responses to GnRH are exaggerated from three to six weeks post partum and then show responses equivalent to those seen in the normal follicular phase of the cycle (Keye & Jaffe, 1976). It is apparent therefore that while the LH and FSH responses to GnRH are diminished in the immediate puerperium, during lactation the pituitary contains adequate stores of both LH and FSH, as shown by the responses to GnRH. During the normal menstrual cycle the ovulatory discharge of LH is induced by the increasing concentrations of oestradiol secreted during the follicular phase. Injection of oestrogen will mimic this response, initially suppressing LH and FSH concentrations (negative feedback) and then inducing a release of both LH and FSH (positive feedback). Administration of oestrogen to lactating and non-lactating women at 7, 30 and 100 days of lactation suppressed LH and FSH concentrations to a greater extent in lactating than in non-lactating women, and failed to induce positive feedback in the lactating women (Baird et al. 1979). These results suggest that, while the pituitary can respond to GnRH, the hypothalamic response to oestrogen stimulation is altered and is implicated in the maintenance of amenorrhoea.
EFFECTS OF LACTATION ON FERTILITY A S McNeilly 4
Mechanism of Lactatlonal Amenorrhoea
oestrogen, can all be caused by selective increase of prolactin concentrations in women either by treatment with thyrotrophinreleasing hormone or by specific dopamine receptor-blocking agents (e.g. sulpiride) (Robyn et al. 1976; Bonnet & Schneider, 1977). In fact, amenorrhoea has been induced in women by hyperprolactinaemia caused by the long-term administration of sulpiride (Robyn et al. 1976). The maintenance of the anovular state could be achieved by an action of the high concentrations of prolactin on the secretion of GnRH. If this is reduced so that LH pulsatility is abolished, the developing follicles will not receive the correct signal to ensure adequate oestrogen secretion. Even if this is achieved the block of the positive feedback action of oestrogen by the high concentrations of prolactin will prevent or drastically reduce the release of the mid-cycle ovulatory discharge of LH and lead to either anovulation or an inadequate luteal phase. It is clear that, while the available evidence strongly suggests that it is the high concentrations of prolactin per se that are responsible for the maintenance of hyperprolactinaemic amenorrhoea, the mechanisms behind this action remain to be elucidated. It is also apparent that a clearer understanding of the relationship between suckling frequency, high prolactin concentrations and resumption of ovarian activity during lactation, and a simple reliable method of detecting when ovulation has recommenced, must be sought before the full potential of breast feeding as a reliable and safe method of contraception can be exploited.
REFERENCES
Kemmann E, Gerazell C A, Beinert W C, Beling C B& Jones J R (1977) Am. J. Obstet. Gynecol. 129, 145-149 Keye W R Jr&JaffeR B (1976)7. Clin. Endocrinol. Metab. 42,1133-1138 Kolata G B (1974) Science (New York) 185,932-934 Lachdin G C L , Abu-Fadil S & Yen S S C (1977)/. Clin. Endocrinol. Metab. 44,1163-1174 Lastra M de la * Lladoj C (1977) / . Clin. Endocrinol. Metab. 44,921-923 LeMtire W J, Shapiro A G, Riggall F & Yang N S T (1974) / . Clin. Endocrinol. Metab. 38,916-918 McNatty K P, Sawers R S & McNeilly A S (1974) Nature (London) 250, 653-655 McNeflly A S (1977) / . Biosoc. Sci. suppL no. 4, pp. 5-21 Nakano R, Mori A, Kayashima F, Washio M & Tojo S (1915) Am. J. Obstet. Gynecol. 121,187-192 Perez A, Vela P, Masnick G S & Potter R G (1972) Am. J. Obstet. Gynecol. 114,1041-1047 Pozo E del, (joldstein M, Friesen H G, Brun R del Re & Eppenberger U (1975),4m./. Obstet. Gynecol. 123, 719-723 Reyes F I, Winter J S D & Faiman C (1972) Am. J. Obstet. Gynecol 114, 589-594 Robyn C, Delvoye P, Exter C van, Vekemans M, Caufriei A, Nayer P de, Delogne-Desnoeck J & L'Hermite M (1976) In: Crosignani P G A Robyn C, ed. Prolactin and human reproduction, pp. 71-97 (Proceedings of the Serono Symposia, voL 11). Academic Press, London Rolland R, Lequin R M, ScheUekens L A & Jong F H de (1975) Clin. Endocrinol. 4, 15-25 Sharman A (1967)Int. J.FertU. 12,14-16 Short R V (1976) In: Breast-feeding and the mother, pp. 73-86 (Ciba Foundation symposium n.s. no. 45). Elsevier; Excerpta Medica; NorthHolland, Amsterdam Thomer M O, McNeilly A S, Hagen C & Besser G M (1974) Br. Med. J. 2, 419-422 Zanartu J, Dabincens A, Kastin A J & Schally A V (1974) Ferttl. SteriL 25, 160-169 Zarate A, Canales E S, Son* J, Leon C, Garrido J & Fonseca E (1974)
