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Original Studies |
Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Stephanie B. Seminara, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 505, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: seminara.stephanie{at}mgh.harvard.edu
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Abstract |
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Baseline patterns of gonadotropin secretion and gonadotropin
responsiveness to exogenous pulsatile GnRH were examined in the
proband. Low amplitude pulses of both LH and free 
-subunit (FAS)
were detected during 24 h of every 10 min blood sampling. The
proband then received exogenous pulsatile GnRH iv for ovulation
induction, and daily blood samples for gonadotropins and sex steroids
were monitored. At the conventional GnRH replacement dose for women
with hypogonadotropic hypogonadism (75 ng/kg), no follicular
development occurred. At a GnRH dose of 100 ng/kg, the level and
pattern of gonadotropin secretion more closely mimicked the follicular
phase of normal women; a single dominant follicle was recruited, and an
endogenous LH surge was elicited. However, the luteal phase was
inadequate, as assessed by progesterone levels. At a GnRH dose of 250
ng/kg, the gonadotropin and sex steroid dynamics reproduced those of
normal ovulatory women in both the follicular and luteal phases, and
the proband conceived. The FAS responses to both conventional and high
dose GnRH were within the normal range.
The following conclusions were made: 1) Increased doses of GnRH may be used effectively for ovulation induction in some patients with GnRH receptor mutations. 2) Higher doses of GnRH are required for normal luteal phase dynamics than for normal follicular phase function. 3) Hypersecretion of FAS in response to exogenous GnRH, which is a feature of congenital hypogonadotropic hypogonadism, was not seen in this patient with a GnRH receptor mutation.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recent reports have demonstrated resistance of hypogonadotropic
patients with GnRH receptor mutations to either single GnRH injections
(6) or exogenous pulsatile GnRH (5, 6, 7). However, as some patients with
GnRH receptor mutations have presented with partial hypogonadism,
suggesting some, albeit limited, responsiveness to endogenous GnRH, we
hypothesized that a subset of such patients might demonstrate
responsiveness to exogenous GnRH and thus be candidates for GnRH
therapy with appropriate dose adjustments. This report describes the
successful use of pulsatile GnRH for ovulation induction and conception
in a female patient with a compound heterozygous GnRH receptor
mutation. The incremental range of GnRH doses employed demonstrates the
variable sensitivity of different stages of the menstrual cycle to GnRH
dose. The lack of free -subunit (FAS) hyperresponsiveness to GnRH
replacement distinguishes this patient from others with HH.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The proband (II:1) presented with primary amenorrhea (Fig. 1
). During adolescence, she had a small
amount of pubic and axillary hair, but no breast development. She
received oral estrogens for approximately 1.5 yr, but discontinued this
medication as a college freshman. She was subsequently given two
courses of Provera without estrogen pretreatment, one of which was
followed by a withdrawal bleed. She presented to the Reproductive
Endocrine Associates of Massachusetts General Hospital at age 25 yr for
a second opinion of her amenorrhea. Her family history was notable for
a younger sister who had also failed to menstruate spontaneously.
Physical examination was notable for eunochoid habitus, small breasts,
and normal external genitalia. Baseline LH and FSH levels were 0.3 and
0.5 IU/L, respectively. PRL and estradiol levels were 1.8 ng/mL and
less than 20 pg/mL, respectively. In response to a single bolus of 100
µg GnRH, iv, gonadotropin responses were markedly diminished, with a
peak LH level of 1.3 IU/L at 30 min and a peak FSH level of 1.6 IU/L at
120 min. GH and cortisol responses to insulin-induced hypoglycemia were
normal. Brain imaging was normal, and the karyotype was 46,XX.
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The patient conceived three times on pulsatile GnRH (250 ng/kg), but suffered recurrent pregnancy loss between 7–11 weeks gestation. She then underwent exogenous gonadotropin therapy, where she conceived again, but suffered two additional pregnancy losses. An embryo/trophoblast toxic factor was identified through an embryotoxic factor-lymphocyte assay (10). Her sister was treated with exogenous gonadotropins and bore three children: one twin pregnancy and one singleton.
