1 Departments of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, 2 Emory University, Atlanta, GA 30322, 3 Department of Pediatrics and Medicine, University of Chicago, Chicago, IL 60637, 4 Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, GA 30912, USA
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Abstract |
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Key words: androgens/FSH deficiency/LH excess/ovary
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Introduction |
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Case report |
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Reproductive endocrine evaluation
The patient underwent a detailed reproductive endocrine evaluation at 21 years of age in the University of Chicago General Clinical Research Center (GCRC), after discontinuing the oral contraceptive pill for one month and giving informed consent. The study protocols were approved by the University of Chicago Institutional Review Board. Her height was 155 cm and her weight was 53.2 kg. There was no hirsutism (Ferriman and Gallway score of 4; normal <8), breasts and pubic hair were Tanner stage 5, and the pelvic examination was normal. An initial blood sample was drawn for immunoactive FSH, LH and free testosterone. The patient then received dexamethasone 0.5 mg four times daily for 4 days prior to and continuing throughout the endocrine evaluation to suppress adrenal function. Following admission to the GCRC, she underwent a transvaginal pelvic ultrasound followed by blood sampling every 10 min from 7.00 p.m. to 6.00 a.m. Serum immunoactive FSH and LH were determined for each sample; inhibin A and B, bioactive FSH and free -subunit were determined in a pooled sample. The following morning, a human chorionic gonadotrophin (HCG) test was performed. A blood sample was drawn for baseline testosterone, free testosterone and estradiol. The following steroid intermediates were also determined: 17-hydroxyprogesterone (17-Prog), androstenedione, 17-hydroxypregnenolone and dehydroepiandrosterone. HCG 5000 IU was then administered i.m. and blood was drawn 24 h later for repeat steroid measurements.
The patient remained off any sex steroids for another month, then returned to the GCRC for a second HCG study which was like the first except she received 300 IU of recombinant human FSH s.c. in the morning, 24 h prior to the HCG test. A blood sample was drawn 24 h later for steroids and inhibin A and B, and HCG 5000 IU was administered. She then returned 24 h after HCG (48 h after FSH) for a final blood sample for steroid measurements (Figure 1).
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Results |
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One month later, during the second GCRC study, estradiol increased substantially 24 h after FSH administration (2880 pg/mL). Inhibin B was near the lower limit of the normal range at baseline and rose to above the range for menstruating women 24 h after FSH injection (Table I). In contrast, inhibin A was present at low concentrations.
The response of testosterone and the steroid intermediates to the two HCG tests have been previously reported (Barnes et al., 2000). In brief, all steroid concentrations 24 h after the second HCG injection (48 h after FSH) were greater than at 24 h after the first HCG injection (HCG alone). The difference between the two HCG tests was most dramatic for testosterone, which was unaffected by the first HCG test (12 ng/dl before and after HCG), but increased from 16 to 41 ng/dl after the second, FSH-primed HCG test.
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Discussion |
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The point at which FSH is necessary for follicular development in the human ovary is debated (Gougeon, 1996; McGee and Hsueh, 2000
). Despite having no detectable FSH, our patient had multicystic ovaries with follicles up to 5 mm in diameter. Similar sized follicles have been reported in some women with FSH receptor mutations (Aittomaki et al., 1996
; Beau et al., 1998
); however, those FSH receptor mutations may not be completely inactivating. These findings are in contrast to FSH ß- and FSH receptor-knockout mice, in which antral follicles are not maintained (Kumar et al., 1997
; Dierich et al., 1998
). In studies of human ovarian xenografts transplanted into the kidney capsule of immunodeficient and hypogonadotrophic mice, FSH was required for the growth of follicles beyond the two-layer granulosa cell stage (Oktay et al., 1998
), which is about the point at which the FSH receptor gene is first expressed in human follicles (Oktay et al., 1997
). Although the xenograft data are in contrast to our findings, it is likely that the endocrine and growth factor milieu of the in-situ human ovary is very different than that in the immunodeficient, hypogonadotrophic mouse.
