This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lambalk, C. B. Articles by Schoemaker, J. Search for Related Content PubMed PubMed Citation Articles by Lambalk, C. B. Articles by Schoemaker, J.

Increased Levels and Pulsatility of Follicle-Stimulating Hormone in Mothers of Hereditary Dizygotic Twins¹

Division of Reproductive Endocrinology, Research Institute for Endocrinology, Reproduction and Metabolism (C.B.L., L.deB., C.H.DeK., E.S., C.P.-S., J.S.); and Department of Psychonomics of the Faculty of Psychology (D.I.B.), Free University, Amsterdam, The Netherlands 1007 MB

Address all correspondence and requests for reprints to: C.B. Lambalk, Department of Obstetrics and Gynaecology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: cb.lambalk{at}azvu.nl

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
According to the endocrine model of hereditary dizygotic twinning, high FSH is responsible for multiple ovulation and pregnancy. Our study explored the underlying neuroendocrine causes.

In a prospective clinical study, we compared the third day of menses parameters of episodic secretion of LH and FSH, the pituitary response to LHRH, plasma estradiol, and dimeric inhibin A and B in 16 regularly menstruating and 9 postmenopausal mothers of dizygotic twins with a family history of twinning and 14 premenopausal and 9 postmenopausal controls. Seven of 16 premenopausal mothers of twins had abnormally high FSH levels of more than 10 IU/L compared with 1/14 in controls (P = 0.024). In the premenopausal mothers of twins, mean FSH concentrations (P = 0.025) and FSH pulse frequency (P = 0.003) were significantly elevated, whereas FSH pulse amplitude and FSH response to LHRH were unaltered. For LH, neither the secretory parameters nor the response to LHRH was different. There were no differences between estradiol and inhibin A and B levels. Postmenopausal mothers of twin and controls did not differ with respect to the secretory pattern of LH and FSH.

We conclude that under equal ovarian feedback conditions, premenopausal mothers of a dizygotic twin have hyper stimulation by endogenous FSH caused by neuroendocrine, hypothalamic, or pituitary mechanisms. This is the result of altered responsiveness to ovarian feedback and/or pituitary or suprapituitary, non-LHRH-like mechanisms that stimulate pulsatile FSH.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
NATURAL dizygotic twinning often occurs on a hereditary basis (1, 2). Furthermore, maternal age above 35 yr carries an increased risk of dizygotic twinning (3). Multiple follicle growth and subsequent multiple ovulation seem a logical explanation. Both have been demonstrated in mothers of hereditary dizygotic twins (4, 5). Usually, ongoing development of one dominant follicle takes place when a certain threshold in the level of plasma FSH is only marginally exceeded (6, 7). Multiple follicle growth is related to FSH levels higher than this threshold or to levels exceeding the threshold for too long a time (8). Milham (9) introduced an endocrinological model explaining the epidemiological observations for dizygotic twinning. According to this model, pituitary gonadotropins such as FSH and LH are responsible for the increased ovulation in mothers of dizygotic twins. Several studies have shown increased plasma gonadotropin levels in mothers of dizygotic twins (10, 11, 12).

Our study tested the hypothesis that a pituitary or suprapituitary hereditary difference exists that causes increased FSH levels in mothers of hereditary dizygotic twins. Both LH and FSH are clearly secreted in a pulsatile fashion during the early follicular phase (13). Pulsatile LH can be considered a good representation of the episodic activity of the hypothalamic LHRH pulse generator. Obviously, in cases of elevated FSH levels, detailed analysis of its episodic secretion, in concert with that of LH, could potentially reveal responsible mechanisms. We report here the pulsatile secretion of LH and FSH and the responsiveness to a test dose of LHRH in mothers of hereditary dizygotic twins compared with controls. Measurements took place on the third day of menstruation during the luteo-follicular transition of the cycle when recruitment of new follicles takes place (8). To evaluate the role of the ovary as a potential cause of differences in gonadotropin secretion, the levels of estradiol and dimeric inhibin A and B were also measured. Inhibin A, which is produced by the ovary in the luteal phase, and inhibin B, which is produced by the ovary in the follicular phase, are now clearly considered to be of physiological importance in the regulation of the menstrual cycle because of their selective negative feedback of FSH secretion (14). In a further attempt to define ovarian factors in hereditary dizygotic twinning, episodic gonadotropin secretion was evaluated in absence of ovarian feedback, i.e. after menopause, in mothers of twins and controls.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

