Patient 32: Premature Thelarche

Author: Daniele Di Corcia
Date: 30/05/2012



9 Months Year Old

Clinical Examinations:

FSH result was 6.6 UI/L
After 2 months FSH was 7.7 UI/L



2012-05-30T08:06:13 - Daniele Di Corcia

Daniele Di Corcia, Marta Leporati, Alberto Salomone

Generally, a thelarche (see figure 1 and 2) is the onset of secondary (postnatal) breast development, usually occurring at the beginning of puberty in girls. Thelarche is usually noticed as a firm, tender lump directly under the centre of the nipple (papilla and areola). Thelarche is also referred to as a "breast bud", or more formally as Tanner stage 2 breast development (Tanner stage 1 being the entirely undeveloped pre-pubertal state).
Thelarche may occur on one side first, or both sides simultaneously.
Thelarche is the first physical change of puberty in about 60% of girls, usually after 8 years. It is a result of rising levels of estradiol. It is typical for a woman's breasts to be unequal in size, particularly while the breasts are developing. Statistically it is slightly more common for the left breast to be the larger. In rare cases, the breasts may be significantly different in size, or one breast may fail to develop entirely. Although breast development can occur as a part of normal male puberty, it is termed gynecomastia, and the term "thelarche" is not used with reference to male breast development. When thelarche occurs at an unusually early age, it may be the first manifestation of precocious puberty. If no other changes of puberty or sex hormone effects occur, it is referred to as isolated premature thelarche, and needs no treatment.

Figure 1(Clinical images)
Figure 2(Ovarian ultrasound through the bladder, demonstrating large cysts in a small volume ovary as seen in premature thelarche)

Link Figure 1
Link Figure 2

Thelarche - Wikipedia
Thelarche - Case Reports 1
Thelarche - Case Reports 2
Thelarche - Case Reports 3
Thelarche - Case Reports 4
Thelarche - Case Reports 5
Thelarche - Case Reports 6

Case History

In the case described hereby, a 9-months-old female patient was admitted to the hospital showing breast development. The FSH result was 6.6 UI/L and, after 2 months, 7.7 UI/L. The diagnosis was of premature thelarche. This is a benign, self-limiting condition which is characterized by breast development with no other signs of sexual maturation. There is no pubic or axillary hair development, behavior is normal, growth is normal and the skeletal age is appropriate. The breast development has atypical appearance with relatively immature nipple development and is never more than Tanner Breast Stage III. Breast development is usually asymmetrical and the breasts increase and decrease in size at about 6-weekly intervals. The condition tends to resolve after about 1–2 years and then the onset of normal puberty occurs at the appropriate age and in the normal way. Very occasionally, vaginal bleeding can occur. Isolated premature thelarche is a relatively common condition. It is characterized by FSH dominance and overnight gonadotropin secretion, which is characterized by single FSH pulses. On ultrasound the ovaries are small, but often contain large follicular cysts, which increase and decrease in synchrony with the breast development.


There may well be two types of premature thelarche. The classical type commences during the first year of life and tends to resolve by the age of 2. The second form of premature thelarche, of which the age of onset is over 2 years of age and this tends to be more persistent and with a higher incidence of uterine bleeding. In this ‘non-classical’ form of premature thelarche, it may well be associated with progression to gonadotropin-dependent precocious puberty. Isolated premature thelarche is a condition which is easy to diagnose clinically and requires no treatment.
Early thelarche—which is sometimes, but not always, coupled with early menarche—seems to influence breast cancer risk in and of itself. Precocious puberty is associated with increased risk for breast cancer in adult life (Ahlgren, 2004). The tempo of puberty may also affect later breast cancer risk: a long period between breast budding and first ovulation creates a wide “estrogen window” that is thought to be favorable to the future development of breast cancer (Okobia and Bunker, 2005).
The signal that launches the sequence of pubertal changes is gonadotropin releasing hormone (GnRH). GnRH is produced by the hypothalamus (see Figure 3 and 4), that part of the brain that sits directly above the pituitary gland and directs its activity. More specifically, the pubertal process begins when GnRH is released in hourly pulses from a small group of about 1,000 specialized cells within the hypothalamus. These cells are called GnRH-secreting neurons (Hughes and Gore, 2007). In all mammals, GnRH is both necessary and sufficient to induce puberty (Ebling, 2005). That is, the administration of GnRH can, all by itself, trigger the events of puberty. Puberty will not occur in its absence. Released from the hypothalamus in intermittent bursts, GnRH is shuttled, via a portal blood system, to the pituitary gland. In response to these pulsating GnRH signals, the pituitary releases its two other hormones—follicle stimulating hormone (FSH) and luteinizing hormone (LH)—which then travel through the bloodstream to the ovaries. Here, they initiate a dramatic rise in the production of steroidal sex. hormones, including a potent form of estrogen called estradiol. The maturation of the ovaries into estrogen-secreting glands is the definitive event of puberty. Estradiol, in turn, initiates breast development, among other changes.

Figure 3 (Saggital MRI showing hypothalamic hamartoma leading to central precocious puberty)

Figure 4

Link Figure 3
Link Figure 4

The follicle stimulating hormone (FSH) is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrops of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) act synergistically in reproduction. Specifically, an increase in FSH secretion by the anterior pituitary causes ovulation.
The FSH-receptor is a transmembrane receptor and represents a G protein-coupled receptor. Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary, testis and uterus.
It is characterized by an extended domain, with an extracellular leucine-rich region and multiple potential sites of glycosylation. It is encoded by a gene along more than 85 kilobases, contains 10 exons, 9 of which encode for the extracellular domain. It contains 678 amino acids and its activation involves the cyclic AMP system, in regulating both the steroidogenesis that the gametogenesis. The mechanism of action of gonadotropin in the ovary is similar to that in the testis.
The interaction between the hormone and its receptor leads to a change in the conformation of the receptor itself, which in turn activates a system signal coupled to the protein G membrane-associated (Figure 5)

Link Figure

Figure 5

G proteins are a subgroup of regulatory proteins. The formation of gonadotropin-receptor complex results in the replacement of guanosine diphosphate (GDP) subunit linked to a with guanosine triphosphate (GTP), which leads to bond the adenylate cyclase.

Adenylate cyclase catalyzes the conversion of ATP to 3',5'-cyclic AMP (cAMP) and pyrophosphate. cAMP is an important molecule in eukaryotic signal transduction, a so-called second messenger. (Figure 6).

Link Figure

Figure 6

High levels of cAMP activate the system of the protein-kinase A (PKA). PKA modulates the function of a large variety of intracellular proteins, through phosphorylation of specific residues of serine and threonine.
PKA activates CREB, a cellular transcription factor, which binds the cAMP response element, altering the transcription and therefore the synthesis of the protein. CREB binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes.

Aromatase Gene Transcription

Here we are in the second case: there is an increasing of aromatase gene transcription. Only a single gene, the CYP19, encodes for aromatase enzyme. The gene, located on chromosome 15q21.1, has nine coding exons and a number of alternative non-coding first exons, that regulate tissue specific expression. High levels of FSH can then lead to an increase of the aromatase synthesis and therefore to a large production of estradiol.

AddThis Social Bookmark Button