Human Reproduction, Vol. 18, No. 3, 502-505,
March 2003
© 2003 European Society of Human Reproduction and Embryology
Pseudo-isolated FSH deficiency caused by an inhibin B-secreting granulosa cell tumour: Case report
1 Pediatric & Reproductive Endocrinology Branch, National Institutes of Health, Bethesda, MD 20892 and 2 Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
3 To whom correspondence should be addressed at: NICHD, Pediatric & Reproductive Endocrinology Branch, Building 10, Room 9D-42, Bethesda, MD 20892, USA. e-mail: segarsj{at}mail.nih.gov
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Abstract |
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Isolated FSH deficiency due to a mutation in the FSH
subunit is characterized by an extremely low serum FSH concentration. We report a patient who presented with an FSH of 0.8 mIU/ml and infertility associated with anovulation. Endocrinological assessment and immunohistochemistry revealed that a granulosa cell tumour was secreting inhibin B and suppressing FSH; however, LH and estradiol were within their normal ranges. Upon removal of the tumour, inhibin B decreased and FSH levels rose to normal values. The patient subsequently conceived and delivered successfully. Based on this case and on those previously described in the literature, we suggest that inhibin B levels should be evaluated in anovulatory patients having a clinical presentation consistent with functional hypothalamic amenorrhoea and very low to normal values of FSH.
Key words: FSH deficiency/granulosa cell tumour/hypothalamic amenorrhoea/infertility/inhibin B
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Introduction |
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It is universally accepted that gonadotrophin stimulation of the ovaries is critical for follicular growth and development of secondary sex characteristics. True isolated FSH deficiency presents as idiopathic hypogonadotrophic hypogonadism, and is a rare cause of primary amenorrhoea. Three women with a mutation of the FSH
subunit have been described (Matthews et al., 1993
; Layman et al., 1997; Matthews and Chatterjee, 1997) and in each instance a mutation in codon 61 (Val61X) of exon 3 in the FSH subunit was found, and in one case the patient was also a compound heterozygote for a Cys51Gly missense mutation (Layman et al., 1997). All cases were characterized by primary amenorrhoea, absent to low FSH, low levels of estradiol, and normal LH.
However, not all patients with serum levels consistent with isolated FSH deficiency have a mutation in the FSH chain. FSH and LH release is both positively and negatively affected by estrogen and progesterone, and at least three protein hormones secreted by the ovary: activin A, and inhibins A and B (Magoffin and Jakimiuk, 1997; Lockwood et al., 1998; Welt et al., 2002). Inhibin B is secreted by granulosa cells and acts on the pituitary to directly suppress FSH production.
We report a woman with an inhibin B-secreting granulosa cell tumour that presented with infertility and values of circulating FSH consistent with isolated FSH deficiency. The finding of elevated inhibin B may be an invaluable test in the assessment of patients with apparent idiopathic hypogonadotrophic hypogonadism or functional hypothalamic amenorrhoea to alert the clinician of a possible ovarian tumour.
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Case report |
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A 36 year old gravida 0 woman presented to her primary physician with a 9 month history of secondary amenorrhoea after stopping oral contraceptive pills. She reported normal progress through puberty. Her menstrual cycles began at age 12 years and the patient reported occasionally missing a cycle prior to starting the oral contraceptives. She remained on oral contraceptives for 10 years prior to presentation. Physical examination was unremarkable and revealed a weight of 131 lbs, height 5 feet 3 inches, blood pressure of 115/68 mmHg. Normal secondary sex characteristics were present with no evidence of virilization. Body mass index was within normal range. A pelvic ultrasound revealed a slightly enlarged left ovary with multiple cysts, which was interpreted as polycystic ovarian syndrome (PCOS). Withdrawal bleeding was induced with medroxyprogesterone acetate (10 mg/day for 10 days).
Cycle day 3 blood sampling revealed FSH = 0.8 mIU/ml, LH = 6.7 mIU/ml and estradiol = 129 pg/ml (Table I). The patient was diagnosed with anovulation caused by PCOS, and was started on clomiphene citrate 50 mg/day on cycle days 5–9. No evidence of ovulation was seen with urinary LH or day 21 progesterone. The dose was increased to 100 mg/day and then to 150 mg/day, but the patient remained anovulatory. A clomiphene citrate challenge test (CCCT) was then performed, showing a 3-fold increase in LH levels, with practically no response in FSH (Table II).