The study was approved by the local Committee of Ethics on Research in Human Subjects. Mothers of dizygotic twins were recruited by means of an advertisement in a annually published newsletter sent to all volunteers being registered in the Dutch Twin Register. This register is kept up to date at the division of Psychonomics from the Faculty of Psychology of the Free University of Amsterdam. Volunteering mothers of twins had to have given birth to spontaneous dizygotic twins of unequal sex before the age of 36 yr and had to have had at least one other dizygotic twin in a first or second degree female relative. They had to be in good general health without any current medical treatment. Women with hormonal treatment in the 6 months preceding the study were excluded. Premenopausal mothers had to have a regular menstrual cycle varying between 21–35 days in length. Postmenopausal mothers had to be at least 3 yr after menopause. The control singleton mothers had to meet the same criteria but with the requirement of having given birth to at least two singleton pregnancies before the age of 36 yr and had to be without twins in the family.

Blood sampling

Blood samples were collected on the third day of menstruation in the premenopausal group. All participants kept a basal body temperature chart to verify ovulation in the study cycle. In the postmenopausal group, the blood sampling took place on a convenient working day.

Serial blood samples for LH and FSH determination were taken every 10 min for 6 h via an indwelling catheter with a heparin lock in a convenient forearm vein. Sampling was always started between 0800–0900 h. Immediately after the last sample, an LHRH challenge with an iv injection of 100 µg LHRH (HRF, Wyeth, Hoofddorp, The Netherlands) followed, and three additional samples were taken after 30, 60, and 90 min for LH and FSH measurement.

Assays

Dimeric LH and FSH were measured in duplicate by means of a double first monoclonal and second polyclonal antibody immunoradiometric assay (IRMA-mat BYK-Sangtec Diagnostica GmbH & Co., Dietzenbach, Germany) with a lower detection limit of 0.2 IU/L. References for expression of LH and FSH were first International Reference Preparations 68/40 and second International Reference Preparations 78/549, respectively. LH intraassay coefficients of variation (CV) were 4.3% and 2.4% at the levels of 3 U/L and of 23 U/L, respectively. FSH intraassay CVs were 3% and 1.8% at levels of 7 U/L and 74 U/L, respectively. Interassay CVs were below 8% for both gonadotropins. For each individual, all samples were measured in the same assay for each hormone.

Inhibin A and B were measured in duplicate with two-site enzyme-linked immunoassays (Serotec, Oxford, UK) (14, 15). CVs were less than 5% within a plate, and less than 7% between plates of both assays. The sensitivity was 3 pg/mL for inhibin A and 15 pg/mL for inhibin B. Both hormones were measured in duplicate. Estradiol was measured by means of radio immunoassay (Sorin Biomedical, Silage, Italy) with a lower limit of detection of 18 pmol/L and CVs of less than 5%.

Pulse analysis

The analysis used was a computerized version of a previously developed and validated method (16, 17). The algorithm is valid for replicate repeated measurements of LH and FSH, with a less than 5% chance of indication of nonexisting pulses in series of 100 samples taken from pooled serum. This method is of particular value in detecting episodic secretion of hormones with relatively long half-lives, because pulses are indicated when a significant rise occurs without the requirement of a subsequent decline. Nadirs preceding the pulses are indicated as marker points in the hormone patterns rather than the pulses themselves.

Statistical analysis

For each subject, the mean concentrations of LH and FSH, the mean pulse amplitude over the day, and the frequency of LH and FSH pulses per 6 h were calculated. The maximal gonadotropin increment was taken as a parameter for the response to the LHRH challenge.

LH and FSH pulses were indicated to have occurred not synchronously when their beginnings were more than 10 min apart (18). From each subject, the number of FSH pulses that occurred singularly or in concordance with an LH pulse was estimated, and means per group were compared.

Hormone levels were transformed logarithmically before statistical analysis. Student’s t test was used for comparison of means. Linear regression analysis was performed with the following dependent variables: mean concentrations, pulse frequencies per 6 h, pulse amplitudes, and responses to LHRH challenge. Twinning feature and smoking habits, expressed as number of pack years as a potential confounder, (19) were the independent variables. Fisher’s exact test was used to evaluate significance of incidence of occurrence of high FSH values. Two- sided P < 0.05 was considered to indicate statistical significance.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Basic characteristics of study population

We studied 16 premenopausal mothers of dizygotic twins and 14 controls. Their basic characteristics are summarized in Table 1. The mothers of twins did not differ from the controls with respect to age, parity, body mass index, and time from last delivery. However, they had smoked significantly more and their menstrual cycle length was 2 days less.