Andreassen B & Tyson J E (1976) / . Clin. Endocrinol. Melab. 42, 11141122 Baird D T, McNeilly A S, Sawers R & Sharpe R M (1979) /. Clin.. Endocrinol. Melab. (In press) Berman M L, Hanson K & Hellman I L (1972) Am. /. Obstet. Gynecol. 114, 524-534 Besser G M, Parke L, Edwards C R W, Forsyth I A & McNeilly A S (1972) Br. Med. J. 3,669-672 Bonnet H G & Schneider H P G (1977) In: Croiignani P G & Robyn C, ed. Prolactin and human reproduction, pp. 153—159 (Proceedings of the Serono Symposia, vol. 11). Acaderhic Press, London Bonnar J, Franklin M, Nott P N & McNeilly A S (1975) Br. Med. J. 4, 82-84 Bonte M, Akingeneye E, Gashakamba M, Mbarutso E & Nolens M (1974)
Int.J.Fertil. 19,97-102 Chartier M & Gillain M (1964) Bull. Soc. R. Belg. Gynecol. Obstel. 34, 2 7 1 278 Delvoye P, Demaegd M, Delogne-Desnoeck J & Robyn C (1977) J. Biosoc. Sci. 9,447-451 Delvoye P, Badawi M, Demaegd M & Robyn C (1978) In: Robyn C & Harter M, ed. Progresi In prolactin physiology and pathology, pp. 213— 232 (Proceedings of an international symposium, Nice, 20-27 October 1977). Elsevier/North-Holland Biomedical Press, Amsterdam Eaton J W & Mayer A J (1953) Hum. Biol. 25,206-264 EI-Mmawi M F & Foda M S (1971) Am. J. Obsut. Gynecol. I l l , 17-21 Fink G ( l 979) Br. Med. Bull. 35,155-160 Glass M R, Shaw R W, Butt W R, Logan-Edwards R & London D R (1975) Br.Mcd.J. 3,274-275 Hardy J (1973) In: Kohler P O & Ross G T, ed. Diagnosis and treatment of pituitary tumors, pp. 179-185 (International Congress Series no. 303). Excerpta Medic*, Amsterdam Jeppsson S, Rannevik G & KuQander S (1974) Am. J. Obstet. Gynecol. 120, 1029-1034 Kamal I, Hefnawi F, Ghoneim M, Taliat M, Younis N, Tagui A & Abdalla
M (1969) Am. J. Obstet. Gynecol. 105,314-323
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It is clear from the review of the literature that high blood concentrations of prolactin are closely associated with both lactational and some pathological forms of amenorrhoea. In both situations the question arises whether prolactin per se is implicated as the causal agent in hyperprolactinaemic anovulation or whether either the suckling stimulus in lactation or an undefined disturbance of hypothalamic activity (resulting in reduced secretion of prolactin-inhibiting factor and resultant increase of prolactin concentrations) is the primary cause of the amenorrhoea. Or the high concentrations of prolactin may be secondary, associated with but not causally related to the amenorrhoea. Several studies suggest that prolactin per seis indeed a major factor. As we have seen, specific suppression of prolactin, either by removal of a prolactin-secreting microadenoma or by specifically blocking prolactin secretion by Parlodel in both pathological hyperprolactinaemia and in lactation, results in a resumption of normal ovarian and menstrual cyclicity. While Parlodel treatment may act by repletion of depleted hypothalamic dopamine reserves, the resumption of cyclicity following removal of an adenoma secreting prolactin alone clearly suggests that prolactin per se is a principal causative agent in hyperprolactinaemic anovulation. Similarly, a loss in the pulsatile secretion of LH and of the positive feedback effect of oestrogen on LH and FSH release, and an increase in sensitivity to the negative feedback effects of
Obslet. Gynecol. (New York) 44,819-822
Kava H W, Klinger H P, Molnar J J & Romney S L (1968) Am. / . Obstet. Gynecol 102,122-124
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EFFECTS OF LACTATION ON FERTILITY A S McNeilly
EFFECTS OF LACTATION ON FERTILITY ALAN S McNEILLY PhD Medical Research Council Reproductive Biology Unit Edinburgh 1
2
3 4
Epidemiological studies a Lactation and the birth interval b Ovulation and menstruation post partum Endocrinology of lactational amenorrhoea a Endocrinology of lactation b Gonadotrophins during lactation c Ovarian activity in lactation Pathological hyperprolactinaemia Mechanism of lactational amenorrhoea References
