Pregnancy following ovarian induction in a patient withpremature ovarian failure and undetectable serumanti-Müllerian hormone
Isao Tsuji, Kazumi Ami and Nahoko FujinamiDepartment of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osaka, Japan
Abstract
We report the first case, to the best of our knowledge, of successful conception following ovarian induction ina patient with premature ovarian failure and undetectable serum anti-Müllerian hormone. A 34-year-oldwoman was referred because of ovarian amenorrhea. After endogenous gonadotrophins were normalized byhormone-replacement therapy and gonadotrophin-releasing hormone agonist, ovarian induction was per-formed using exogenous gonadotrophins. On ovarian induction day 8, one follicle had reached a meandiameter of 19.6 mm, the serum estradiol level had increased to 516 pg/mL, and human chorionic gonadot-rophin (HCG) was injected. On HCG injection day 7, ultrasonography was unable to detect the follicle, andserum progesterone levels had increased to 6.1 ng/mL. One month after HCG injection, ultrasonographydetected an intrauterine fetus with beating heart. Even with serum anti-Müllerian hormone levels below thethreshold of detection, there is a chance for patients with premature ovarian failure.Keywords: anti-Müllerian hormone, infertility, ovarian induction, premature ovarian failure, pregnancy.
Introduction
Anti-Müllerian hormone (AMH) is a dimeric glycopro-tein belonging to the transforming growth factor-bfamily. AMH is secreted from the granulosa cells ofpreantral and small antral follicles and inhibits therecruitment of primordial follicles into the growingphase.1 Serum AMH is detectable after birth, and con-centrations peak in puberty. In adult women, serumAMH levels have been shown to decline gradually withage, becoming undetectable in menopause.2,3 AMH is anaccurate indicator of the presence of ovarian follicles.4
Recently, AMH was found to be a good predictor forovarian response to controlled ovarian hyperstimula-tion from assisted reproductive technology (ART);5,6
however, measurement of AMH is not recommendedas a predictor of pregnancy.1
Premature ovarian failure (POF) is defined as thecessation of ovarian function before 40 years of age. It is
not a rare condition, and is estimated to affect 0.1% ofwomen by 30 years and 1% by 40 years.7 Althoughmany causes have been suggested, including genetic,autoimmune, and iatrogenic, the cause is unknown in alarge proportion of cases.8 POF represents an endo-crine status similar to after menopause, with elevatedgonadotrophins and low estrogen levels. The cessationof ovarian function in POF is not necessarily perma-nent. Pregnancies have been reported in 5–10% of POFpatients;9 however, it is extremely difficult to conceivebecause follicular growth is often not confirmed, andthe response to ovarian induction is poor in mostwomen with POF.10
Pregnancies have been reported in women withundetectable serum AMH. However, in these patients,serum follicle stimulating hormone (FSH) levels werenormal.11,12 Pregnancy has also been reported in apatient with POF induced by galactosemia who hadundetectable serum AMH.13 Here, we report the first
Received: June 27 2012.Accepted: September 19 2012.Reprint request to: Dr Isao Tsuji, Department of Obstetrics and Gynecology, Kinki University Faculty of Medicine 377-2,Ohno-Higashi Osakasayama, Osaka 589-8511, Japan. Email: [email protected]
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doi:10.1111/j.1447-0756.2012.02068.x J. Obstet. Gynaecol. Res. Vol. 39, No. 5: 1070–1072, May 2013
1070 © 2013 The AuthorsJournal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
case, to the best of our knowledge, of successful con-ception following ovarian induction in a patient withPOF and undetectable serum AMH.
Case Report
Our patient was a 34-year-old nulligravida woman,height 157 cm, weight 50 kg (body mass index 20.3 kg/m2). She did not smoke or drink alcohol, and hermedical history was insignificant. She had reachedmenarche at 13 years of age and had a regular 28–30-day menstrual cycle. Her menses became irregular atthe age of 28 years, and she developed amenorrhea at31 years of age. She underwent endocrinological evalu-ation at another institution. Her FSH, luteinizinghormone (LH), and estradiol (E2) serum levels were95.4 mIU/mL, 31.7 mIU/mL, and 14 pg/mL, respec-tively. Because she wanted children, she underwentovarian induction and received clomiphene citrate, acombination of clomiphene citrate and exogenousgonadotrophins, hormone replacement therapy (HRT),and again a combination of clomiphene citrate andexogenous gonadotrophins, but still failed to grow fol-licles. At the age of 33 years, she was referred to ourinstitution. The results of endocrinological evaluationswere as follows: FSH 25.8 mIU/mL, LH 12.3 mIU/mL,prolactin (PRL) 9.6 ng/mL, E2 < 10 pg/mL, testoster-one 0.25 ng/mL, thyroid-stimulating hormone 1.7 mU/mL, and AMH < 3.0 pM (0.4 ng/mL). Her homeostasismodel assessment as a clinical index of insulin resis-tance was 1.4 (normal). Antinucleotide antibody wasnegative. Her karyotype was normal (46, XX). Ultra-sonography revealed a normal-sized uterus; however,ovaries and follicles were not detected.