Normal controls
One hundred and nine women between the ages of 18–40 yr with regular cycles (25–35 days) had gonadotropins and sex steroids measured daily during a complete ovulatory cycle to define the normal ranges for these hormones (9, 11, 12, 13). In addition, FAS was measured in a subset of 24 subjects (14). Samples were drawn at the same time of day. All subjects were euthyroid, normoprolactinemic, of normal body weight, and taking no medications. All had evidence for ovulation in a cycle preceding their study cycle, as assessed by midluteal phase P4 levels and/or basal body temperature charts.
Congenital IHH
The patient’s FAS response to pulsatile GnRH was compared to that of 11 women with either IHH (n = 5) or Kallmann syndrome (n = 6) as previously described (14). The latter group were defined by the following criteria: 1) absence of spontaneous puberty by age 18 yr; 2) primary amenorrhea; 3) absence of pulsatile gonadotropin secretion during 12–24 h of frequent (every 10 min) blood sampling; 4) normal basal and stimulated levels of TSH, PRL, GH, and cortisol on baseline and stimulated testing; and 5) no evidence of a mass lesion on brain imaging of the hypothalamic-pituitary region. After the baseline frequent gonadotropin sampling study confirmed the absence of pulsatile LH secretion, patients underwent ovulation induction using pulsatile GnRH at 75 or 100 ng/kg, iv. The frequency of GnRH administration was adjusted to mimic the frequency changes that occur during a normal menstrual cycle. A blood sample was obtained each day of the cycle, approximately 45 min after a GnRH pulse, for LH, FSH, E2, P4, and FAS (14). Samples were drawn at the same time of day.
Assays
Serum LH and FSH concentrations were determined by immunoassays
calibrated against the Second International Reference Preparation of
human menopausal gonadotropin (WHO 71/223) (13, 15, 16), with a minimal
detectable dose of 0.8 IU (human menopausal gonadotropin, WHO
71/223)/L. Inter- and intraassay coefficients of variation were less
than 10%. FAS was measured by a monoclonal antibody RIA, using a
highly purified -subunit of hCG as the standard (17, 18).
Data analysis
Pulsatile hormone secretion was assessed using the modified version of the Santen and Bardin method as previously described (9, 19). Levels of LH, FSH, E2, and P4 during each cycle were analyzed in relation to the day of ovulation, as previously defined (9). The integrated P4 level across the luteal phase (P4 sum) was calculated by summing the values between day -2 in relation to the day of ovulation and the day before the following menses. Conception cycles were excluded from this analysis. Hormone levels between the proband and normal women were compared using unpaired t tests. To compare FAS levels between the proband and IHH women, serum levels of FAS were analyzed in relation to the first 7 days of GnRH administration. Values are expressed as the mean ± SEM unless otherwise specified, and P < 0.05 was accepted as significant.
DNA extraction and sequencing
After providing informed consent, whole blood samples were donated by individuals I:1, I:2, II:1, II:2, and II:3, and DNA was extracted. Exons of the GnRH receptor were amplified by PCR using sets of primers reported previously (3). Amplified products were sequenced in both the forward and reverse directions using the AmpliTaq Dye Terminator Cycle Sequencing kit and an ABI PRISM 377 DNA sequencer (Perkin-Elmer Corp., Foster City, CA).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Direct sequencing revealed two heterozygotic mutations in the
proband as indicated in Fig. 2, A and B. In
Exon 1, a guanine was substituted for an adenine at position 317,
yielding a Gln106Arg mutation in the first
extracellular loop (Fig. 2A). In exon 3, an adenine was substituted for
a guanine at position 785, yielding an Arg262Gln
mutation in the third intracellular loop (Fig. 2B). The proband’s
sister was found to have identical mutations; the proband’s brother
had none. Each parent was found to be heterozygous, indicating that the
patient had inherited germline mutations.
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Baseline LH and FAS profiles from the proband (II:1) are depicted
in Fig. 3. Five LH pulses and four FAS pulses
of low amplitude were identified. Interestingly, a one to one
concordance between LH and FAS pulses was not observed. The mean LH
level was 2.0 ± 0.1 mIU/mL, and the mean FAS level was 122.2
± 1.8 ng/L. The mean LH and FAS pulse amplitudes were 1.2 ± 0.1
and 43.0 ± 4.6, respectively.
