Is “restoration of ovarian function or ovarian reserve” possible after ovarian surgery?

16 02 2010

We read the prospective study by Chang et al. (1) regarding the effect of ovarian surgery on ovarian reserve with great interest. The authors reported the impact of laparoscopic cystectomy on ovarian reserve in 20 ovarian cysts including endometrioma, mature teratoma and mucinous cystadenoma.

There is no doubt that any surgical procedure involving ovaries may compromise ovarian reserve. The findings of the study regarding the endometriomas are especially important, since there has been a continuing debate on whether endometriomas should be excised in infertile patients before assisted reproductive technologies (ART), or left in place owing to the surgery related damage to ovarian reserve.

Current studies showed that anti-Mullerian hormone (AMH) is a promising marker of ovarian reserve which is expressed from granulosa cells (2, 3). The AMH expression is initiated in the smallest growing follicles and declines in the early antral stages as one follicle is selected for dominance while remaining growing follicles become atretic (4). Previous studies demonstrated that AMH is a more reliable marker for chemotherapy associated ovarian damage, which shows more rapid change after chemotherapy compared to serum follicle-stimulating hormone (FSH) or inhibin B (5).

Furthermore, as opposed to sustained postchemotherapy serum levels of AMH, Anderson et al. (6) demonstrated that serum levels of FSH and inhibin B may recover in time leading to a “misinterpretation” as ovarian reserve is recovered (6). Notably, when chemotherapy is given in extremely high doses, i.e., in patients undergoing hematopoietic stem cell transplantation, premature ovarian failure is almost inevitable and no recovery is possible, with only a handful of primordial or growing follicles surviving.

In the light of the findings of the clinical study by Chang et al. (1), as was discussed by the authors, it is likely that AMH secretion is decreased as a result of both direct mechanical damage and electroinjury to the growing follicles. In theory, it is possible that among the follicle stockpile, actively growing follicles are most likely to be damaged by electrocoagulation or mechanical dissection compared to non-dividing quiescent primordial follicles. The possible compromise in ovarian microvasculature may have a further detrimental effect on the growing follicles and the granulosa cells that primarily secrete AMH. Moreover, it is not clear whether temperature increase in the “healthy” ovarian portions ensuing electrocoagulation has a negative effect on all growing follicles in the coagulated ovary (7).

The classical dogma regarding the fate of primordial follicles indicates that ovarian reserve diminishes inexorably throughout a woman’s life, which occurs in any physiological condition. Ovarian transplantation studies clarified that the time required for a primordial follicle to reach preantral stages is about 120 days from its quiescence (8). The increasing AMH secretion from the newly growing preantral follicles (4), and its contribution to the “seemingly laboratory recovery of ovarian reserve” in about 90 days is the main possible explanation of the findings of the study.

When analyzing the findings of the current study, “restoration of ovarian function” or “restoration of decreased ovarian reserve” may not be a correct definition since it implies “formation of new ovarian follicles”. The hypothetical role of germ cell renewal to clarify this controversy can only be a speculation, rather than an established scientific fact, on the grounds of the current knowledge in humans. A possible role of bone morphogenetic protein to induce AMH gene expression may elucidate the primary role of AMH in follicular transition (9).

Murat Sönmezer, M.D.a,b
Salih Taşkın, M.D.a
Tolga Taşçı, M.D.a
Batuhan Özmen, M.D.a,b
Cem Atabekoğlu, M.D.a,b

aAnkara University School of Medicine
Department of Obstetrics and Gynecology
bAnkara University Center for Research on Human Reproduction
Ankara, Turkey

References
1. Chang HJ, Han SH, Lee JR, Jee BC, Lee BI, Suh CS, et al. Impact of laparoscopic cystectomy on ovarian reserve: serial changes of serum anti-Müllerian hormone levels. Fertil Steril 2009 Apr (in press).

2. Baarends WM, Uilenbroek JT, Kramer P, Hoogerbrugge JW, van Leeuwen EC, Themmen AP et al. Anti-Mullerian hormone and anti-Mullerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin-induced follicle growth. Endocrinology 1995;136:4951– 62.

3. Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, et al. Anti-Mullerian hormone expression pattern in the human ovary: Potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 2004;10:77– 83.

4. Sahambi SK, Visser JA, Themmen AP, Mayer LP, Devine PJ. Correlation of serum anti-Müllerian hormone with accelerated follicle loss following 4-vinylcyclohexene diepoxide-induced follicle loss in mice. Reprod Toxicol 2008;26:116-22.

5. Oktay K, Oktem O, Reh A, Vahdat L. Measuring the impact of chemotherapy on fertility in women with breast cancer. J Clin Oncol 2006;24:4044-6.

6. Anderson RA, Themmen AP, Al-Qahtani A, Groome NP, Cameron DA. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod 2006;21:2583-92.

7. Mertyna P, Dewhirst MW, Halpern E, Goldberg W, Goldberg SN. Radiofrequency ablation: the effect of distance and baseline temperature on thermal dose required for coagulation. Hyperthermia 2008;24:550-9.