The pulsatile nature of FSH and LH secretion was clearly discernible in both groups. Figure 1 shows the patterns of gonadotropin secretion in two premenopausal mothers of twins and two controls. Mean ± SD FSH levels (the overall average of all 37 samples per subject) of the premenopausal mothers of a dizygotic twin were 9.8 ± 5.5 IU/L, which is about 65% higher compared with control values of 6.0 ± 3.0 IU/L (P = 0.025). This coincided with a significant increase (P = 0.003) in FSH pulse frequency of 4.8 ± 1.5 pulses/6 h compared with 3.0 ± 1.5 pulses/6 h (Fig. 2). In mothers of twins, higher FSH levels were significantly associated with an increase in FSH pulse frequency (linear regression analysis: P = 0.0215). After correction for the differences in smoking habits, the tendency for twinning still was shown to be an independent determinant for elevation of FSH levels and pulse frequency. In the linear regression model, age and body mass did not appear to be a determinant of FSH level. The mean FSH pulse amplitude and the maximum response to LHRH challenge were not significantly different. Compared with controls (1/14), significantly more mothers of twins (7/16) had one or more individual FSH values above 10 IU/L (P = 0.024). In the postmenopausal mothers of twins, FSH secretory parameters were not different from controls (Fig. 2).

View larger version (22K): [in this window] [in a new window]   Figure 1. Examples of secretion pattern and response to LHRH in two mothers of hereditary twins and two mothers of singletons. Solid lines represent FSH; dashed lines represent LH. , Denote start of an FSH pulse; , indicate LH pulses.

View larger version (19K): [in this window] [in a new window]   Figure 2. Means and SD of different parameters of episodic LH (upper panels) and FSH (lower panels) in premenopausal (left side) and postmenopausal (right side) mothers of dizygotic twins (solid bars) and controls (open bars). *, P = 0.025; **, P = 0.003.

In the premenopausal and postmenopausal mothers of twins, the parameters for episodic LH secretion did not differ from controls (Fig. 2). In the premenopausal mothers, mean plasma levels of 17-ß estradiol and dimeric inhibin A and B levels showed no difference between the two groups (Table 3).

The mean number and range of FSH pulses occurring without a concurrent LH pulse was a mean of 2.19 (range, 0–7) in mothers of twins, which was significantly more compared with controls (mean 0.93; range, 0–4; P = 0.033). The number of FSH pulses that had occurred synchronous with an LH pulse was not significantly different. In the postmenopausal mothers, no differences were observed with respect to number of individual LH and FSH pulses.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the present study, we attempted to show more precisely the site of origin of any difference in gonadotropin secretion related to dizygotic twinning. In line with Milham’s (9) hypothesis and in agreement with earlier findings by Martin et al. (10, 11) we observed elevated follicular phase levels of FSH in mothers with a hereditary history of dizygotic twins. We found that this is associated with a rise in the FSH pulse frequency without any changes in other characteristics of pulsatile FSH.

Furthermore, we evaluated ovarian feedback by measuring estradiol levels and inhibin A and B to explain the elevated FSH levels. We found no changes in any of these negative feedback hormones, which is in line with earlier human studies (5, 10, 11). In addition, in the Booroola sheep model for dizygotic twinning, which exhibits an autosomal dominant gene (FecB) associated with elevated FSH levels and localized to a region homologous to the human chromosome 4, there is no evidence for differences in bioactive inhibin secretion (20). This argues against diminished negative ovarian feedback as the primary cause of elevated FSH levels in mothers of dizygotic twins.