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Ovulation induction cycles using sequentially increasing doses of
GnRH (75, 100, and 250 ng/kg) are depicted in Fig. 4, A–C. Levels of gonadotropins and sex
steroids are superimposed upon the normative ranges for these hormones
as determined in 109 normally cycling women. Figure 4A depicts the
first and only cycle using exogenous pulsatile GnRH at a dose of 75
ng/kg. There was no evidence of follicular development, as assessed by
either ultrasound or serum E2 levels, and an
endogenous LH surge did not occur. Mean LH and FSH levels over the 27
days of therapy were 12.9 ± 1.2 and 15.2 ± 0.5 IU/L,
respectively. Mean E2 and
P4 levels were 50.0 ± 2.7 pg/mL and
0.5 ± 0.0 ng/mL, respectively.
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). In contrast to 75 ng/kg, at this
higher dose of pulsatile GnRH, a single dominant follicle was evident
by ultrasound in each cycle, and an endogenous LH surge occurred. The
preovulatory maximum E2 levels were comparable to
those observed in normal ovulatory women (261 ± 24.7
vs. 302.6 ± 10.1 pg/mL). The serum LH level at the
time of the surge in these three cycles was less than that observed in
normal women, with the difference achieving statistical significance
(71.8 ± 5.9 vs. 117.5 ± 6.2 IU/L;
P < 0.05) although still within 1
SD of the normal range. FSH levels were
comparable to those in normal subjects at the midcycle surge (20.3
± 2.7 vs. 23.2 ± 0.9 IU/L). P4
production by the corpus luteum was markedly reduced, as assessed by
the maximum value and the integrated luteal phase
P4 level (5.1 ± 2.9 vs.
23.2 ± 0.7 ng/mL; P < 0.05; P4
sum, 29.3 vs. 134.6; P <
0.05).
The dose of GnRH was then increased to 250 ng/kg, and eight more cycles
were performed (Fig. 4C). The emergence of a single dominant follicle
was evident, and an endogenous midcycle surge occurred in all cycles.
Preovulatory peak E2 levels were comparable to
those in normal women (329.6 ± 16.7 vs. 302.6 ±
10.1 pg/mL). Mean LH levels at the time of the midcycle surge were
below the mean observed in normal women (70.6 ± 11.1
vs. 117.5 ± 6.2 IU/L; P < 0.05), but
within 1 SD of the normal range. FSH levels were
almost identical to normal at the midcycle surge (23.3 ± 4.0
vs. 23.2 ± 0.9 IU/L). Most notably, compared to the
cycles performed at 100 ng/kg, the midluteal peak
P4 level for the eight cycles performed at 250
ng/kg was not different from that observed in normal women (19.9
± 2.0 vs. 23.2 ± 0.8 ng/mL). The integrated
P4 value in the nonconception cycles was
comparable to that seen in normal women (114.7 vs. 134.6)
and significantly different from that in the cycles at 100 ng/kg (114.7
vs. 29.3; P < 0.05).
Response to pulsatile GnRH: FAS
The FAS response of the proband to pulsatile GnRH therapy was
compared to those in 11 patients with IHH and 109 normal ovulatory
women (Fig. 5). A marked increase in FAS
above the normal range was seen in patients with IHH in response to
pulsatile GnRH (14). This exaggerated FAS response was not apparent in
the proband at either the 75 or 250 ng/kg dose.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mutations in the GnRH receptor of the proband are identical to those first reported in a man and his sister with incomplete HH (3). The Gln106Arg substitution in the first extracellular loop decreases hormone binding, and the Arg262Gln mutation (third intracellular loop) impairs signal transduction (3). As these represent partial loss of function mutations, we hypothesized that high dose pulsatile GnRH replacement could overcome these receptor defects. Although all patients with GnRH receptor mutations could be treated with exogenous gonadotropins, this therapeutic modality harbors the risk of hyperstimulation and multiple gestation. The use of pulsatile GnRH in properly selected patients with GnRH receptor mutations represents a safer and more physiological fertility option than exogenous gonadotropins, as has been demonstrated in other models of HH (21, 22).
