Administration of Kisspeptin to Subjects With Reproductive Disorders

The master reproductive hormone GnRH (gonadotropin-releasing hormone) is essential for normal
reproductive function. People with hypogonadotropic hypogonadism (IHH), hyperprolactinemia,
and polycystic ovarian syndrome (PCOS) do not secrete or respond to GnRH in a normal way. In
this study, investigators will give participants, kisspeptin— a hormone that is naturally
found in the human body and is known to be a powerful stimulus of GnRH secretion. They may
also give participants GnRH to determine if participants will be able to fully respond to
kisspeptin.

The goal of this study is to use kisspeptin administration to probe the condition of GnRH
neurons in people with various reproductive disorders to better understand the underlying
reasons for the disorders. Investigators hope to gain new insights into GnRH neuronal
function (or dysfunction) that will lead to better diagnostics in the future.

Individuals interested in learning more may email MGHKisspeptinResearch@partners.org or call
617-726-8484.

A. Healthy Subjects

All healthy subjects will meet the following criteria:

- normal puberty with respect to onset and pace,

- no chronic diseases,

- no prescription medications for at least 2 months with the exception of seasonal
allergy medications and hormone replacement therapy,

- no illicit drug use or excessive alcohol consumption (< 10 drinks/week),

- no history of a medication reaction requiring emergency medical care,

- normal physical exam and laboratory studies within reference range.

Additional criteria based on subject population:

1. Healthy Men:

- between 21 and 40 years old,

- normal erectile and ejaculatory function, no history of reproductive disorders,

- testicular volume >15 ml.

2. Healthy women:

- between 21 and 40 years old,

- not breastfeeding or pregnant,

- menstrual cycles between 25 and 35 days in duration, at least 11 periods/year,
with no more than 5 days variability in cycle duration,

- no evidence for androgen excess (hirsutism or acne),

- at screening, negative hCG pregnancy test,

- negative screening for Factor V Leiden for those who might receive estradiol
treatment as a part of this study.

3. Healthy postmenopausal women:

- between 50 and 60 years old,

- no menstrual periods within the last year,

- previous history of menstrual cycles between 25 and 35 days in duration, with no
more than 5 days variability in cycle duration,

- if applicable, able to undergo washout from hormone therapy,

- no evidence for androgen excess (hirsutism or acne),

- negative screening for Factor V Leiden for those who might receive estradiol
treatment as a part of this study.

B. Subjects with Reproductive Disorders

All subjects with reproductive disorders will meet the following criteria:

- 18 years or older,

- all medical conditions stable and well controlled,

- no prescription medications known to affect reproductive endocrine function for at
least 2 months except for medications used to treat the subject's reproductive
condition,

- no history of a medication reaction requiring emergency medical care,

- no illicit drug use or excessive alcohol consumption (<10 drinks/week),

- for women, not breastfeeding or pregnant,

- if applicable, able to undergo appropriate washout from hormone therapy,

- normal physical exam and laboratory studies within protocol reference ranges,

- for women, at time of screening negative hCG pregnancy test.

Additional criteria based on subject population:

1. Men and women with hypogonadotropic hypogonadism,

- Confirmed diagnosis by low sex steroids in the setting of low or inappropriately
normal gonadotropins,

- If needed, additional labs and imaging tests may be performed.

2. Women with Polycystic Ovarian Syndrome (PCOS)

- Confirmed diagnosis of PCOS,

- If needed, additional labs and imaging tests may be performed.

3. Men and women with hyperprolactinemia

- confirmed diagnosis of elevated levels of prolactin measured via blood test,

- no pituitary adenoma or a microprolactinoma (<10 mm). Patients with a
macroprolactinoma confirmed on MRI imaging will be excluded,

- willing to complete a dopamine agonist washout.