Our observation of no differences in the secretion of FSH in postmenopausal mothers of twins compared with controls would nevertheless suggest a role for the ovary. It should be noted, however, that under postmenopausal conditions, subtle differences in FSH secretion may easily be obscured by the great hourly and interindividual variability in secretion of this hormone. Furthermore, it is possible that despite equal levels of hormones exerting negative feedback as measured with immunoassays, differences may exist in biological activity. However, the inhibin assays that were used only measured intact dimeric hormone, which correlates well with biological activity (14). We cannot rule out the possibility that still unknown ovarian hormones that regulate feedback of gonadotropin secretion are involved. Specific FSH stimulatory substances like activins, which are homodimers of the ß-chains of inhibin but not their binding protein follistatin, may be involved in the natural rise of FSH in aging women (21). Others claim however, that activin is not involved in the gonadal regulation of the menstrual cycle (22). A logical explanation of our observations would be that differences in response to gonadal feedback signals are present. This would favor the pituitary and/or the hypothalamus as the primary sites involved in altered gonadotropin secretion in mothers of dizygotic twins.

A difference in FSH moiety that would result in increased serum half-life, thereby accounting for greater circulating concentrations in the mothers of twins, does not seem likely, because in our study the higher FSH levels can be attributed to a clear increase in the number of pulses. Several observations rule out an altered activity of the LHRH pulse generator as the cause of the increase in FSH pulse frequency. In the first place, the increase only concerned additional FSH pulses without a simultaneous LH pulse. In the second place, FSH pulse amplitudes were unaltered and there was no change in maximal response to LHRH. This makes it unlikely that an increased pituitary sensitivity to smaller LHRH pulses has caused the additional FSH pulses. Finally, and probably most convincing, is our observation that none of the dynamic parameters of the LH secretion were different in the mothers of the twins.

For the initiation and maintenance of FSH secretion, pulsatile LHRH is an absolute prerequisite (23). There are indications that once FSH synthesis has started, spontaneous release by the pituitary may occur without LHRH stimulation. In particular, this part of FSH secretion is under the control of negative feedback through inhibin (24). In addition to this autonomous FSH secretion, pulsatile FSH secretion occurs in association with exogenous or endogenous LHRH pulses (25, 26), but the link between LHRH and FSH pulses is much less than between LHRH and LH pulses. The occurrence of single FSH pulses in earlier studies in postmenopausal women (18, 25, 27) without a concomitant LH pulse, indicates the presence of LHRH-independent factors governing episodic FSH secretion. This is also supported by the recent observations in sheep of clear FSH pulses in jugular vein blood without significant LHRH elevations in serially sampled blood from pituitary portal blood vessels (28). Altered activity of such factors are probably involved in the increased number of FSH pulses in mothers of twins. There are several possibilities for the nature of this(ese) factor(s). In the first place, spontaneous pituitary FSH secretion may occur in temporary bursts independent of any releasing factor. However, there are no data available that would support such a secretory mechanism. Alternatively, mothers of dizygotic twins may have genes that are activated that code for a still-putative separate FSH releasing hormone (29, 30), or they may carry mutations in the gene coding for LHRH, resulting in synthesis of an LHRH- like peptide preferably inducing secretion of FSH over LH (31).

In our view, it seems valid to assume that an hereditary trait of having dizygotic twins is the result of endogenous hyperstimulation by FSH in a significant proportion of mothers. A high proportion of mothers of twins in this study had one or more FSH values over 10 IU/L. Within the specifications of the assay that was used in this study, this observation is usually associated with incipient ovarian failure when observed in regularly menstruating women. This is thought to be caused by a diminished ovarian reserve (32). There are indications that being a mother of a dizygotic twin (either on an hereditary or nonhereditary basis) is a risk for earlier menopause (33). In the present study however, the postmenopausal mothers of hereditary dizygotic twins did not differ with controls in age at menopause. This might have been the result of undetectable results because of small sample size, but it may also indicate that incipient ovarian failure and hereditary dizygotic twinning are different entities. On the other hand, the natural rise of follicular phase FSH levels, as observed in general after 30 yr of age, may be the underlying cause of the risk of nonhereditary dizygotic twinning (3) with increased maternal age. Somewhat to our surprise, we could not show a relation between age and FSH. Probably a substantially larger number of subjects are needed to find these differences. Anyway, it should be noted that not all patients with high FSH levels in the early follicular phase should be considered to have premature incipient ovarian failure.

In conclusion, the endocrine hypothesis of an elevated FSH in hereditary dizygotic twinning seems valid. Our results favor pituitary- or LHRH-independent factors from higher regions of the brain leading to more FSH and hereby causing dizygotic twinning.