Previous studies have demonstrated that a GnRH dose of 25 ng/kg is sufficient to restore normal pituitary and gonadal function in men with HH (23, 24). However, in women with hypothalamic amenorrhea, 25 ng/kg appears to represent a threshold dose for folliculogenesis, with successful ovulation occurring only 80% of the time (25). Conversely, a dose of 100 ng/kg can cause higher than normal follicular phase FSH levels, elevated preovulatory E2 levels, multiple folliculogenesis, and high early luteal phase P4 levels (25). Notably, however, a GnRH dose of 75 ng/kg results in follicular and luteal phase dynamics indistinguishable from normal and an overall rate of ovulation 95% higher than that seen with 25 ng/kg (8). Therefore, 75 ng/kg was chosen as the initial starting dose for this index patient. However, as seen in the first ovulation induction cycle, this dose effected a negligible gonadotropin response and was subsequently increased to 100 ng/kg. At this higher dose, follicular phase FSH levels were within the normal range, yielding a single dominant follicle. An endogenous midcycle LH surge was present, although the LH peaks were significantly blunted compared with those observed in normal women.
Despite successful follicle recruitment, however, the luteal phases of the ovulation induction cycles performed at 100 ng/kg were inadequate, with a shortfall in serum P4 levels compared to those in normal ovulatory women. Findings similar to those observed in this patient were seen in the 80% of hypothalamic amenorrhea patients who responded to the threshold dose of 25 ng/kg, iv, pulsatile GnRH, i.e. luteal phase P4 production was significantly reduced (25). During the mid- and late luteal phases, P4 secretion correlates with LH pulsatile release (16) and is quite sensitive to LH dosage. Studies using a GnRH antagonist indicate the importance of gonadotropins (26) and in particular LH (27) in the maintenance of the corpus luteum. Despite successful folliculogenesis in our patient, no conceptions occurred during the 100 ng/kg cycles, perhaps due to this luteal phase abnormality.
During the subsequent pulsatile GnRH cycles at 250 ng/kg, the gonadotropin and sex steroid dynamics of the proband recapitulated those of normal ovulatory women. Although previous reports have demonstrated that doses within this range in women with hypothalamic amenorrhea can cause mild ovarian hyperstimulation, elevated E2 and P4 responses, and multiple gestation (28), this patient developed a single dominant follicle in each cycle and conceived three times. These data clearly indicate that the dose of GnRH of 100 ng/kg was adequate for folliculogenesis in the setting of a partially functioning GnRH receptor, but a higher dose of 250 ng/kg was necessary for fully normal luteal function. Hence, this experience once again demonstrates the critical sensitivity of the corpus luteum to GnRH-induced gonadotropin secretion.
Both men and women with HH demonstrate excessive secretion of FAS during physiological replacement with exogenous pulsatile GnRH (14, 20). In men, this response is seen as early as 3 days after initiation of pulsatile GnRH and continues despite the achievement of normal levels of gonadotropins, testosterone, and testicular growth (20). In women, this rise in FAS also begins early in GnRH treatment, but is further dependent on cycle stage, with the greatest increments observed in the early follicular phase (14). The cause of this exaggerated FAS response is not clear. In studies using long acting GnRH agonists, LH levels fall, but circulating levels of FAS paradoxically increase (29, 30, 31). Such desensitization appears unlikely to be the predominant mechanism of the excessive secretion of FAS observed during GnRH replacement in HH patients, as supraphysiological FAS levels can be observed with GnRH doses as low as 5–10 ng/kg (20), and desensitization of FAS in response to increasing frequencies of pulsatile GnRH has been demonstrated in subjects with HH (32). Our group has hypothesized that as yet unrecognized factors may independently modulate FAS secretion and that this defective FAS-suppressing factor in HH subjects is unmasked in the setting of exogenous GnRH replacement (20). In this report, the proband’s FAS levels failed to rise above the normal range at GnRH doses of 75 and 250 ng/kg, suggesting that abnormal regulation of FAS in response to GnRH is not a feature of HH secondary to GnRH receptor mutations.