Taking the findings of her previous evaluation intoconsideration, which included suppression of serumgonadotrophins levels by HRT, we diagnosed her con-dition as idiopathic POF. She was informed that shehad little chance of pregnancy because of undetectableserum AMH, but because of her strong desire for chil-dren, we proposed trying ovarian induction by admin-istering exogenous gonadotrophins and suppressingendogenous gonadotrophins.
She initially received estrogen replacement therapy(ERT) (conjugated estrogens 0.625 mg) daily for 4 months,but her serum E2 level was 67 pg/mL and folliculargrowth was not detected. The serum gonadotrophinlevels did not decrease (FSH 26.0 mIU/mL, LH 16.5 mIU/mL). A combination of ERT and gonadotrophin-releasinghormone (GnRH) agonist (leuprorelin acetate 1.88 mg)were administered monthly for 3 months, which led to
decreased levels of serum FSH (7.3 mIU/mL) and LH(1.9 mIU/mL). She then received human menopausalgonadotrophin (HMG), 300 IU/day for ovarian induction.ERT was administered throughout the period of ovarianinduction. On ovarian induction day 8, ultrasonographyrevealed one follicle with a mean diameter of 19.6 mm,and an elevated level of serum E2 (516 pg/mL). Thepatient was injected with 5000 IU of human chorionicgonadotrophin (HCG) and was advised to have coitus thefollowing day. On HCG injection day 7, ultrasonographycould not detect the follicle, and her serum progesteronelevels were elevated at 6.1 ng/mL. On HCG injection day14, a pregnancy test was positive. One month after HCGinjection, ultrasonography revealed an intrauterine fetuswith beating heart. Retesting of serum AMH at the time ofultrasonography again found the level to be below thethreshold of detection. The patient’s pregnancy is nowongoing.
Discussion
AMH correlates with antral follicle counts3 and is anaccurate indicator of the presence of ovarian follicles.4
Serum AMH levels in POF patients are often extremelylow or less than the threshold of detection.14–16 Low orundetectable levels of AMH suggest depletion ofovarian follicles, which has been confirmed by ovarianbiopsies.14 Pregnancies have been reported in 5–10% ofpatients with POF under this condition.9 Pregnancieshave been reported in women with undetectable serumAMH. However, in these patients, FSH levels werenormal.11,12 Pregnancy has also been reported in apatient with POF induced by galactosemia who hadundetectable serum AMH.13
It has been suggested in POF that tonic high levels ofLH induced inappropriately early luteinization andthus impaired normal follicle function,17 and that thehypergonadotropic condition led to impaired ovarianresponse.9 Therefore, various treatments, includingoral contraceptives, HRT, and GnRH agonist, havebeen performed to restore ovarian function in POF.These treatments suppress elevated endogenous gona-dotrophins and are followed by ovarian induction. Asuccessful pregnancy following a spontaneous ovula-tion has been reported during or after HRT.18–20 Tart-agni et al. suggest that pretreatment with ERT improvesthe success rate of ovarian induction with exogenousgonadotrophins in patients with POF. A threshold levelof FSH less than 15 mIU/mL should be achievedbefore starting ovarian induction.19 It has been hypoth-esized that declining endogenous FSH levels induce
Pregnancy and POF
© 2013 The Authors 1071Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
upregulation of FSH receptor expression in granulosacells and result in the improvement of ovarian responseto exogenous gonadotrophins.9 To restore ovarian func-tion, it is important to normalize serum LH levels.17
Dehydroepiandrosterone (DHEA) has been reportedto improve pregnancy chances with POF. Mamas andMamas claimed a small case series of five POF patients,who spontaneously conceived while on DHEA.21
Interestingly, serum FSH levels had decreased in allpatients. Androgens have been shown to promote pre-antral follicle growth and reduction in follicle atresia.Androgens assume a central role in follicular develop-ment and female fertility.22 DHEA supplementationimproves ovarian function.
Even with serum AMH levels below the threshold ofdetection, there is a chance for patients with POF. Thepregnancy of our patient should provide hope for POFpatients with markedly diminished ovarian reserve.
Disclosure
The authors report no conflicts of interest. The authorsalone are responsible for the content and writing ofthe article.
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