	Acknowledgments

 
We thank Dr. G.J. van Daal for his helpful comments during the final preparation of the manuscript and our skillful research nurse C. Thuys for the help in carrying out all the experiments. Finally, we appreciate Wyeth, Hoofddorp, The Netherlands, for generously donating HRF for the LHRH challenge tests, and Sanofi Winthrop, Maassluis, The Netherlands, for their financial support for covering travel expenses of the volunteers in this study.

	Footnotes

 
¹ This work was supported by the Foundation for Scientific Research in Gynaecology, Free University, Amsterdam.

Received July 2, 1997.

Revised October 14, 1997.

Accepted October 28, 1997.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Parisi P, Gatti M, Prinzi G, Caperna G. 1983 Familial incidence of twinning. Nature. 304:626–628.[CrossRef][Medline]
2. Lichtenstein P, Olaussen PO, Kallen AJB. 1996 Twin births to mothers who are twins: a registry based study. Br Med J. 312:879–881.[Abstract/Free Full Text]
3. Bulmer MG. 1970 The biology of twinning in man. Oxford: Clarendon Press.
4. Martin NG, Shanley S, Butt K, Osborne J, O’Brien G. 1991 Excessive follicular recruitment, and growth in mothers of spontaneous dizygotic twins. Acta Genet Med Gemellol Roma. 40:291–301.[Medline]
5. Gilfillan CP, Robertson DM, Burger HG, Leoni MA, Hurley VA, Martin NG. 1996 The control of ovulation in mothers of dizygotic twins. J Clin Endocrinol Metab. 81:1557–1562.[Abstract]
6. Schoemaker J, van Weissenbruch MM, Scheele F, van der Meer M. 1993 The FSH threshold concept in clinical ovulation induction. Ballieres Clin Obstet Gynaecol. 7: 297–308.
7. Brown JB. 1978 Pituitary control of ovarian function-concepts derived from gonadotropin therapy. Aust NZ J Obstet Gynecol. 18:47–54.
8. Baird DT. 1987 A model for follicular selection, and ovulation: lessons from superovulation. J Steroid Biochem. 27:15–23.[CrossRef][Medline]
9. Milham S. 1964 Pituitary gonadotrophin, and dizygotic twinning. Lancet. 2: 566.
10. Martin NG, Olsen ME, Theile H, El Beaini JL, Handelsman D, Bhatnagar AS. 1984 Pituitary-ovarian function in mothers who have had two sets of dyzygotic twins. Fertil Steril. 41:878–880.[Medline]
11. Martin NG, Robertson DM, Chenevix Trench G, de Kretser DM, Osborne J, Burger HG. 1991 Elevation of follicular phase inhibin, and luteinizing hormone levels in mothers of dizygotic twins suggests nonovarian control of human multiple ovulation. Fertil Steril. 56:469–474.[Medline]
12. Nylander PP. 1973 Serum levels of gonadotrophins in relation to multiple pregnancy in Nigeria. Br J Obstet Gynaecol. 80:651–653.
13. Booth Jr RA, Weltman JY, Yankov VI, et al. 1996 Mode of pulsatile follicle-stimulating hormone secretion in gonadal hormone-sufficient and -deficient women—a clinical research center study. J Clin Endocrinol Metab. 81:3208–3214.[Abstract]
14. Groome NP, Illingworth PJ, O’Brien M, et al. 1996 Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab. 81:1401–1405.[Abstract]
15. Groome NP, Illingworth PJ, O’Brien M, et al. 1994 Detection of dimeric inhibin throughout the human menstrual cycle by two-site enzyme immunoassay. Clin Endocrinol (Oxf). 40:717–723.[Medline]
16. Lambalk CB, de Koning J, Van Kessel H, Van Rees GP, Schoemaker J. 1985 Calculation of the intra-assay variation per assay, and its relevance to LH pulse detection. IRCS Med Sci. 13:1183–1184.
