Low Serum Levels of FSH, LH and Prolactin in Luteal Phase Inadequacy

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1 Endocrinol. Japon. 1985, 32 (2), Low Serum Levels of FSH, LH and Prolactin in Luteal Phase Inadequacy HISANORI MINAKAMI, KOZO KIMURA AND TARO TAMADA Department of Obstetrics and Gynecology, Jichi Medical School Minamikawachi-machi, Tochigi-ken Abstract In order to elucidate the relationship between prolaction (PRL) levels and corpus lutcum function in humans, assessment of temporal relationship between levels of PRL, LH, FSH, estradiol and progesterone was made in eleven normal cycling women and six short luteal women. All hormones were determined by specific radioimmunoassay. The mean PRL level in the luteal phase was higher than that in the follicular phase in normal women. On the other hand, no difference mean was seen between the PRL levels of follicular and luteal phases in short luteal women. In addition, follicular and luteal phase secretion of PRL in the short luteal phase (SLP) was lower than that in the normal control. LH and FSH in the follicular and luteal phases, estradiol secretion in the late follicular and early to mid-luteal phases in SLP were also lower than those in the control. These observations were consistent with the hypothesis that SLP is a sequel to aberrant folliculogenesis. In addition, it is inferred that low PRL levels in the SLP might be due to inadequate augmentation by estrogen, rather than giving PRL any positive controlling role in the maintenance of corpus luteum function. Keceived November 19, 1984 Although there have been many reports on changes in serum PRL levels during the normal menstrual cycle, no definite pattern has yet been established. No cyclic changes were found by some authors (Ehara et al., 1973, McNeilly and Chard 1974, Epstein et al., 1975). On the other hand, Robyn et al. (1973), Franchimont et al. (1976), Vekemans et al. (1977) and Djursing et al. (1981) reported an increase during the ovulatory and luteal phase as compared to the follicular phase. With regard to the relationships between the levels of PRL and corpus luteum function, several studies (Jeweliwicz et al., 1974, Seppala et al., 1976, Corenblum et al., 1976, Miihtenstedt et al., 1978, Bahamondes et al., 1979) revealed that hyperprolactinemia was often associated with luteal insufficiency. Few reports on PRL levels in normoprolactinemic women with a short luteal phase, however, were available. Therefore, the role of PRL in the regulation of luteal function has not been clarified. This study was undertaken to reinvestigate and confirm the cyclic changes in PRL in a normal menstrual cycle and to study the levels of PRL in the SLP. Based on these studies, the role of PRL in regulation of luteal function will be discussed.

2 266 MINAKAMI et al. Endocrinol. April 1985 Japon. Subjects and Methods Seventeen volunteers aged were bled at least five times per week throughout an ovulatory cycle between 0800 and 1100 hours for the measurement of FSH, LH, PRL, estradiol and progesterone. Six out of seventeen women showed short term basal body temperature elevation for less than 10 days and eleven out of seventeen women showed a high phase lasting 12 or more days. None of them had received any treatment for at least 3 months prior to blood sampling. Plasma was separated by centrifugation within 60 minutes and stored at -20 Ž until assayed. Serum PRL, LH, and FSH were determined using a double antibody radioimmunoassay kit supplied by Daiichi Isotope Co. (Japan). The intra and interassay coefficients of variation for PRL are 6% and 13% respectively. The intraassay coefficients of variation for LH and FSH are 5.8% and 7.3%, respectively and interassay coefficients of variation are 12% and 13%, respectively. Gonadotropin values are expressed as miu/ml 2nd IRP-hMG. Serum estradiol was measured by RIA as previous described (Araki et al., 1978). Serum progesterone was determined using a RIA kit provided by Midori-Juji (Japan). The intra and interassay coefficients of variation are 7% and 19%, respectively. To minimize the effect of interassay variation on all occasions, samples from an individual cycle were measured in duplicate