It has long been recognized that the return of menstruation and fertility is delayed in women who suckle their babies, and it has been suggested that breast feeding acts as a natural birth spacer—Nature's own contraceptive (Short, 1976). In societies where breast milk is the sole nutrition for the baby lactational amenorrhoea may last for two to three years, giving a birth interval of three to four years. Our understanding of the mechanisms underlying lactational amenorrhoea has advanced rapidly in the last few years, owing mainly to the recognition and purification of human prolactin and the establishment of specific and sensitive radioimmunoassay methods for its detection in blood. This paper reviews our present knowledge of the mechanisms underlying the maintenance of infertility associated with lactation. 1
b Ovulation and Menstruation post Partum While in many cases the duration of amenorrhoea parallels the period of full lactation this is certainly not always the case. Several studies have shown that there may be no intervening menstruation between two successive conceptions, clearly showing that menstruation is an unreliable indicator of fertility. Many of the difficulties in giving a reliable estimate of the period of lactational infertility lie in the definition of full lactation. In many western societies babies are fed on a rigid time regimen and it is often the practice to eliminate night-time feeds early in the course of lactation. While the amount of milk taken by the baby fed according to a time regimen may well be comparable to that taken by a baby who is fed on demand, even where the baby sleeps with the mother, the consequence in terms of the influence of breast feeding on fertility may be very different Few studies have related the period of lactational infertility to the number of suckling episodes each day, although there are several studies of the duration of amenorrhoea itself, and of the time at which ovulation recommences. During breast feeding the first ovulation post partum has been detected as early as day 33 and sporadic ovulations between day 34 and day 42 have been demonstrated by either meastirement of basal body temperature or endometrial biopsy (Chartier & GiUain, 1964; Sharman, 1967; Kava et al. 1968; Perez et al. 1972). The
Epidemiological Studies
a Lactation and the Birth Interval In many societies the newborn infant is totally reliant on breast milk for its survival. Thus breast feeding is of fundamental importance for the growth and development of the offspring. It is now clear that, associated with the production of milk, lactation also inhibits reproductive activity. It should be emphasized that the relationship between lactation and lactational amenorrhoea is not through the process of milk secretion but is related to the endocrine consequences of the continual application of the suckling stimulus. That breast feeding plays a profound role in the control of fertility is illustrated by a comparison between the length of the infertile period and alterations in the mode of breast feeding, particularly in societies moving from a rural to an urban way of life. In the nomadic IKung hunter-gatherers of the Kalahari, babies are breast fed with minimal supplementation for three to four years. This is related to a prolonged period of infertility associated with the period of lactation and results, in the total absence of contraception, in a birth interval of approximately four years, i.e., an average period of lactational infertility of over 151
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three years. When the IKung forsake the nomadic way of life and settle in agricultural communities where breast feeding is supplemented with grain meal and cows' milk the birth interval is reduced to under three years, a decrease associated primarily with the reduced intensity of breast feeding (Kolata, 1974). An obvious consequence of the decreased birth interval is an increase in the number of children born in the reproductive lifespan of the women and a consequent increase in population growth. A similar situation has been documented in Rwandese women (Bonte et al. 1974), where in the rural areas babies are breast fed on demand and 50% of women had conceived within 23 months post partum. In the urban areas where breast feeding was confined to a more rigid timetable, with a consequent reduction in the number of suckling episodes, the interval to conception