As the number of patients identified with GnRH receptor mutations grows, it is important to compare clinical and biochemical phenotypes in patients (both within and across families) as well as to correlate these observations with genotypes. Recent reports have described variable degrees of hypogonadism within an affected kindred containing GnRH receptor defects. In one report, a male proband (one allele, Arg262Gln; other allele, Gln106Arg and Ser217Arg) with complete HH demonstrated an absence of responses to single bolus GnRH, a GnRH agonist, and pulsatile GnRH administered at a dose of 20 µg/pulse (263 ng/kg) every 120 min, sc (6). In contrast, his sisters, bearing the same mutation, had normal breast development and a positive response to single injections of GnRH. One sister had detectable pulses in response to pulsatile GnRH administered at a dose of 20 µg/pulse (286 ng/kg) every 90 min, sc. In a second report, two affected males with GnRH receptor mutations (Ala129Asp, Arg262Gln) demonstrated spontaneous LH pulsatile activity, but their affected sister demonstrated no endogenous LH secretion (7). Moreover, responses to pulsatile GnRH varied between family members.
The patient reported here adds to the variety of biochemical responses to GnRH that patients with GnRH receptor mutations may demonstrate. As noted, our proband had an identical mutation to that of the sister of the proband from the first GnRH receptor case report (3), but lacked the spontaneous thelarche described in that paper. Therefore, it is certainly possible that other genes, in addition to the GnRH receptor, may modify receptor function or gonadotropin responsivity.
Although very valuable, some caution should be exercised regarding the interpretation of biochemical testing in these patients. First, the use of pulsatile GnRH in previous reports has been very brief (10 days or less) and has utilized a variety of doses and frequency regimens (6, 7). Second, some studies have used different doses of GnRH on affected family members within a kindred, making comparisons in responsiveness difficult (7). Third, the clinical usefulness of single bolus GnRH tests has been debated in the office setting (33), and the role of such testing in patients with GnRH receptor mutations is even more uncertain. Fourth, different pulse analysis programs have been employed in the literature to assess endogenous LH and FAS secretory patterns. Criteria for what constitutes a pulse differ in different detection algorithms, which may be particularly relevant in the setting of the low amplitude pulses described in these patients.
Unfortunately, despite five successful conceptions (three during pulsatile GnRH and two during exogenous gonadotropins), this patient suffered recurrent pregnancy loss. RT-competitive PCR has recently revealed both GnRH and GnRH receptor messenger ribonucleic acid in human endometrial stromal and epithelial cells throughout all phases of the menstrual cycle, suggesting a role for GnRH in the support of early implantation (34). Moreover, GnRH and GnRH receptor messenger ribonucleic acid expression have been identified in human preimplantation embryos, suggesting a role for GnRH in both embryonic development and implantation (35). As the patient’s sister, carrying the same GnRH receptor mutation, conceived successfully and carried two pregnancies to term, it is not clear what role, if any, the GnRH receptor mutation had in the early pregnancy losses suffered by the index case. However, as the experience with the full spectrum of the GnRH receptor mutations grows, it will be interesting to determine whether the phenotype of recurrent miscarriage is part of the spectrum of this disorder.
In summary, this report extends the biochemical phenotype of patients carrying GnRH receptor mutations. The proband demonstrates that pulsatile GnRH therapy is a safe and effective therapeutic option for some patients with HH and GnRH receptor mutations. Her data suggest that the luteal, as opposed to the follicular, phase of the menstrual cycle requires higher doses of GnRH for normal function.
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Footnotes |
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Received August 9, 1999.
Revised October 21, 1999.
Accepted October 27, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit levels during pulsatile GnRH
replacement in women with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 83:241–247. subunit of glycoprotein hormones
by assay with use of a monoclonal antibody. Clin Chem. 34:2022–2025.
subunit in males with isolated gonadotropin-releasing hormone
deficiency-a clinical research center study. J Clin Endocrinol
Metab. 80:3682–3688.[Abstract]
-subunit is superior to luteinizing hormone as a
marker of gonadotropin-releasing hormone despite desensitization at
fast pulse frequencies. J Clin Endocrinol Metab. 1999:1028–1036.
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