The prompt estradiol and inhibin B responses 24 h after exogenous FSH suggest that our patient's antral follicles contained granulosa cells that had developed normally in the absence of FSH. Our findings are similar to those in two other patients with isolated FSH deficiency who ovulated and had a successful pregnancy after ~14 days of menotrophin therapy (Rabinowitz et al., 1979; Matthews et al., 1993
). Ovulation after a short exposure to menotrophins implies that some healthy follicles had reached the point of recruitability without FSH exposure, since ~14 days are required for an ovulatory follicle to develop from follicles a few millimeters in diameter, in contrast to the 3 months required to develop from the pre-antral stage (Gougeon, 1996
). These earlier reports and our findings suggest that in the complete absence of FSH stimulation, human ovarian antral follicles can develop up to 5 mm in diameter.
Our patient had no clinical or laboratory evidence of ovarian hyperandrogenism despite a mean LH concentration, LH pulse characteristics and ovarian follicular sizes typical for PCOS. On ultrasound her multicystic ovaries lacked the excess stroma of classic polycystic ovaries. Indeed, her ovaries produced little, if any, androgen. Her baseline and dexamethasone-suppressed free testosterone were lownormal. The administration of HCG led to minimal stimulation of 17-Prog or other thecal cell steroids. However, we have previously shown that exogenously administered FSH augmented her LH- and HCG-stimulated production of testosterone and all steroids of thecal cell origin (Barnes et al., 2000). This suggests that FSH action, probably via granulosa cell-produced paracrine intermediates, is necessary for thecal cells to respond to LH. One of many such paracrine factors is inhibin B, which increased markedly with FSH administration in this patient (Barnes 1998
).
These findings are relevant to the role of LH excess in the pathogenesis of the ovarian hyperandrogenism of PCOS. It has been reported that 75% of women with clinical evidence of PCOS have an elevated LH concentration and 94% have an increased LH/FSH ratio (Taylor et al., 1997). These gonadotrophin secretory abnormalities have been thought to play an important role in the development of the ovarian hyperandrogenism characteristic of PCOS (Hall, 1993
). In a related study, we found that a woman with a constitutively activating mutation of the LH receptor, identified because she was the mother of two sons with gonadotrophin-independent precocious puberty, had no clinical or laboratory evidence of ovarian hyperandrogenism (Rosenthal et al., 1996
). Thus, increased LH stimulation, even in the presence of FSH, appears to be insufficient to induce the hyperandrogenism and stromal hyperplasia of PCOS. The findings in the previous, as well as the current, case report support the hypothesis that thecal cell androgen secretion in response to excessive LH stimulation is strictly limited by intra-ovarian factors. Ovarian hyperandrogenism is more likely a result of escape from down-regulation by these intra-ovarian factors than a result of elevated LH concentrations (Ehrmann et al., 1995
). Taken together, our studies support the hypotheses that normal ovarian androgen production depends on both FSH and LH and that excessive ovarian androgen production is a result of abnormal intra-ovarian regulation, and not of excessive LH stimulation.
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Acknowledgements |
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L.C.L. was supported by NIH grant support PHS NICHD HD33004; R.L.R. was supported by NIH grant support RR-00055 (CRC).
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Notes |
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References |
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Aittomaki, K., Herva, R., Stenman, U-H. et al. (1996) Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J. Clin. Endocrinol. Metab., 81, 37223726.[Abstract]
Barnes, R.B. (1998) The pathogenesis of polycystic ovary syndrome: lessons from ovarian stimulation studies. J. Endocrinol. Invest., 21, 567579.[ISI][Medline]
Barnes, R.B., Rosenfield, R.L., Burstein, S. et al. (1989) Pituitaryovarian responses to nafarelin testing in the polycystic ovary syndrome. N. Engl. J. Med., 320, 559565.[Abstract]
Barnes, R.B., Namnoum, A., Rosenfield, R.L. et al. (2000) Effect of follicle-stimulating hormone on ovarian androgen production in a woman with isolated follicle-stimulating hormone deficiency. N. Engl. J. Med., 343, 11971198.
Beau, I., Touraine, P., Meduri, G. et al. (1998) Novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. J. Clin. Invest., 102, 13521359.