post partum for 50% of women had dropped to nine months, only five months longer than if the women had not breast fed at all. It is important to recognize that one consequence of the move from a rural to an urban way of life may be an improvement of the nutritional status of the mother. Thus while the decrease in the intensity of breast feeding may well be directly related to the decrease in the infertile period associated with lactation, it may also be related to the better nutritional status of the mother. However, in North American Hutterite communities where mothers breast feed their babies on demand, have a high standard of health and nutrition and use no form of contraception, the average birth interval was still 21.7 months (Eaton & Mayer, 1953). This gave an average period of lactational infertility of 12-13 months even when nutrition was presumably optimal. Similar studies have been carried out in Eskimos and South American communities with the same conclusions. Lactation by maintaining a prolonged period of infertility reduces the possible number of children born during the reproductive life-span of a woman and as a consequence acts as a natural contraceptive and a limiter of population growth. Thus Short (1976) has concluded that, throughout the world as a whole, more births are prevented by lactation than by all other forms of contraception put together.
EFFECTS OF LACTATION ON FERTILITY A S McNeilly
2
to two years) in women studied in Zaire and the degree of elevation was directly related to the number of suckling episodes. Prolactin concentrations remained at least three times the normal basal values for more than one year, when breast feeding occurred more than six times each day. If breast feeding took place only one to three times each day, prolactic concentrations returned to normal basal values within six months post partum (Delvoye et al. 1977). Since high concentrations of prolactin may be implicated in the maintenance of lactational amenorrhoea it is clearly necessary to relate all observations on the onset of ovarian activity to the number of daily suckling episodes during lactation. b Gonadotrophins during Lactation i Follicle-stimulating hormone (FSH). As a result of the high concentrations of placental oestrogens and progesterone, blood concentrations of FSH are suppressed during pregnancy and at term are low normal or undetectable. In all women, whether breast feeding or not, blood concentrations increase post partum until by 15-20 days post partum they are within the normal range of the follicular phase. Thereafter in lactating women FSH remains in the upper normal range during the first year of lactation (Reyes et al. 1972; Bonnar et al. 1975; Rolland et al. 1975; Keye & Jaffe, 1976). During the second year post partum FSH concentrations decline to normal concentrations of the early follicular phase (Delvoye et al. 1978). ii Luteinizing hormone {Lit). Blood concentrations of LH are not measurable immediately post partum because of the cross-reaction of human chorionic gonadotrophin in the radioimmunoassays used. It is probable, however, that concentrations are extremely low, as the pituitary content of LH during late pregnancy is less than 1% of that of normally cyclic women (de la Lastra & Llados, 1977). By 15-20 days post partum LH concentrations have increased and are low normal (Reyes et al. 1972; Bonnar et al. 1975; Rolland et al. 1975; Keye & Jaffe, 1976). Despite the return to low normal basal levels of LH, no pulsatility of LH secretion (a feature of normally cyclic women) occurs during lactation (Bonnet & Schneider, 1977); this indicates a reduced hypothalamic secretion of gonadotrophin-releasing hormone (GnRH). LH concentrations increase when prolactin concentrations fall to normal at the time of weaning (Rolland et al. 1975). In non-lactating women LH concentrations remain low during the early puerperium, with a return to normal cyclic concentrations during the third to fifth week when prolactin concentrations return to normal (Bonnar et al. 1975). ill Gonadotrophin response to GnRH and oestrogen. The secretion of both LH and FSH is under the control of GnRH released from the hypothalamus (see Fink, 1979). To determine whether the low concentrations of LH seen during lactational amenorrhoea were due to a decreased ability of the pituitary to