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The patient was then referred to our reproductive endocrine clinic for further evaluation with a tentative diagnosis of hypothalamic amenorrhoea. Laboratory studies revealed: TSH = 1.6 IU/ml (normal range 0.27–4.20), free thyroxine = 1.07 ng/dl (0.71–1.85); prolactin = 6.2 ng/ml (normal range 3.9–29.5), free testosterone = 3.9 pg/ml (1.0–8.5), testosterone = 34 ng/dl (15–70). Magnetic resonance imaging of the sella turcica was normal. Repeat pelvic ultrasound revealed an enlarged heterogeneous left ovary measuring 6.7x4.6x5.4 cm (Figure 1). Inhibin B level was elevated at 147 pg/ml (normal range <73 pg/ml for pre-menopausal female; (Quest Diagnostics, Inc., Nichols Institute, San Juan Capistrano, CA, USA). The inhibin assay was an enzyme-linked immunosorbent assay directed against inhibin B, and cross-reactivity against
-inhibin was 0.62 at 50% inhibition of binding level. Intra-assay coefficient of variation (CV) was 5%, inter-assay CV was 11.2% with sensitivity of 7 pg/ml (Interscience Institute, Inglewood, CA, USA).
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The clinical findings were suggestive of an ovarian tumour. A markedly enlarged left ovary and a small right ovary were found at exploratory laparotomy. A left salpingoophorectomy was performed (Figure 2). There was no evidence of spread to other pelvic organs. Histological examination disclosed a 6.5 cm circular granulosa cell tumour confined to the left ovary. Pathology examination was consistent with a benign tumour, although 5–10 mitoses were present in some microscopic fields and close follow-up was recommended. Immunohistochemical staining of the tumour was performed with Vector Elite ABC Kit using Serotec mouse anti-human
B antibody (MCA1661) at a 1:100 dilution and mouse anti-human antibody (MCA951S) at a 1:50 dilution. Secondary antibody staining was with Vector biotinylated anti-mouse antibody furnished with the kit at a 1:200 dilution. Quantification of immunodetection was performed with a colour CCD camera and an Olympus (Optical Elements Corporation, Dulles, VA, USA) microscope. Results revealed strong staining for inhibin B and weak to absent staining for inhibin A, when compared with control ovarian tissue-containing granulosa cells (Figure 3). Post-operative hormone levels on cycle day 3 were as follows: LH = 5.6 mIU/ml, FSH = 9.1 mIU/ml, estradiol = 55 pg/ml, and inhibin B = 15 pg/ml. An increase in LH, FSH and estradiol occurred after a post-operative CCCT (Table II). The patient conceived following the CCCT and delivered a normal healthy infant at term.
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Discussion |
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TopAbstractIntroductionCase reportDiscussionReferences |
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Our patient presented with a serum FSH level consistent with an FSH
mutation, but a clinical history inconsistent with that diagnosis. She had a normal progression through puberty and normal estradiol levels. She presented with the conflicting findings of almost undetectable FSH with normal estradiol and LH. The initial misdiagnosis of PCOS was based on the clinical scenario of secondary amenorrhoea with a positive withdrawal bleed after progestin administration, a clinical mistake mentioned in other reports (Porestsky et al., 1988; Fox and Dreycott, 1996). However, closer evaluation revealed that an inhibin B-secreting granulosa cell tumour caused the extremely low FSH value. In addition to immunohistochemistry, our results were confirmed with dynamic testing of the hypothalamic–pituitary ovarian axis before and after surgical resection of the tumour.
Inhibin A and B are secreted by the granulosa cells of the ovary in response to FSH and play an essential role in the regulation of follicular development. The recent development of specific assays for inhibin A and inhibin B (Groome et al., 1996) have clarified their respective roles in follicular development (Welt et al., 2002). Both inhibins suppress FSH levels, providing a negative feedback loop for FSH production (Groome et al., 1996; Soules et al., 1998; Welt et al., 2002). Several studies have shown that serum levels of inhibin are elevated in patients with ovarian sex-cord stromal tumours and that secretion may not be dependent upon FSH stimulation (Lappohn et al., 1989; Jobling et al., 1994; Hildebrandt et al., 1997; Risbridger et al., 2001). Not only are granulosa cell tumours capable of secreting inhibin B as well as inhibin A (Petraglia et al., 1998; Robertson et al., 1999; Ala-Fossi et al., 2000), but fibrothecomas and other ovarian tumours secrete biologically active inhibin molecules (Hildebrandt et al., 1997; Burger et al., 2001). It is worth noting that circulating inhibins in women with ovarian cancer are structurally similar, are of similar molecular weight (Robertson et al., 2002), and in most cases function similarly to inhibins produced from normal ovarian tissue.