Christin-Maitre, S., Taylor, A.E., Khoury, R.H. et al. (1996) Homologous in vitro bioassay for follicle-stimulating hormone (FSH) reveals increased FSH biological signal during the mid- to late luteal phase of the human menstrual cycle. J. Clin. Endocrinol. Metab., 81, 20802088.[Abstract]
Dierich, A., Sairam, M.R., Monaco, L. et al. (1998) Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc. Natl Acad. Sci. USA, 95, 1361213617.
Ehrmann, D.A., Barnes, R.B. and Rosenfield, R.L. (1995) Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr. Rev., 16, 322353.[ISI][Medline]
Gougeon, A. (1996) Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr. Rev., 17, 121155.[ISI][Medline]
Hall, J.E. (1993) Polycystic ovarian disease as a neuroendocrine disorder of the female reproductive axis. Endocrinol. Metab. Clin. North Am., 22, 7592.[ISI][Medline]
Kumar, T.R., Wang, Y., Lu., N. et al. (1997) Follicle-stimulating hormone is required for ovarian follicle maturation but not male fertility. Nature Genet., 15, 201204.[ISI][Medline]
Lavoie, H.B., Martin, K.A., Taylor, E., et al. (1998) Exaggerated free alpha-subunit levels during pulsatile gonadotropin-releasing hormone replacement in women with idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab., 83, 241247.
Layman, L.C. and McDonough, P.G. (2000) Mutations of follicle stimulating hormone-beta and its receptor in human and mouse: genotype/phenotype. Mol. Cell. Endocrinol., 161, 917.[ISI][Medline]
Layman, L.C., Lee, E.J., Peak, D.B. et al. (1997) Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone ß-subunit gene. N. Engl. J. Med., 337, 607611.
Levrant, S.G., Barnes, R.B. and Rosenfield, R.L. (1997) A pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism. Hum. Reprod., 12, 14161420.[Abstract]
Matthews, C.H., Borgato, S., Beck-Peccoz, P. et al. (1993) Primary amenorrhoea and infertility due to a mutation in the ß-subunit of follicle-stimulating hormone. Nature Genet., 5, 8386.[ISI][Medline]
McGee, E.A. and Hsueh, A.J.W. (2000) Initial and cyclic recruitment of ovarian follicles. Endocr. Rev., 21, 200214.
Oktay, O., Briggs D. and Gosden, R.G. (1997) Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles. J. Clin. Endocrinol. Metab., 82, 37483751.
Oktay, O., Newton H., Mullan J. et al. (1998) Development of human primordial follicles to antral stages in SCID/hpg mice stimulated with follicle-stimulating hormone. Hum. Reprod., 13, 11331138.[Abstract]
Rabinowitz, D., Benveniste, R., Lindner, J. et al. (1979) Isolated follicle-stimulating hormone deficiency revisted. N. Engl. J. Med., 300, 126128.[ISI][Medline]
Rosenfield, R.L., Barnes, R.B. and Ehrmann, D.A. (1994) Studies of the nature of 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J. Clin. Endocrinol. Metab., 79, 16861692.[Abstract]
Rosenthal, I.M., Refetoff, S., Rich, B. et al. (1996) Response to acute challenge with gonadotropin releasing hormone agonist in two half-brothers and their mother with a constitutively activating mutation of the luteinizing hormone receptor. J. Clin. Endocrinol. Metab., 81, 38023806.[Abstract]
Taylor, A.E., McCourt, B., Martin, K.A. et al. (1997) Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 82, 22482256.
Themmen, A.P.N. and Huhtaniemi, I.T. (2000) Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitarygonadal function. Endocr. Rev., 21, 551583.
Van Cauter, E. and Copinschi, G. (eds) (1981) Human pituitary hormones: circadian and episodic variations. Martinus Nijhoff, The Hague, pp. 221235.
Waldstreicher, J., Santoro, N.F., Hall, J.E., et al. (1988) Hyperfunction of the hypothalamicpituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J. Clin. Endocrinol. Metab., 66, 165172.[Abstract]
Welt, C.K., Adams, J.M., Sluss, P.M. et al. (1999) Inhibin A and inhibin B responses to gonadotropin withdrawal depends on stage of follicle development. J. Clin. Endocrinol. Metab., 84, 21632169.
Submitted on February 28, 2001; accepted on August 21, 2001.