release LH and FSH, the sensitivity of the pituitary to GnRH stimulation has been assessed by several groups of workers. During the first seven days post partum the FSH and LH response is absent or low both in breast-feeding and nonbreast-feeding mothers. In fully breast-feeding mothers a diminished LH response but normal FSH response to GnRH was seen at six to eight weeks of lactation (Jeppsson et al. 1974; LeMaire et al. 1974; Andreessen & Tyson, 1976; Keye & Jaffe, 1976). In long-term lactation of one to two years' duration, the FSH increase in response to GnRH remains exaggerated, while the LH increase is similar to that seen in the normal luteal phase (Delvoye et al. 1978). This situation is similar to that seen in
Endocrinology of Lactational Amenorrfaoca
Lactational amenorrhoea is a result of failure of ovarian activity associated with lactation. To understand the mechanisms that relate to this situation it is necessary to review the hormonal control of lactation, and the status of the hypothalamopituitary gonadal axis during the period of lactational amenorrhoea. a Endocrinology of Lactation It is not the purpose of this review to detail the endocrine events that lead to the onset and maintenance of milk secretion in women, since this has been reviewed recently (see McNeilly, 1977). However, a brief summary of these events is necessary to our understanding of the possible mechanisms involved in lactational amenorrhoea. It should first be pointed out that the secretion of prolactin from the pituitary is primarily under inhibitory control from the hypothalamus and the inhibitory substance is currently thought to be dopamine. During pregnancy the secretory alveolar tissue in the breast proliferates under the influence of placental steroids, placental lactogen and possibly prolactin. Blood concentrations of prolactin increase progressively throughout pregnancy under the influence of the increasing concentrations of placental steroids. During pregnancy, milk secretion is inhibited by a direct action of steroids on the breast At delivery, blood concentrations of prolactin are eight to 20 times the normal and remain high in the immediate seven days post partum even in the absence of suckling. Milk secretion begins two to three days post partum in response to the suckling of the baby and the time of onset of lactation is directly related to the withdrawal of the inhibitory influence of the placental steroids immediately post partum. In non-breastfeeding mothers prolactin concentrations decline and reach the normal concentrations of non-pregnant women 15-20 days post partum. In breast-feeding women blood concentrations of prolactin remain high for the duration of lactation, and prolactin is released at the majority of suckling episodes in response to tactile stimulation of the nipple. As lactation progresses the amount of prolactin released at each episode may decline but basal concentrations of prolactin remain high. The mechanism behind this is unknown. High basal concentrations of prolactin have been demonstrated in long-term lactation (eighteen months
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number of women ovulating at this time is very small. Perez et al. (1972) showed that of 170 subjects, 24 ovulated while fully nursing, 49 while partially nursing and 97 only after the baby had been weaned. In agreement with this El-Minawi & Foda (1971) showed by endometrial biopsy that 96% of the breastfeeding women investigated were anovulatory, an observation supported by Berman et al. (1972) in Alaskan Eskimos. In contrast with these findings, Kamal et al. (1969) reported an incidence of pregnancy during lactation in Egyptian women as high as 5 7%, of whom 44% were still amenorrhoeic. It is clear that there is considerable disagreement concerning the time of recurrence of ovarian function and obviously lactational amenorrhoea is not, in a proportion of women, a time when infertility can be guaranteed. As indicated however, full lactation does not adequately define the nature of the lactation and more attention should be paid to relating the onset of ovarian activity with the number of suckling episodes each day. Nevertheless, in a considerable number of women breast feeding does suppress ovarian activity and they remain infertile if not amenorrhoeic until breast feeding ceases.
