Ovarian cysts are a common cause for gynecological surgery. Owing to the complexity of ovarian composition and function, the etiology of ovarian cysts can vary greatly, including benign or malignant tumors, endometriosis and inflammation, etc. Some cysts only result from reproductive endocrine dysfunction and may resolve without surgery after endocrine correction. Ovarian hyperstimulation is such a condition. With multiple follicles developing, the ultrasound images of the ovaries appear similar to multilocular cystadenoma with multiple septa. Usually, ovarian hyperstimulation syndrome (OHSS) is caused by iatrogenic superovulation. Excessive exogenous FSH stimulates multiple follicular growth simultaneously. In some rare cases, spontaneous OHSS related with pregnancy has been described as depending on activating mutations of the FSH receptor (FSHR) gene, causing ovarian hyper-responsiveness to circulating FSH or even cross-responsiveness of FSHR to hormones having a structure similar to FSH, such as human chorionic gonadotrophin (hCG) or TSH 2 3 . Eutopic or ectopic gonadotrophin adenoma secreting FSH can also present with multiple follicular cysts in ovaries 4 5 . Without considering these endocrine disorders as a possible etiology, clinicians are likely to assume a diagnosis of neoplasm, leading to unnecessary ovarian surgery.

Hypothyroidism is another endocrine disorder associated with ovarian hyperstimulation, yet is often ignored in its evaluation. There have been spontaneous OHSS cases reported in pregnant women with hypothyroidism 6 7 8 . In an animal model of hypothyroidism induced with thiouracil, animals exhibited an increased sensitivity to the cyst-formative action of pregnant mare serum gonadotrophin and hCG 9 . However, without hCG, hypothyroidism rarely results in the formation of enlarged multicystic ovaries. Since Van Wyk and Grumbach first described the combination of multicystic ovaries, juvenile hypothyroidism and precocious puberty in 1960, sporadic cases of this syndrome have been reported in pre-pubertal or adolescent girls 10 11 12 13 . For adults, only single-digit cases have been reported, from age 19 to 26 14 15 16 17 . These cases are similar to the case presented here. The ultrasound pictures in each of these cases revealed similar typical multiple cysts of varied sizes, as would be expected in OHSS (Table 1).

Just as hypothyroidism may be missed as a cause of ovarian hyperstimulation, the presence of ovarian cysts are often overlooked in patients with hypothyroidism, particularly in nongestational adults. Without symptoms of precocious puberty such as the Van Wyk and Grumbach syndrome in young girls, it is much easier to ignore reproductive organ ultrasound evaluations in hypothyroid adults. Furthermore, without hCG triggering the release of certain ovarian vasoactive substances 18 , these nongestational adults lack the typical complications of ovarian hyperstimulation, such as severe abdominal distention, serious hemoconcentration, massive ascites or pleural effusion. In the few such cases that have been reported, patients were referred to hospitals only due to too a large abdominal mass or acute abdomen.

There are several hypotheses about the mechanism of ovarian cyst formation associated with hypothyroidism.

First, TSH, FSH and their receptors have related structures. Extremely high concentrations of TSH in hypothyroidism may be sufficient to cause the activation of FSHR. Experiments from Anasti validated that recombinant human TSH could elicit a dose-dependent cyclic adenosine monophosphate response in the in vitro human FSHR bioassay, though the concentration of TSH required for half-maximal stimulation was several logs greater than that of FSH 19 . This provides a major potential mechanism for severe hypothyroidism resulting in ovarian hyperstimulation.

A second possible mechanism may be related to a change in pituitary gonadotropin levels. Though gonadotropin levels of hypothyroid women are usually normal 20 , the patients with multilocular ovaries reported by us and most other authors showed relatively high FSH and low LH levels. The mechanism of such endocrine change remains enigmatic. It is suggested that an "overlap" effect in the negative feedback response occurs, so that not only TSH but also gonadotropins are stimulated by extremely high TRH 1 . These remarkably high endogenous FSH levels can effectively stimulate the follicles. One reason for low LH levels despite elevated FSH may be that in the pituitary-hypothalamic axis LH and FSH synthesis and secretion are differentially regulated. Slow GnRH pulse frequencies favor FSH production and secretion, whereas rapid frequencies favor LH production and secretion 21 22 23 . It may be that hypothyroidism is associated with slow GnRH pulse. Blunted or delayed LH response to GnRH has been found in some hypothyroid women 20 . Another possible reason for the FSH and LH mismatch is that high TRH can induce hyperprolactinemia which also can impair LH pulse by intermittent reductions in GnRH secretion 24 . A third explanation may be the presence of another regulation pathway for FSH secretion, involving estrogen and activin at the pituitary level. In our case, due to the low level of LH, the theca cells could not produce enough testosterone for granulosa cells to biosynthesize estrogen. The low estrogen status in turn enhanced FSH secretion, persistently stimulating follicular enlargment without a concomitant rise in estrogen concentrations.

A third possible mechanism has been hypothesized to be due to FSHR activating mutations permitting or amplifying the affect of hCG or TSH on the follicles. The mutations of Asp⁵⁶⁷Asn, Thr⁴⁴⁹Ile, Thr⁴⁴⁹Ala and Ile⁵⁴⁵Thr were found in women with spontaneous OHSS in pregnancy 25 26 27 . FSHR gene polymorphisms may influence FSHR protein responsiveness as well, particularly codons 307 and 680 27 . However, Ryan sequenced the FSHR gene in eight juvenile patients with VW syndrome. No FSHR mutation was identified and no difference in the responses to rFSH or rTSH in different FSHR allelic combinations was found 12 . Likewise, in our patient, we found no FSHR exon mutations. The genotype in our case was homozygous Thr³⁰⁷-Asn⁶⁸⁰. While FSHR gene mutations and polymorphism may be associated with ovarian hyperstimulation, there is no evidence that they are essential to its pathogenesis.

Fourth, TSH may sensitize the ovaries to gonadotropin stimulation by stimulating nuclear thyroid receptors in the granulosa cells, thereby exacerbating ovarian hyperstimulation 28 .

Fifth, myxedematous-type infiltration might also account for the interference of steroidogenesis in the ovary and contribute to ovarian cystic changes.

Despite multiple hypotheses for the association between hypothyroidism and ovarian hyperstimulation, the exact mechanism is not yet clear. It is uncertain why hypothyroidism is so common while concomitant ovarian hyperstimulation appears to be so rare. All reported cases are associated with severe hypothyroidism with TSH more than 100 mU/l, and even as high as 4,191 mU/l. Besides, different pathways may function in different cases. In our case, extremely high TSH and FSH were the main causes. Furthermore, it is not fully understood why this syndrome is only seen in girls or young women. Maybe young gonads are particularly susceptible to stimulation by TSH or FSH.

Although the precise etiopathology of this disorder remains speculative, the treatment approach is for ovarian hyperstimulation due to hypothyroidism is clear. Evidence exists that supplementation with thyroid hormone can lead to the complete regression of the multicystic ovarian enlargement, even in patients with high CA-125 levels 15 . Surgical exploration in these cases should be performed only for emergent cases such as ovarian torsion or rupture. If at the time of surgery ovarian neoplasm is suspected, precautionary frozen sectioning should be performed prior to oophorectomy. When adequate thyroid replacement therapy fails to resolve ovarian enlargement, surgical excision should be considered. Panico reported an ovarian wedge resection for persistent ovarian enlargement after adequate thyroid replacement therapy for 14 months. The histological section in their case showed a benign ovarian cyst with extensive hemorrhage and myxedematous infiltration 10 . Other treatments, such as aspiration 11 , may be considered as well for persistent cysts.