In their report of inhibin as a marker for granulosa cell tumours, Lappohn et al. (1989) described three women with infertility, elevated inhibin levels, and granulosa cell tumours. There are at least two detailed case reports of granulosa cell tumours that presented with secondary amenorrhoea and infertility associated with elevated inhibin levels (Sakamoto et al., 1998; Hiroi et al., 2000), although the association of granulosa cell tumours with infertility and secondary amenorrhoea has been described without mention of inhibin levels (Porestsky et al., 1988; Willemsen et al., 1993; Fox and Draycott, 1996). Sakamoto et al. (1998) reported a granulosa cell tumour in a 42 year old with low FSH (0.8 mIU/ml) and normal LH (17 mIU/ml), findings similar to our report. They also reported an elevated serum inhibin of 17 IU/ml (Sakamoto et al., 1998), but in contrast with our report, inhibin A was detected in the tumour cells. Hiroi et al. (2000) reported a patient with early menopause at age 44 years who was subsequently diagnosed with a granulosa cell tumour 4 years later. The patient was found to have suppressed FSH of <1.0 mIU/ml and an elevated inhibin of 218.7 IU/ml. After removal of the tumour, FSH and inhibin levels returned to the normal post-menopausal range. The tumour stained for inhibin, but the distinction between inhibin A and inhibin B was not reported.
Since inhibin B may be produced by ovarian tumours other than granulosa cell tumours (Flemming et al., 1996; Hildebrandt et al., 1997; Petraglia et al., 1998; Robertson et al., 1999; Burger et al., 2001), suppression of FSH, amenorrhoea and subsequent infertility may result from these tumours as well. There is one report of an ovarian fibrothecoma in a woman presenting with secondary amenorrhoea and infertility. Meyer et al. (2000) reported a 37 year old female with LH = 22.7 mIU/ml, FSH <1.5 mIU/ml and estradiol of 26 pg/ml. Serum inhibin B was extremely high, at 1154 pg/ml. The fibrothecoma stained strongly for the inhibin subunit.
The ability of ovarian tumours to cause infertility by secretion of FSH-suppressing hormones is relevant to the possible association of infertility medication, specifically clomiphene citrate, with ovarian tumours (Willemsen et al., 1993; Rossing et al., 1994; Tarlatzis et al., 1995). As in our patient, the diagnosis of an ovarian tumour may be established only after treatment with clomiphene citrate in an attempt to correct anovulation ultimately caused by the tumour itself. Our results lend support to the possibility that an existing ovarian tumour secreting inhibin must be taken into account in assessment and analysis of the association between infertility medication and ovarian tumours. This is an important consideration, since 71% of fibrothecomas, 60% of mucinous cystadenocarcinomas, and 18% of poorly differentiated ovarian carcinomas may secrete inhibins (Hildebrandt et al., 1997; Robertson et al., 1999; Burger et al., 2001; Risbridger et al., 2001). In support of a transient effect upon fertility caused by the tumour itself (rather than long-standing infertility attributable to another aetiology), in many instances reports have shown that a high rate of spontaneous pregnancy may follow removal of the ovarian tumour (Willemsen et al., 1993; Salle et al., 1997; Unkila-Kallio et al., 2000), a point which we have also noted (Cisar et al., 2001).
In summary, the value of measuring serum inhibin in the assessment of women with secondary amenorrhoea has not been emphasized. A subset of patients diagnosed with functional hypothalamic amenorrhoea may have occult ovarian tumours. Low FSH levels coupled with normal estradiol levels in a patient warrants further evaluation with inhibin B even in cases where ovaries appear normal on ultrasound. Elevated inhibin in this setting may alert the clinician to the presence of an unsuspected tumour.
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Submitted on August 7, 2002; accepted on November 26, 2002.
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