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c Ovarian Activity in Lactation Following delivery, the placental steroids, including oestradiol and progesterone, are cleared rapidly from the blood and reach basal values within seven days. Progesterone concentrations do not increase until ovarian cyclicity resumes and a corpus luteum is formed. Oestradiol is secreted predominantly from the developing ovarian follicle and thus monitors follicular development. In non-lactating women a rise in basal oestradiol concentrations occurs at about 17 days post partum, indicating a resumption of follicular development at a time when prolactin concentrations have returned to normal (Bonnar et al. 1975; Rolland et al. 1975); and ovarian function together with ovulation can return as soon as 19-24 days post partum (Rolland et al. 1975). In lactating women oestradiol concentrations are significantly lower than in non-lactating women from day 17 onwards (Bonnar et al. 1975; Rolland et al. 1975; Baird et al. 1979) and remain so until the resumption of ovarian activity. In one study, urinary oestrogen output remained basal while prolactin concentrations were high in breast-feeding women for up to 250 days post partum, indicating absence of ovarian follicular development (Baird et al. 1979). Thus, despite circulating concentrations of FSH and LH within the normal early follicular phase range, no ovarian follicular development occurs during the period of lactation so long as the prolactin concentrations are high (Reyes et al. 1972; Bonnar et al. 1975; Rolland et al. 1975). These observations suggest that the ovary may be refractory to gonadotrophin stimulation when under the influence of prolactin. However, while gonadotrophin stimulation immediately post partum (7-15 days) failed to stimulate oestrogen secretion (Zarate et al. 1974; del Pozo et al. 1975), thereafter either exogenous gonadotrophin (Nakano et al. 1975; Andreassen & Tyson, 1976) or GnRH-induced increases in endogenous gonadotrophin (Zanartu et al. 1974; Andreassen & Tyson, 1976) did stimulate ovarian follicular development and oestro-
3
With the advent of radioimmunoassays for human prolactin it has become abundantly apparent that, in 15-20% of cases of secondary amenorrhoea, prolactin concentrations are high. In many cases hyperprolactinaemia results from increased secretion of prolactin from a tumour either within the pituitary or interfering with the median eminence. Galactorrhoea is not frequently associated with hyperprolactinaemia. As in lactation, pathologically high concentrations of prolactin are associated with normal or low blood concentrations of LH and FSH and adequate release in response to GnRH (see e.g., Thorner et al. 1974). Pulsatility of LH secretion is also absent and there is failure of positive feedback of LH secretion following administration of oestrogen (Glass et al. 1975). Suppression of prolactin concentrations to normal, either by surgical removal of a prolactin-secreting microadenoma (Hardy, 1973) or by treatment with Parlodel (bromocriptine mesylate; CB154, Sandoz) (e.g. Besser et al. 1972), leads to a resumption of normal menstrual cyclicity. These results clearly support the contention that high concentrations of prolactin are related to the lack of ovarian cyclicity. As in lactational amenorrhoea, in pathological hyperprolactinaemia the ovaries remain responsive to either gonadotrophin stimulation (Kemmann et al. 1977) or GnRH-stimulated LH and FSH secretion (Lachelin et al. 1977), and normal ovarian cyclicity can be maintained in the face of high prolactin concentrations provided an adequate dose of gonadotrophin is given (Kemmann et al. 1977). This short resume of pathological hyperprolactinaemia serves to illustrate the relationship between high prolactin concentrations and the absence of ovarian cyclicity and suggests that there may be a causal relationship between the two, as seems to be the case in lactational amenorrhoea. 153
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Pathological Hyperprolactinaemia
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gen secretion. Thus, as far as oestrogen secretion is concerned, the ovary remains responsive to gonadotrophin stimulation. These observations lead to the conclusion that high concentrations of prolactin, while being closely associated with ovarian inactivity, may not act directly on the ovary. It must be recognized, however, that maintenance of ovarian function by exogenous gonadotrophins may overcome any direct inhibitory effect of prolactin on the gonad. In vitro, high concentrations of prolactin, equivalent to those seen in lactation, inhibit progesterone production by human granulosa cells even in the presence of high concentrations of both LH and FSH (McNatty et al. 1974). Thus prolactin may alter the intrafollicular mechanisms whereby granulosa cells are programmed for their subsequent secretory activity as luteal cells following ovulation. To summarize the reproductive endocrine status in lactational amenorrhoea, prolactin concentrations are increased in response to the repeated suckling stimulus of breast feeding. Blood concentrations of FSH are high normal and of LH low normal without pulsatile secretion, and yet there is an absence of ovarian activity as judged by an absence of oestrogen secretion. Despite adequate releasable LH and FSH in the pituitary, oestrogen fails to induce a positive feedback release of LH and the hypothalamo-pituitary axis appears more sensitive to the negative feedback effects of oestrogen. Upon weaning there is an immediate drop in blood concentrations of prolactin and an increase in blood concentrations of LH and oestradiol, indicating prompt resumption of ovarian activity, and ovulation occurs within 14-30 days (Rolland et al. 1975).