within the same assay. In each group, the mean levels of LH, FSH and PRL were calculated for the follicular, ovulatory and luteal phases. The ovulatory period corresponds to the 2 days prior to and 2 days following the LH peak. The difference was analyzed by Student's t-test. Results The patterns of PRL, LH and FSH for normal and short luteal phase cycle are compared in Fig. 1. All data have been centered on the LH peak. Although the variation in PRL is quite large from day to day, the mean level (+SE) of plama PRL during the luteal phase was significantly (p<0.01) higher than that of the follicular phase in normal cycles (18.9 }1.2ng/ml vs 14.5 }0.8ng/ml). On the other hand, in the SLP, no PRL rise was found in the luteal phase. In addition, follicular and luteal phase secretions of PRL in the SLP (10.7 }0.8ng/ml and 12.1 }1.0ng/ml) were significantly (p<0.01) lower than those found in normal cycles (14.5 }0.8ng/ml and 18,9 secretions of LH (18.0 }0.8mIU/mI and 6.5 (p<0.001) lower than those (26.7 }1.3mIU/ ml and 17.1 }1.0mIU/ml) in normal cycles. Follicular and luteal phase secretions of FSH (8.9 }0.3mIU/ml and 3.7 }0.2mIU/ ml) in the SLP were significantly (p<0.02 and p<0.01) lower than those (10.0 }0.3 miu/ml and 5.1 }0.2mIU/ml) in normal cycles as well. The means }SEM of estradiol during the late follicular phase and early to mid-luteal phase of both groups are shown in Fig. 2 (left panel). Estradiol secretion in each phase of SLP (97+10pg/ml and 104 }11pg/ml) was significantly (p<0.02 and p<0.01) lower than that (187 }21pg/ ml and 188 }16pg/mI) in the normal cycle. Progesterone secretion between 3 day and 9 day following the LH peak in the SLP was also significantly (p<0.001) lower than that in the normal cycle (7.4 }0.7ng/ml vs 14.0 Discussion With regard to the relationship between the PRL level and luteal phase defect, several authors have emphasized the fact that hyperprolactinemia is causally related to the luteal phase defect (Jeweliwicz et. al., 1974, Seppala et al., 1976, Corenblum et al., 1976, Mtihlenstedt et al., 1978, Bahamondes et al., 1979). Indeed, bromocriptine, a dopamine agonist corrects these luteal phase defects by lowering PRL levels as reflected by the endometrial histology, cycle length, and increased pregnancy rate (Saunders et al., 1979, DelPozo et al., 1979, Andersen et al.,

3 Vol.32, No.7 PROLACTIN IN SHORT LUTEAL PHASE 267 Fig. I. Plasma PRL, LH and FSH in normal and short luteal phase (SLP). The normal means-i-sem are shown as shaded areas. The mean }SEM of plasma PRL, LH and FSH in SLP are shown as closed circles and bars. The means }SEM of plasma PRL, LH and FSH in follicular, ovulatory and luteal phases of both groups are shown on the right. Shaded and open columns indicate normal cycle and SLP. 1979). However, hyperprolactinemia accounts for only 23% or less of infertility (Pepperell et al., 1981). We have paid attention to the relationship between the remaining non.- hyperprolactinemic short luteal phase and the PRL level. In the present study it is clearly demonstrated that the PRL level in the SLP is lower than that found in the normal cycle. McNatty et al. (1974) reported that the production of progesterone by human granulosa cells in vitro requires an adequate concentration of PRL. Therefore, it is possible to speculate that a low level of PRL concentration in the SLP observed in our study is too low to maintain normal corpus luteum function. Indeed, Schulz et al., (1978) reported that the inhibition of PRL secretion, with bromocriptine caused defective progesterone synthesis in normal women. However, their treatment with bromocriptine brought about a marked fall in plasma PRL to levels below assay sensitivity (2ng/ml). Such a low level of PRL may cause defective progesterone synthesis as described by McNatty et al. (1974). To our knowledge, there have been no reports of a spontaneous pathologic hypoprolactinemic condition leading to infertility. In addition, Lenton et al. (1977) succeeded in getting a high pregnancy

