- Email: [email protected]
Female Ratio After Induced Ovulation
r-
II
REFERENCES 1. Lindstrom LH, Widerlov E, Gunne LM, Wahlstrom
!",
Terenius L: Endorphins in human cerebrospinal flUld: clinical correlations to some psychotic states. Acta Psy-. chiat Scand 57:153, 1978 2. Cohen MR, Cohen RM, Pickar D, Weingartner H, Murphy DL, Bunnley WE Jr: Letter to the Editor. Lancet 2:1110, 1981 3. Margules DL, Moisset B, Lewis MJ, Shi~rij~ H, Per: CB: J3-Endorphin in association with overeatmg m genetIcally obese mice (ob/ob) and rats (lalla). Science 202:988, 1978
They may all deny that they are searching for it, but the Holy Grail for the reproductive endocrinologist is a biochemical marker for premenstrual syndrome (PMS). Chuong et al. give it a good t? by measuring premenstrual serum levels of 6 dlfferent neuropeptides in 20 PMS phenotypes. The secret will not yield so readily as Dr. Reid suggests. The search, in fact, is becoming increasingly complex. The numbers of new and different neuropeptides are overwhelming. They are rivaled only by the numbers of new and different growth factors. Authors and correspondents agree that we are remote from the central site of synthesis and secretion of ~-endorphin (~-Ep). The editor suggests, however, that assumptions about anything relative to PMS may deter the quest for the Holy Grail. Dogmas are not immutable, as evidenced by the recent report from Rockefeller University describing a messenger ribonueleic acid for proopiomelanocortin (POMC) in the ovaries of rodents and primates. Furthermore, these transcripts seem to be under the control of gonadotropins. 1 This is not the first report to suggest that POMC mRNA and even immunoreactive ~-Ep are localized within animal ovaries, including follicular fluid. 2 Perhaps an ovary gone awry is the culprit after all. Assuming one has the appropriate clinical phenotype the opportunity to study day-to-day variations in the POMC transcripts during a single cycle should be enough to send dedicated PMS investigators into orbit around the pituitary . . . or around the ovary, as the case may be. P. G. McD., Letters, Editor REFERENCES
2. Lovegren E, Zimniski S, Puett D: Immunoreactive J3-endorphin in the gonadotropin-primed immature rat ovary. Proceedings of the 19th Miami Winter Symposium, Vol. 4, Edited by David Puett et al. Cambridge, Cambridge University Press, 1986, p 48
Male/Female Ratio After Induced Ovulation To the Editor: I have hypothesized that maternal gonadotropin levels at the time of conception have a direct preconceptional effect on the sex of the zygote, high levels of hormone being associated with subsequent female births. Ben-Rafael et a1.,l in their discussion of the hypothesis, fail, in two respects, to give full weight to the evidence for it. 1. The total data on the sexes of infants following hormonal induction of ovulation are now far more numerous than in 1980, the date of publication cited by these authors. In the most recent survey 2, 3 summarizing the results of 38 samples, there ~ere 1207 males and 1401 females (X 2 = 27.4, P < 0.000001, tested against an expected sex ratio of 106). 2. The suggestion first made by Guerrer0 4 and Harlap,5 that the regression of sex ratio on cycle day of natural insemination is V-shaped, has been confirmed in three studies. 6 - 8 The evidence for both these phenomena is, thus, very good. Whether my proposed explanation is correct is, of course, another matter.
William H. James, PhD. Visiting Worker MRC Mammalian Development Unit Wolfson House (University College London) London, United Kingdom February 24, 1986 REFERENCES 1. Ben-Rafael Z, Matalon A, Blankstein J, Serr DM, Lunen-
2. 3.
4.
1. Chen CoL, Chang C-C, Krieger DT, Bardin WC: Expres-
sion and regulation of proopiomelanocortin-like gene in the ovary and placenta: comparison with the testis. Endocrinol 118:2382, 1986
740
Letters-to-the-editor
5.