17. Scheele F, Lambalk CB, Schoemaker J, et al. 1987 Patterns of LH and FSH in men during high-frequency blood sampling. J Endocrinol. 114:153–160.[Abstract]
18. Veldhuis JD, Johnson ML, Seneta E. 1991 Analysis of copulsatility of anterior pituitary hormones. J Clin Endocrinol Metab. 73:569–576.[Abstract]
19. Cramer DW, Barbieri RL, Xu H, Reichardt JK. 1994 Determinants of basal follicle stimulating hormone levels in premenopausal women. J Clin Endocrinol Metab. 79:1105–1109.[Abstract]
20. Montgomery GW, McNatty KP, Davis GH. 1992 Physiology, and molecular genetics of mutations that increase ovulation rate in sheep. Endocr Rev. 13:309–328.[CrossRef][Medline]
21. Reame NE, Wyman T, Padmanabhan V. 1997 Reduced overall inhibitory tone of gonadal peptide feedback may account for the rise in follicular phase FSH of aging cycling women. Program and Abstracts of the 79th Annual Meeting of the Endocrine Society, Minneapolis MN, 1997, P1–365 (Abstract).
22. Harada K, Shintani Y, Sakamoto Y, Wakatsuki M, Shitsukawa K, Saito S. 1996 Serum immunoreactive Activin A levels in normal subjects, and patients with various diseases. J Clin Endocrinol Metab. 81:2125–2130.[Abstract]
23. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. 1978 Hypophysial responses to continuous, and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 202:631–633.[Abstract/Free Full Text]
24. Jenner AA, de Koning J, Van Rees GP. 1983 Effect of inhibin-like activity on LH-RH-stimulated release of FSH by pituitary glands from female rats in vitro. Life Sci. 32:1091–1098.[CrossRef][Medline]
25. Lambalk CB, Schoemaker J, Van Rees GP, de Koning J, van Dieten HA. 1991 Exogenous vs. endogenous pulses of luteinizing hormone-releasing hormone and secretory patterns of gonadotropins. Fertil Steril. 56:446–452.[Medline]
26. Lambalk CB, Schoemaker J, Van Rees GP, van Dieten HA. 1989 The frequency of pulsatile luteinizing hormone-releasing hormone treatment, and luteinizing hormone and follicle-stimulating hormone secretion in women with amenorrhea of suprapituitary origin. Fertil Steril. 51:416–422.[Medline]
27. Genazzani AD, Petraglia F, Volpogni C, D’Ambrogio G, Facchinetti F, Genazzani AR. 1993 FSH secretory pattern, and degree of concordance with LH in amenorrheic, fertile, and postmenopausal women. Am J Physiol. 264:E776–E781.
28. Padmanabhan V, McFadden K, Mauger DT, Karsch FJ, Midgley ARJ. 1997 Neuroendocrine control of follicle-stimulating hormone (FSH) secretion. I. Direct evidence for separate episodic and basal components of FSH. Endocrinology 138:424–432.
29. Fuchs S, Lundanes E, Leban J, Folkers K, Bowers C. 1979 On the existence, and separation of the follicle stimulating hormone releasing hormone from the luteinizing hormone releasing hormone. Biochem Biophys Res Commun. 88:92–96.[CrossRef][Medline]
30. Mizunuma H, Samson WK, Lumpkin MD, Moltz JH, Fawcett CP, McCann SM. 1983 Purification of a bioactive FSH-releasing factor (FSHRF). Brain Res Bull. 10:623–629.[CrossRef][Medline]
31. Folkers K, Bowers CY, Tang PF, Kubota M. 1986 Decapeptides as effective agonists from L-amino acids biologically equivalent to the luteinizing hormone-releasing hormone. Proc Natl Acad Sci USA. 83:1070–1074.[Abstract/Free Full Text]
32. Scott RTJ, Hofmann GE. 1995 Prognostic assessment of ovarian reserve. Fertil Steril. 63:1–11.[Medline]
33. Martin NG, Healey SC, Pangan TS, Heath AC, Turner G. 1997 Do mothers of dizygotic twins have earlier menopause? A role for fragile X?. Am J Med Genet. 69:114–116.[CrossRef][Medline]