8. Bedaiwy M, El-Nashar S, El Saman A, Evers J, Sandadi S, Desai N, et al. Reproductive outcome after transplantation of ovarian tissue: a systematic review. Hum Reprod Update 2008;23:2709-17.

9. Shi J, Yoshino O, Osuga Y, Koga K, Hirota Y, Hirata T, et al. Bone morphogenetic protein-6 stimulates gene expression of follicle-stimulating hormone receptor, inhibin/activin beta subunits, and anti-Müllerian hormone in human granulosa cells. Fertil Steril 2009;92:1794-8.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.02.035

The Authors Respond:

We would like thank Prof. Sonmezer et al. for their interest in our work (1). Our study investigated the serial changes of serum anti-Müllerian hormone (AMH) levels after laparoscopic ovarian cystectomy. The results showed that serum AMH levels significantly decreased on the seventh day postoperatively compared to the preoperative level. These findings supported that surgery-related ovarian damage could happen. The decreased serum AMH levels after surgery recovered to 65% of preoperative levels after three months.

Ovarian reserve is defined as the functional potential of the ovary and reflects the number and quality of the follicles left in the ovary at any given time (2). However, there are currently no definite estimates to measure quantitative ovarian reserve in reproductive age. Instead, various tests and markers reflecting ovarian reserve have been developed, such as ovarian responses to hyperstimulation (3) or other hormonal tests such as FSH, inhibin B, estradiol, and AMH levels on day 3 of the menstrual cycle (4). Among these factors, serum AMH levels have recently been acknowledged to reflect ovarian reserve as well as serum FSH and E2 levels studied on day 3 of the menstrual cycle. The use of a cycle-independent serum marker to predict the ovarian reserve is thought to be more attractive than the time-consuming and not always well-standardized ovarian reserve tests used in earlier studies (5).

We assessed ovarian reserve by measuring serum AMH level. The change of AMH level indirectly reflects the change in ovarian reserve. Of course, vascular damage during ovarian surgery could induce the initial decrease of serum AMH level.

We suggested several possible mechanisms of recovery in ovarian reserve, as reflected by AMH level, after the initial decrease from ovarian cystectomy. The improvement of serum AMH levels may reflect a reperfusion of ovarian tissue, compensatory reactive hyperfunctioning of granulosa cells, rescue from atretic follicles, and, the most controversial theory, regeneration of ovarian follicles. There may be proliferating germ cells present in the postnatal mammalian ovary that are capable of replenishing the pool of follicles (6).

Acute ovarian failure refers to the loss of ovarian function that arises during or shortly after the completion of cancer therapy. By contrast, “premature menopause” refers to the loss of ovarian function that occurs years after completion of cancer therapy following a window of normal functioning. Many prepubertal and adolescent female cancer survivors demonstrate normalization of FSH levels over time, and only a minority appears to experience irreversible ovarian failure requiring long-term hormone replacement therapy (7). Although histological examinations of ovarian tissue and ultrasound findings of these women have revealed a decreased number of ovarian follicles and follicular growth compared with
age-matched controls, they recovered ovarian function, experienced regular menstruation and even conceived naturally (8). It means that a part of ovarian function has undergone a reversible change during or after cancer therapy.

Because the mechanism of serum AMH improvement after ovarian cystectomy has not been elucidated, “restoration of ovarian reserve” is not definitely incorrect. We are confident that our conclusion should remain as it is. Our study suggests that we should measure serum AMH levels to assess ovarian reserve function more exactly at least 3 months after ovarian cystectomy.

Hye Jin Chang, M.D., Ph.D.a,b
Chang Suk Suha, M.D, Ph.D.a
aDepartment of Obstetrics and Gynecology
bHealth Promotion Center
Seoul National University Bundang Hospital
Seoul, South Korea

References
1. Chang HJ, Han SH, Lee JR, Jee BC, Lee BI, Suh CS et al. Impact of laparoscopic cystectomy on ovarian reserve: serial changes of serum anti-Mullerian hormone levels. Fertil Steril 2009.

2. Block E. Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat (Basel) 1952;14:108-23.

3. Maheshwari A, Fowler P, Bhattacharya S. Assessment of ovarian reserve–should we perform tests of ovarian reserve routinely? Hum Reprod 2006;21:2729-35.

4. Fanchin R, Schonauer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003;18:323-7.

5. Hehenkamp WJ, Looman CW, Themmen AP, de Jong FH, Te Velde ER, Broekmans FJ. Anti-Mullerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab 2006;91:4057-63.

6. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004;428:145-50.

7. Sklar C. Maintenance of ovarian function and risk of premature menopause related to cancer treatment. J Natl Cancer Inst Monogr 2005:25-7.

8. Larsen EC, Muller J, Schmiegelow K, Rechnitzer C, Andersen AN. Reduced ovarian function in long-term survivors of radiation- and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003;88:5307-14.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.02.034

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