feld B, Mashiach S: Male to female ratio after gonadotropin-induced ovulation. Fertil Steril 45:36, 1986 James WH: The sex ratio of infants after hormonal induction of ovulation. Br J Obstet Gynaecol 92:299, 1985 James WH: The sex ratio of infants after hormonal induction of ovulation: author's reply. Br J Obstet Gynaecol 92:993, 1985 Guerrero R: Association of the type and time of insemination within the menstrual cycle with the human sex ratio at birth. N Engl J Med 291:1056, 1974 Harlap S: Gender of infants conceived on different days of the menstrual cycle. N Engl J Med 300:1445, 1979
Fertility and Sterility
6. Spira N: Vieillissements des gametes dans les voies genitales feminines et issue de la grossesse. In INSERM Colloque, No 103, Edited by A Apira, P Jouannet. Paris, INSERM, 1981, P 437 7. France JT, Graham FM, Gosling L, Hair PI: A prospective study of the preselection of the sex of offspring by timing intercourse relative to ovulation. Fertil Steril 41:894, 1984 8. Perez A, Eger R, Domenichini V, Kambic R, Gray RH: Sex ratio associated with natural family planning. Fertil Steril 43:152, 1985
Reply of the Authors: The phenomena pointed out by James is that women treated by clomiphene citrate (CC) or human menopausal gonadotropin (hMG) for induction of ovulation have a lower than expected male/female (MlF) ratio. This in his view supports his hypothesis that the high follicle-stimulating hormone (FSH) production at the time of conception directly promotes the promotion of more female zygotes. 1 , 2 We were aware of James'3 recent larger series, which was a response to our own previous letter.4 The new data mentioned contain results from 38 different samples; however, only 3 samples, each from one center, were large enough (more than 10 infants) for analysis. The others represent data pooled from either case reports of triplets and higher multiple pregnancies (a total of 99 cases) or provided to him as personal communications (1074 cases). The information regarding data collection and completeness, the MlF ratio in singleton, twins, etc., and, most important, the type of drug used for induction of ovulation cannot be evaluated in these cases. Nevertheless, when we combined all the data of singleton infants from James' paper (MiF 240:258; 48.1%) and added the data from our publication, the M/F ratio was 49.5% (319:323), which is not statistically different from the expected ratio. Similar results were obtained from examining his reported MIF ratio in twins. The female predominance, James has noticed in multiple gestation, may alternatively be explained by better survival of female fetuses in the "overpopulated uterus," rather than sex selection through generation of more female zygotes, conditioned by FSH levels. The major problem in the James hypothesis, however, is the assumption that induction of ovulation with CC or hMG is invariably associated with high FSH levels. Although FSH levels are Vol. 46, No.4, October 1986
higher in hMG-treated women than in the normal cycle, they nevertheless vary widely. 5 However, FSH levels in CC patients are hardly increased; and if they are, the increase usually occurs early in the follicular phase, before the zygote is formed. Therefore, it seems to us unwarranted to combine the results from patients treated with CC and hMG. As to the second point,in James' letter, since we did not study MlF ratio in natural cycles, 6 we only discussed Harlap's7 and Guerrero's8 findings and mentioned other papers that have suggested different trends. To sum up, more information on MIF ratio from a large series broken down to the various drugs used (Le., CC, hMG) might prove whether the ratio is affected by induction of ovulation. Nevertheless, we agree with James' last remark.
Zion Ben-Rafael, MD. Department of Obstetrics and Gynecology Hospital of University of Pennsylvania Philadelphia, Pennsylvania 19104 JosefBlankstein, MD. Shlomo Mashiach, MD. Department of Obstetrics and Gynecology The C. Sheba Medical Center and Sackler School of Medicine Tel-Hashomer, Israel June 26, 1986
REFERENCES 1. James WH: Gonadotropin and the human secondary sex