This article has been cited by other articles:

				Z. Z. Zhao, J. N. Painter, J. S. Palmer, P. M. Webb, N. K. Hayward, D. C. Whiteman, D. I. Boomsma, N. G. Martin, D. L. Duffy, and G. W. Montgomery Variation in bone morphogenetic protein 15 is not associated with spontaneous human dizygotic twinning Hum. Reprod., July 9, 2008; (2008) den268v1. [Abstract] [Full Text] [PDF]

				I. Delbaere, H. Verstraelen, S. Goetgeluk, G. Martens, C. Derom, D. De Bacquer, G. De Backer, and M. Temmerman Perinatal outcome of twin pregnancies in women of advanced age Hum. Reprod., June 10, 2008; (2008) den134v1. [Abstract] [Full Text] [PDF]

				C. Hoekstra, Z. Z. Zhao, C. B. Lambalk, G. Willemsen, N. G. Martin, D. I. Boomsma, and G. W. Montgomery Dizygotic twinning Hum. Reprod. Update, January 1, 2008; 14(1): 37 - 47. [Abstract] [Full Text] [PDF]

				K. J. McTavish, M. Jimenez, K. A. Walters, J. Spaliviero, N. P. Groome, A. P. Themmen, J. A. Visser, D. J. Handelsman, and C. M. Allan Rising Follicle-Stimulating Hormone Levels with Age Accelerate Female Reproductive Failure Endocrinology, September 1, 2007; 148(9): 4432 - 4439. [Abstract] [Full Text] [PDF]

				E.A.M. Kuijper, C.B. Lambalk, D.I. Boomsma, S. van der Sluis, M.A. Blankenstein, E.J.C. de Geus, and D. Posthuma Heritability of reproductive hormones in adult male twins Hum. Reprod., August 1, 2007; 22(8): 2153 - 2159. [Abstract] [Full Text] [PDF]

				R.G. Gosden, S.A. Treloar, N.G. Martin, L.F. Cherkas, T.D. Spector, M.J. Faddy, and S.J. Silber Prevalence of premature ovarian failure in monozygotic and dizygotic twins Hum. Reprod., February 1, 2007; 22(2): 610 - 615. [Abstract] [Full Text] [PDF]

				C.H. de Koning, T. Benjamins, P. Harms, R. Homburg, J.M. van Montfrans, J. Gromoll, M. Simoni, and C.B. Lambalk The distribution of FSH receptor isoforms is related to basal FSH levels in subfertile women with normal menstrual cycles Hum. Reprod., February 1, 2006; 21(2): 443 - 446. [Abstract] [Full Text] [PDF]

				A. Sutcliffe, H. A. Spoudeas, D. Nair, P. Bouloux, T. Oliver, P. Sambrook, W. Bannister, C. B. Lambalk, and T. Spector Comparison of serum FSH and Inhibin B levels between adult male dizygotic and monozygotic twins Hum. Reprod., February 1, 2006; 21(2): 447 - 450. [Abstract] [Full Text] [PDF]

				H. Lopez, R. Sartori, and M. C. Wiltbank Reproductive Hormones and Follicular Growth During Development of One or Multiple Dominant Follicles in Cattle Biol Reprod, April 1, 2005; 72(4): 788 - 795. [Abstract] [Full Text] [PDF]

				A. Lukanova and R. Kaaks Endogenous Hormones and Ovarian Cancer: Epidemiology and Current Hypotheses Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 98 - 107. [Abstract] [Full Text] [PDF]

				K. Lutchman Singh, M. Davies, and R. Chatterjee Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing Hum. Reprod. Update, January 1, 2005; 11(1): 69 - 89. [Abstract] [Full Text] [PDF]

				J. de Koning, C.B. Lambalk, F.M. Helmerhorst, and M.N. Helder Is GnRH self-priming an obligatory feature of the reproductive cycle? Hum. Reprod., February 1, 2001; 16(2): 209 - 214. [Abstract] [Full Text] [PDF]

				G. W. Montgomery, D. L. Duffy, J. Hall, B. R. Haddon, M. Kudo, E. A. Mcgee, J. S. Palmer, A. J. Hsueh, D. I. Boomsma, and N. G. Martin Dizygotic Twinning Is Not Linked to Variation at the {alpha}-Inhibin Locus on Human Chromosome 2 J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3391 - 3395. [Abstract] [Full Text]

				T. E. C. Workshop Group Multiple gestation pregnancy Hum. Reprod., August 1, 2000; 15(8): 1856 - 1864. [Abstract] [Full Text] [PDF]

				C. H. de Koning, C. Popp-Snijders, J. Schoemaker, and C. B. Lambalk Elevated FSH concentrations in imminent ovarian failure are associated with higher FSH and LH pulse amplitude and response to GnRH Hum. Reprod., July 1, 2000; 15(7): 1452 - 1456. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lambalk, C. B. Articles by Schoemaker, J. Search for Related Content PubMed PubMed Citation Articles by Lambalk, C. B. Articles by Schoemaker, J.