4 268 MINAKAMI et al. Endocrinol. April 1985 Japon. Fig. 2. The means }SEM of plasma estradiol during -5 day to-1 day and+3 day to+7 day from the LH peak are shown in the left panel. The means }SEM of plasma progesterone during+3 day to +9 day from the LH peak are in the right panel. Shaded are open columns represent normal cycle and SLP. rate in regulary ovulating women with longstanding infertility by reducing the PRL These reports and our observation that concentration to below normal with a bro- follicular secretion of FSH is low in the SLP, strongly suggest that inadequacy of estrogen rapidly augments pituitary PRL the corpus luteum had a basis in defective secretion (Yen et al., 1974, Robyn et al., follicular maturation caused by subnormal 1976). A positive correlation between estrogen levels and PRL levels would account (1982), that metoclopramide-induced hyper- FSH levels. A report by Kauppila et al. for a higher PRL level in the normal luteal prolactinemia impaired human ovarian follicular maturation followed by luteal dysfunction, further supports the abovementioned phase (Franchimont et al., 1976, Vekemans et al., 1977, Djursing et al., 1981). Based on these reports, lower levels of PRL associated with a significant decrease in estra- hypothesis irrespective of differences in specific etiologies. This impaired follicular diol in the SLP shown in the present study maturation would be followed by low folli- could be explained by a decrease in augmentation by estrogen, rather than giving PRL any positive controlling role in the maintenance of corpus luteal function. Whether deficiencies in corpus luteal function originate during the early stages of follicle maturation and/or in the immediate preovulatory interval has not yet been established. Sherman and Korenman (1974) reported that in short luteal phases, preovulatory estradiol levels were subnormal and luteal phase secretion of both estradiol and progesterone was lower than normal. Mean mid-follicular phase FSH was also lower than found in a group of normal cycles (Sherman and Korenman 1974). Subnormal serum FSH levels during the follicular phase are followed by diminished progesterone circulating during the luteal phase of the menstrual cycle in both women (Ross et al., 1970) and monkeys (Wilks et al., 1976). More Specifically, Stouffer and Hodgen (1980) induced SLP in monkeys. They treated them during the follicular phase with charcoal-extracted porcine follicular fluid which selectively suppresses serum FSH levels. Sheehan et al., (1982) induced luteal phase defects in normal women by treating them, during the early follicular phase, with LHRH analog which suppressed FSH levels. Furthermore, Balmaceda et al. (1983) reported that significant suppression of gonadotropin levels after ovulation with inhibitory LHRH analog did not affect corpus luteal function. cular estradiol secretion as observed in our study. We do like to think this deficient follicular estradiol secretion and successive luteal dysfunction accompanying with low secretion of estradiol account for low PRL levels in non-hyperprolactinemic SLP. Our

5 Vol.32, No.2 PROLACTIN IN SHORT LUTEAL PHASE 269 finding that LH levels in the SLP are low has not been shown in humans, but was shown in monkeys (Wills et al., 1976). Larger and specific experimental studies will be needed to give this result significance in the SLP. Acknowledgements We wish to thank Mrs Y. Yoshida for secretarial assistance, and Miss Yoko Sato and Miss Yosuko Sato for technical assistance. References Andersen, A. N., J. F. Larsen, P. C. Eskildsen, M. Knoth, S. Micic, B. Svenstrup and J. Nielsen (1979). Treatment of hyperprolactinemic luteal insufficiency with bromocriptine. Acta. Obstet. Gynecol. Scand., 58, Araki, S., H. Minakami, S., Konuma, A. Akabori and T. Tamada (1978). Analysis of the positive feedback effect of estrogen on the release of gonadotropin in women. Endocrinol. Jap., 25, Bahamondes, L., W. Saboya, M. Tarnbascia and M. Trevisan (1979). Galactorrhea, infertility, and short luteal phases in hyperprolactinemic women: early stage of amenorrhea-galactorrhea? Fertil. Steril., 32, Balmaceda, J. P., M. R. Borghi, D. H. Coy, A. V. Schally and R. H. Asch (1983). Suppression of postovulatory gonadotropin levels does not affect corpus luteurn function in rhesus monkeys. J. Clin. Endocrinol. Metab., 57, Corenblum, B., N. Pairaudeau and A. B. Shewchuk (1976). Prolactin hypersecretion and short luteal phase defects. Obstet. Gynecol., 47, DelPozo, E., H. Wyss, G. Tolis, J. AIcaniz, A. Campana and F. Naftolin (1979). Prolactin and deficient luteal function. Obstet. Gynecol., 53, Djursing, H., C. Hagen, J. Moller. and C. Christiansen (1981). Short- and long term fluctuations in plasma prolactin concentration in normal subjects. Acta. Endocrinol. (Kbh), 97, 1-6. Ehara, Y., T. Siler, G. Vandenberg, Y. N. Sinha and S. S. C. Yen (1973). Circulating prolactin levels during the menstrual cycle: episodic release and diurnal variation. Am. J. Obstet. Gynecol., 117, Epstein, M. T., A. S. McNeilly, M. A. F. Murray and T. D. R. Hockaday (1975). Plasma testosterone and prolactin in the menstrual cycle. Clin. Endocrinol. (O.xf), 4, Franchimont, P., C. Dourcy, J. J. Legros, A. Reuter, Y. Vrindts-Gevaert, J. K. Van Cauwenberge and U. Gaspard (1976). Prolactin levels during the menstrual cycle. Clin. Endocrinol. (Oxf), 5, Jeweliwicz, R., I. Dyrenfurth, M. Warren, A. G. Frantz and R. L. Vande Wiele (1974). Effect of thyrotropin-releasing hormone (TRH) upon the menstrual cycle in women. J. Clin. Endocrinol. Metab., 39, Kauppila, A., P. Leinonen, R. Vihko and P. Ylostalo (1982). Metoclopramide-induced hyperprolactinemia impairs ovarian follicle maturation and corpus luteum function in women. J. Clin. Endocrinol. Metab., 54, Lenton, E. A., O. S. Sobowale and I. D. Cooke (1977). Prolactin concentrations in ovulatory but infertile women: treatment with bromocriptine. Br. Med. J., 2, McNatty, K. P., R. S. Sawers and A. S. McNeilly (1974). A possible role for prolactin in control of steroid secretion by the human Graafian follicle. Nature, 250, McNeilly, A. S. and T. Chard (1974). Circulating levels of prolactin during the menstrual cycle. Clin. Endocrinol. (Oxf), 3, Muhlenstedt, D., H. G. Bohnet, J. P. Hanker and H. P. G. S. Schneider (1978). Short luteal phase and prolactin. Int. J. Fertil., 23, Pepperell, R. J. (1981). Prolactin and reproduction. Fertil. Steril., 35, Robyn, C., P. Delvoye, J. Nokin, M. Vekemans, M. Badawi, F. P. Perez-Lopez, and M. L'Hermite (1973). Prolactin and human reproduction. International symposium on human prolactin. (ed. by J. L. Pasteels and C. Robyn) pp Excerpta Medica, Amsterdam Robyn, C. and M. Vekemans (1976). Influence of low dose oestrogen on circulating prolactin, LH and FSH levels in post-menopausal women. Acta. Endocrinol. (Kbh), 83, Ross, G. T., C. M. Cargille, M. B. Lipsett, P. L. Rayford, J. R. Marshall, C. A. Strott and D. Rodbard (1970). Pituitary and gonadal hormones in women during spontaneous and induced ovulatory cycles. Recent. Prog. Horm. Res., 26, 1-62.

6 270 MINAKAMI et al. Endocrinol. April 1985 Japon. Saunders, D. M., J. C. Hunter, H. R. Haase and G. R. Wilson (1979). Treatment of luteal phase inadequacy with bromocriptine. Obstet. Gynecol., 53, Schulz, K. D., W. Geiger, E. DelPozo and H. J. Kunzig (1978). Pattern of sexual steroids, prolactin, and gonadotropic hormones during prolactin inhibition in normally cycling women. Am. J. Obstet. Gynecol., 132, Seppala, M., E. Hirvonen and T. Ranta (1976). Hyperprolactinemia and luteal insufficiency. Lancet, 1, Sheehan, K. L., R. F. Casper and S. S. C. Yen (1982). Luteal phase defects induced by an agonist of luteinizing hormone-releasing factor: a model for fertility control. Science, 215, Sherman, B. M. and S. G. Korenman (1974). Measurement of plasma LH, FSH, estradiol and progesterone in disorders of the human menstrual cycle: the short luteal phase. J. Clin. Endocrinol. Metab., 38, Stouffer, R. L. and G. D. Hodgen (1980). Induction of luteal phase defects in rhesus monkeys by follicular fluid administration at the onset of the menstrual cycle. J. Clin. Endocrinol. Metab., 51, Vekemans, M., P. Delvoye, M. L'Hermite and C. Robyn (1977). Serum prolactin levels during the menstrual cycle. J. Clin. Endocrinol. Metab., 44, Wilks, J. W., G. D. Hodgen and G. T. Ross (1976). Luteal phase defects in the rhesus monkey: the significance of serum FSH: LH ratios. J. Clin. Endocrinol. Metab., 43, Yen, S. S. C., Y. Ehara and T. M. Siler (1974). Augmentation of prolactin secretion by estrogen in hypogonadal women. J. Clin. Invest., 53,