ratio. Br Med J 281:711, 1980 2. James WH: Time of fertilization and sex of infants. Lancet 1:1124, 1980 3. James WH: The sex ratio of infants born after hormonal induction of ovulation. Br J Obstet Gynaecol 92:299, 1985 4. Ben-Rafael Z, Blankstein J, Mashiach S: BBT chart in AID pregnancy cycles (Letter). Fertil Steril 41:328, 1984 5. Ben-Rafael Z, Mastroianni L, Meloni F, Strauss JF, Flickinger GL: Changes in serum sex hormone-binding globulin, free estradiol, and testosterone during gonadotropin treatment. Fertil Steril 46:593, 1986 6. Ben-Rafael Z, Matalon A, Blankstein J, Serr DM, Lunenfeld B, Mashiach S: Male to female ratio after gonadotropin-induced ovulation. Fertil Steril 45:36, 1986 7. Harlap S: Gender of infants conceived on different days of the menstrual cycle. N Engl J Med 300:1445,1979 8. Guerrero R: Association of the type and time of insemination within the menstrual cycle with the human sex ratio at birth. N Engl J Med 291:1056, 1974
Letters-to-the-editor
741
II
REFERENCES 1. Lindstrom LH, Widerlov E, Gunne LM, Wahlstrom
!",
Terenius L: Endorphins in human cerebrospinal flUld: clinical correlations to some psychotic states. Acta Psy-. chiat Scand 57:153, 1978 2. Cohen MR, Cohen RM, Pickar D, Weingartner H, Murphy DL, Bunnley WE Jr: Letter to the Editor. Lancet 2:1110, 1981 3. Margules DL, Moisset B, Lewis MJ, Shi~rij~ H, Per: CB: J3-Endorphin in association with overeatmg m genetIcally obese mice (ob/ob) and rats (lalla). Science 202:988, 1978
They may all deny that they are searching for it, but the Holy Grail for the reproductive endocrinologist is a biochemical marker for premenstrual syndrome (PMS). Chuong et al. give it a good t? by measuring premenstrual serum levels of 6 dlfferent neuropeptides in 20 PMS phenotypes. The secret will not yield so readily as Dr. Reid suggests. The search, in fact, is becoming increasingly complex. The numbers of new and different neuropeptides are overwhelming. They are rivaled only by the numbers of new and different growth factors. Authors and correspondents agree that we are remote from the central site of synthesis and secretion of ~-endorphin (~-Ep). The editor suggests, however, that assumptions about anything relative to PMS may deter the quest for the Holy Grail. Dogmas are not immutable, as evidenced by the recent report from Rockefeller University describing a messenger ribonueleic acid for proopiomelanocortin (POMC) in the ovaries of rodents and primates. Furthermore, these transcripts seem to be under the control of gonadotropins. 1 This is not the first report to suggest that POMC mRNA and even immunoreactive ~-Ep are localized within animal ovaries, including follicular fluid. 2 Perhaps an ovary gone awry is the culprit after all. Assuming one has the appropriate clinical phenotype the opportunity to study day-to-day variations in the POMC transcripts during a single cycle should be enough to send dedicated PMS investigators into orbit around the pituitary . . . or around the ovary, as the case may be. P. G. McD., Letters, Editor REFERENCES
2. Lovegren E, Zimniski S, Puett D: Immunoreactive J3-endorphin in the gonadotropin-primed immature rat ovary. Proceedings of the 19th Miami Winter Symposium, Vol. 4, Edited by David Puett et al. Cambridge, Cambridge University Press, 1986, p 48
Male/Female Ratio After Induced Ovulation To the Editor: I have hypothesized that maternal gonadotropin levels at the time of conception have a direct preconceptional effect on the sex of the zygote, high levels of hormone being associated with subsequent female births. Ben-Rafael et a1.,l in their discussion of the hypothesis, fail, in two respects, to give full weight to the evidence for it. 1. The total data on the sexes of infants following hormonal induction of ovulation are now far more numerous than in 1980, the date of publication cited by these authors. In the most recent survey 2, 3 summarizing the results of 38 samples, there ~ere 1207 males and 1401 females (X 2 = 27.4, P < 0.000001, tested against an expected sex ratio of 106). 2. The suggestion first made by Guerrer0 4 and Harlap,5 that the regression of sex ratio on cycle day of natural insemination is V-shaped, has been confirmed in three studies. 6 - 8 The evidence for both these phenomena is, thus, very good. Whether my proposed explanation is correct is, of course, another matter.
William H. James, PhD. Visiting Worker MRC Mammalian Development Unit Wolfson House (University College London) London, United Kingdom February 24, 1986 REFERENCES 1. Ben-Rafael Z, Matalon A, Blankstein J, Serr DM, Lunen-
2. 3.
4.
1. Chen CoL, Chang C-C, Krieger DT, Bardin WC: Expres-
sion and regulation of proopiomelanocortin-like gene in the ovary and placenta: comparison with the testis. Endocrinol 118:2382, 1986
740
Letters-to-the-editor
5.