prepubertal girls where the FSH response to GnRH is greater than the LH response, although in lactating women the LH response is much greater than it is before puberty. In non-breast-feeding women the LH and FSH responses to GnRH are exaggerated from three to six weeks post partum and then show responses equivalent to those seen in the normal follicular phase of the cycle (Keye & Jaffe, 1976). It is apparent therefore that while the LH and FSH responses to GnRH are diminished in the immediate puerperium, during lactation the pituitary contains adequate stores of both LH and FSH, as shown by the responses to GnRH. During the normal menstrual cycle the ovulatory discharge of LH is induced by the increasing concentrations of oestradiol secreted during the follicular phase. Injection of oestrogen will mimic this response, initially suppressing LH and FSH concentrations (negative feedback) and then inducing a release of both LH and FSH (positive feedback). Administration of oestrogen to lactating and non-lactating women at 7, 30 and 100 days of lactation suppressed LH and FSH concentrations to a greater extent in lactating than in non-lactating women, and failed to induce positive feedback in the lactating women (Baird et al. 1979). These results suggest that, while the pituitary can respond to GnRH, the hypothalamic response to oestrogen stimulation is altered and is implicated in the maintenance of amenorrhoea.
EFFECTS OF LACTATION ON FERTILITY A S McNeilly 4
Mechanism of Lactatlonal Amenorrhoea
oestrogen, can all be caused by selective increase of prolactin concentrations in women either by treatment with thyrotrophinreleasing hormone or by specific dopamine receptor-blocking agents (e.g. sulpiride) (Robyn et al. 1976; Bonnet & Schneider, 1977). In fact, amenorrhoea has been induced in women by hyperprolactinaemia caused by the long-term administration of sulpiride (Robyn et al. 1976). The maintenance of the anovular state could be achieved by an action of the high concentrations of prolactin on the secretion of GnRH. If this is reduced so that LH pulsatility is abolished, the developing follicles will not receive the correct signal to ensure adequate oestrogen secretion. Even if this is achieved the block of the positive feedback action of oestrogen by the high concentrations of prolactin will prevent or drastically reduce the release of the mid-cycle ovulatory discharge of LH and lead to either anovulation or an inadequate luteal phase. It is clear that, while the available evidence strongly suggests that it is the high concentrations of prolactin per se that are responsible for the maintenance of hyperprolactinaemic amenorrhoea, the mechanisms behind this action remain to be elucidated. It is also apparent that a clearer understanding of the relationship between suckling frequency, high prolactin concentrations and resumption of ovarian activity during lactation, and a simple reliable method of detecting when ovulation has recommenced, must be sought before the full potential of breast feeding as a reliable and safe method of contraception can be exploited.
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It is clear from the review of the literature that high blood concentrations of prolactin are closely associated with both lactational and some pathological forms of amenorrhoea. In both situations the question arises whether prolactin per se is implicated as the causal agent in hyperprolactinaemic anovulation or whether either the suckling stimulus in lactation or an undefined disturbance of hypothalamic activity (resulting in reduced secretion of prolactin-inhibiting factor and resultant increase of prolactin concentrations) is the primary cause of the amenorrhoea. Or the high concentrations of prolactin may be secondary, associated with but not causally related to the amenorrhoea. Several studies suggest that prolactin per seis indeed a major factor. As we have seen, specific suppression of prolactin, either by removal of a prolactin-secreting microadenoma or by specifically blocking prolactin secretion by Parlodel in both pathological hyperprolactinaemia and in lactation, results in a resumption of normal ovarian and menstrual cyclicity. While Parlodel treatment may act by repletion of depleted hypothalamic dopamine reserves, the resumption of cyclicity following removal of an adenoma secreting prolactin alone clearly suggests that prolactin per se is a principal causative agent in hyperprolactinaemic anovulation. Similarly, a loss in the pulsatile secretion of LH and of the positive feedback effect of oestrogen on LH and FSH release, and an increase in sensitivity to the negative feedback effects of
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