feld B, Mashiach S: Male to female ratio after gonadotropin-induced ovulation. Fertil Steril 45:36, 1986 James WH: The sex ratio of infants after hormonal induction of ovulation. Br J Obstet Gynaecol 92:299, 1985 James WH: The sex ratio of infants after hormonal induction of ovulation: author's reply. Br J Obstet Gynaecol 92:993, 1985 Guerrero R: Association of the type and time of insemination within the menstrual cycle with the human sex ratio at birth. N Engl J Med 291:1056, 1974 Harlap S: Gender of infants conceived on different days of the menstrual cycle. N Engl J Med 300:1445, 1979
Fertility and Sterility
6. Spira N: Vieillissements des gametes dans les voies genitales feminines et issue de la grossesse. In INSERM Colloque, No 103, Edited by A Apira, P Jouannet. Paris, INSERM, 1981, P 437 7. France JT, Graham FM, Gosling L, Hair PI: A prospective study of the preselection of the sex of offspring by timing intercourse relative to ovulation. Fertil Steril 41:894, 1984 8. Perez A, Eger R, Domenichini V, Kambic R, Gray RH: Sex ratio associated with natural family planning. Fertil Steril 43:152, 1985
Reply of the Authors: The phenomena pointed out by James is that women treated by clomiphene citrate (CC) or human menopausal gonadotropin (hMG) for induction of ovulation have a lower than expected male/female (MlF) ratio. This in his view supports his hypothesis that the high follicle-stimulating hormone (FSH) production at the time of conception directly promotes the promotion of more female zygotes. 1 , 2 We were aware of James'3 recent larger series, which was a response to our own previous letter.4 The new data mentioned contain results from 38 different samples; however, only 3 samples, each from one center, were large enough (more than 10 infants) for analysis. The others represent data pooled from either case reports of triplets and higher multiple pregnancies (a total of 99 cases) or provided to him as personal communications (1074 cases). The information regarding data collection and completeness, the MlF ratio in singleton, twins, etc., and, most important, the type of drug used for induction of ovulation cannot be evaluated in these cases. Nevertheless, when we combined all the data of singleton infants from James' paper (MiF 240:258; 48.1%) and added the data from our publication, the M/F ratio was 49.5% (319:323), which is not statistically different from the expected ratio. Similar results were obtained from examining his reported MIF ratio in twins. The female predominance, James has noticed in multiple gestation, may alternatively be explained by better survival of female fetuses in the "overpopulated uterus," rather than sex selection through generation of more female zygotes, conditioned by FSH levels. The major problem in the James hypothesis, however, is the assumption that induction of ovulation with CC or hMG is invariably associated with high FSH levels. Although FSH levels are Vol. 46, No.4, October 1986
higher in hMG-treated women than in the normal cycle, they nevertheless vary widely. 5 However, FSH levels in CC patients are hardly increased; and if they are, the increase usually occurs early in the follicular phase, before the zygote is formed. Therefore, it seems to us unwarranted to combine the results from patients treated with CC and hMG. As to the second point,in James' letter, since we did not study MlF ratio in natural cycles, 6 we only discussed Harlap's7 and Guerrero's8 findings and mentioned other papers that have suggested different trends. To sum up, more information on MIF ratio from a large series broken down to the various drugs used (Le., CC, hMG) might prove whether the ratio is affected by induction of ovulation. Nevertheless, we agree with James' last remark.
Zion Ben-Rafael, MD. Department of Obstetrics and Gynecology Hospital of University of Pennsylvania Philadelphia, Pennsylvania 19104 JosefBlankstein, MD. Shlomo Mashiach, MD. Department of Obstetrics and Gynecology The C. Sheba Medical Center and Sackler School of Medicine Tel-Hashomer, Israel June 26, 1986
REFERENCES 1. James WH: Gonadotropin and the human secondary sex
ratio. Br Med J 281:711, 1980 2. James WH: Time of fertilization and sex of infants. Lancet 1:1124, 1980 3. James WH: The sex ratio of infants born after hormonal induction of ovulation. Br J Obstet Gynaecol 92:299, 1985 4. Ben-Rafael Z, Blankstein J, Mashiach S: BBT chart in AID pregnancy cycles (Letter). Fertil Steril 41:328, 1984 5. Ben-Rafael Z, Mastroianni L, Meloni F, Strauss JF, Flickinger GL: Changes in serum sex hormone-binding globulin, free estradiol, and testosterone during gonadotropin treatment. Fertil Steril 46:593, 1986 6. Ben-Rafael Z, Matalon A, Blankstein J, Serr DM, Lunenfeld B, Mashiach S: Male to female ratio after gonadotropin-induced ovulation. Fertil Steril 45:36, 1986 7. Harlap S: Gender of infants conceived on different days of the menstrual cycle. N Engl J Med 300:1445,1979 8. Guerrero R: Association of the type and time of insemination within the menstrual cycle with the human sex ratio at birth. N Engl J Med 291:1056, 1974
Letters-to-the-editor
741